Clinical trial NCT02279095
Conditions: Fibrodysplasia Ossificans Progressiva
Keywords: Open-label extension study Clinical trial Phase 2 Efficacy and safety Heterotopic ossification Fibrodysplasia Ossificans Progressiva Flare-up Palovarotene Retinoic acid receptor agonist Retinoic acid receptor gamma agonist Clementia Myositis Ossificans Progressiva Munchmeyer's Disease FOP Ipsen
Sponsor: Clementia Pharmaceuticals Inc.
Start date: 2014-10-09; Completion date: 2022-09-20
Enrollment: 58 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement.

In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.

Detailed description:
The main objective of this Phase 2, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.

The study was divided into four parts: Part A (completed on July 2017), Part B (completed on October 2018), Part C (completed) and Part D (completed). Each part was associated with revised palovarotene treatment regimens.

In Part A, all pediatric and adult participants who successfully completed Study PVO-1A-201 were enrolled and followed for up to 36 months. Participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent).

In Part B, participants who successfully completed Study PVO-1A-201 (including any participant who participated in Part A of Study PVO-1A-202) as well as up to 20 new adult participants were followed for up to 24 months. The Adult Cohort included all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort included all participants with less than 90% skeletal maturity. Any Pediatric Cohort participant who achieved ≥90% skeletal maturity during Part B was considered for enrollment into the Adult Cohort at the discretion of the Investigator. Part B added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the Adult Cohort for up to 24 months. Part B also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the Pediatric Cohort). Treatment could be extended if the flare-up was still ongoing.

In Part C, participants from Part B are being followed for up to an additional 48 months. There will be no new participants in Part C. All eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants).

In Part D, annual post last dose of study treatment assessments for up to 2 years will be obtained in participants who were skeletally immature at the time of study treatment discontinuation in order to obtain longer-term safety data. No new participants will be enrolled into Part D.

Part C plus Part D duration will not exceed 48 months.

All participants will undergo all study procedures as specified in the respective schedule of assessments and for as long as they are not 100% skeletally mature.

Arms: arm 1: Participants received 10 mg palovarotene for 14 days, followed by 5 mg palovarotene for 28 days (or weight-based equivalent) for eligible flare-ups (Part A). arm 2: Participants with at least 90% skeletal maturity received 5 mg palovarotene for up to 24 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B). arm 3: Participants with less than 90% skeletal maturity received weight-adjusted doses of 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B). arm 4: All participants will receive 5 mg palovarotene for up to 48 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part C). Skeletally immature participants will receive weight-adjusted doses.
Interventions: intervention 1: Palovarotene dose level 1 intervention 2: Palovarotene dose level 2 intervention 3: Palovarotene dose level 3 intervention 4: Palovarotene dose level 4
Intervention descriptions: intervention 1: Palovarotene was taken orally once daily at approximately the same time each day. intervention 2: Palovarotene will be taken orally once daily at approximately the same time each day. intervention 3: Palovarotene will be taken orally once daily at approximately the same time each day. intervention 4: Palovarotene will be taken orally once daily at approximately the same time each day.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Clementia Pharmaceuticals Inc. 
 
 
 
Clinical Study Protocol 
A Phase 2, Open-Label Extension, Efficacy and Safety Study of a 
RARγ-Specific Agonist (Palovarotene) in the Treatment of 
Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans 
Progressiva (FOP) 
 
 
Study Number: PVO-1A-202 
 
Original Protocol: 04 June 2014 
Amendment 1: 30 September 2014 
Amendment 2: 22 June 2015 
Amendment 3: 10 March 2016 
Amendment 4: 01 September 2017 
Amendment 5: 06 June 2018 
Amendment 6: 08 March 2019 
Amendment 7: 01 November 2019 
Amendment 8: 30 November 2020 
 
 
Clementia Pharmaceuticals Inc. 
1000, De La Gauchetière, Suite 
1200 Montreal, Quebec, Canada 
H3B 4W5 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure 
without the prior written consent of Clementia Pharmaceuticals Inc. is strictly prohibited 
except to the extent required under applicable laws or regulations. Persons to whom the 
information is disclosed must be informed that the information is confidential and may not 
be further disclosed by them. 
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CLEMENTIA PHARMACEUTICALS INC. 
30 November 2020 
PROPRIETARY AND CONFIDENTIAL 
 
PROTOCOL SIGNATURE PAGE 
A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RARγ-Specific 
Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with 
Fibrodysplasia Ossificans Progressiva (FOP) 
Protocol Number: PVO-1A-202 
Signature of Approval for Protocol PVO-1A-202 (Amendment 8: 30 November 
2020) 
CLEMENTIA PHARMACEUTICALS INC. 
, MD 
NAME: 
SIGNATURE: 
DATE: 
2
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PROTOCOL PVO-1A-202, AMENDMENT 8 
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PROPRIETARY AND CONFIDENTIAL 
 
 
PROTOCOL AMENDMENT 8 SUMMARY OF CHANGES 
 
This eighth amendment to the protocol for Study PVO-1A-202 was finalized on 30 
November 2020. 
 
Location/Section Number 
Change 
Rationale 
Major changes that affected the clinical conduct of the study: 
Protocol Synopsis 
Part D was added for skeletally 
immature subjects who stopped taking 
study drug for any reason before 
completion of Part A/B/C.  Part D 
includes yearly visits for up to a 2-year 
follow-up period following last dose. 
No dosing will occur during Part D.  
Assessments obtained in Part D 
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 D will continue as 
long as subjects remain skeletally 
immature. 
The up to 2-year period would begin 
the last day the subject stopped 
receiving study drug in Part A/B/C. 
The total duration of participation in 
Part C and Part D, is a maximum of 4 
years.  
Secondary objective added for Part D 
to monitor off treatment longer-term 
safety in skeletally immature subjects 
off treatment.  
Safety will be summarized for Part D.  
To implement safety measures 
based on DMC recommendations 
given the serious identified risk of 
premature physeal closure. Part D 
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 drug for any reason 
before completion of Part A/B/C. 
A 2-year follow up is an adequate 
timeframe to assess growth and 
physeal changes off palovarotene 
treatment. Preliminary data 
suggest that the risk of premature 
epiphyseal fusion is higher in 
subjects with open epiphyseal 
growth plates who have received 
the flare-up dosing regimen. A 2-
year follow up is an adequate 
timeframe to assess growth and 
epiphyseal changes off 
palovarotene treatment. 
To allow for provision of study 
medication until commercial 
availability. 
 
 
 
 
 
Tables 1 and 4 
Section 1.1.3.2 Clinical Data 
Section 3.1 Overview of Study 
Design 
Section 3.2 Study Rationale 
Section 7 Study Procedures and 
Assessments 
Section 2.3 Secondary Objectives 
Section 5.7 Subject Withdrawal or 
Early Termination 
Section 9.1.10 Follow-up of 
Adverse Events and Serious 
Adverse Events 
Protocol Synopsis 
Section 3.1 Overview of Study 
Design 
Section 3.2 Study Rationale 
Section 5.1 Study Population 
(Adult and Pediatric Cohorts – Part 
B) 
Section 7.7 Temporary Measures 
(Procedures Related to COVID-19 
Pandemic) 
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 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 D was added to 
ensure continued collection of 
safety data off treatment.  
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30 November 2020 
PROPRIETARY AND CONFIDENTIAL 
 
 
Protocol Synopsis 
Tables 1 and 2 
Sections 2.3 and 4.2 
Secondary Endpoints 
Section 3.1 Overview of 
Study Design 
Section 7 Study Procedures 
& Assessments 
Section 7.2.2 Physical 
Examination 
Section 7.2.3 Body Weight 
and Linear Growth 
Section 7.2.4 Vital Signs 
Section 7.2.5 
Electrocardiogram 
Section 7.2.6 Clinical 
Laboratory Test 
Section 7.3.1 Columbia-
Suicide Severity Rating Scale 
Section 7.3.2 Knee and 
Hand/Wrist Radiographs 
Section 7.4 Efficacy 
Assessments 
Section 7.4.1 Low-dose 
Whole Body Computed 
Tomography 
Section 7.4.2 FOP-Physical 
Function Questionnaire 
Section 7.4.3 PROMIS 
Global Health Scale 
Section 7.4.4 Cumulative 
Analogue Joint Involvement 
Scale 
 
In Part C, subjects may continue on the 
study for up to an additional 12 months. 
 
To allow for provision of study 
medication until commercial 
availability.  
Section 7.3.3 Bone Safety 
Management Plan 
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  subjects 
with FOP. 
Section 7.1 Screening, 
Recruitment, and Informed 
Consent 
Section 7.7 Temporary 
Measures (Procedures 
Related to the COVID 
Pandemic) 
Integrated protocol amendment 7 
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 
≥14 years (who were skeletally 
immature at their last assessment) as 
part of the minimal safety procedures 
To integrate protocol amendment 7 
for 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. 
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PROPRIETARY AND CONFIDENTIAL 
 
prior to re-initiation of palovarotene.   
Changes that did not affect the clinical conduct of the study: 
Table 3 
Removed ECG row that was included 
in error; correcting table and 
footnotes. 
Integration of administrative change 
from protocol amendment 7 
addendum. 
Section 7.6 
Added DMC language. 
Clarifying DMC oversight  
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. 
General 
Corrected minor errors and formatting 
irregularities. 
To provide a consistent 
presentation. 
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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 
Medpace, Inc. 
Clinical Monitoring 
5375 Medpace Way 
Biostatistics 
Cincinnati, Ohio 45227 USA 
Statistical Programming 
Tel: 1.800.730.5779 
Electronic Data Capture System 
Fax: 1.513.579.0444 
Medical Monitoring 
, 
MD Medical 
Monitor Medpace 
 
 
Tel: 
 ext. 
 
Fax: 
 
Email: 
 
Central Laboratory 
Medpace Reference Laboratories 
LLC 5365 Medpace Way 
Cincinnati, Ohio 45227 
USA Tel: 
1.800.749.1737 
Fax: 1.800.705.2177 
Central Electrocardiogram Laboratory 
Medpace Cardiovascular Core 
Laboratory 5365 Medpace Way 
Cincinnati, Ohio 45227 USA 
Tel: 1.513.366.3234 or 1.513.579.9911 
ext. 2126 
Fax: 1.513.366.3237 
Imaging Core Laboratory 
PAREXEL 
Informatics 195 
West Street 
Waltham, MA 02451 
Tel: 1.866.289.4464 
Fax: 1.781.768.5512 
 
6
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PI
PI
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PI
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CLEMENTIA PHARMACEUTICALS INC. 
 
30 November 2020 
PROPRIETARY AND CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
 
Title 
A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RARγ-Specific 
Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with 
Fibrodysplasia Ossificans Progressiva (FOP). 
Sponsor 
Clementia Pharmaceuticals Inc. 
Objectives 
Primary Objective 
• 
To evaluate the safety and efficacy of different palovarotene dosing regimens 
in subjects with FOP. Efficacy will be based on the ability of palovarotene to 
prevent the formation of new heterotopic ossification (HO) as assessed by low-
dose whole body computed tomography (WBCT) scan, excluding head. 
Secondary Objectives 
• 
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 (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 D) 
• 
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 2, multicenter, open-label study that will explore different dosing regimens of 
palovarotene in adult and pediatric subjects with FOP. 
Part A includes all data obtained prior to Amendment 3 (dated 10 March 2016) during 
which pediatric and adult subjects successfully completing Study PVO-1A-201 were 
enrolled and followed for up to 36 months. Any subject experiencing an eligible flare-
up under Part A received treatment with open-label palovarotene at a dose of 10 mg 
once daily for 14 days followed by 5 mg once daily for 28 days (or weight-based 
equivalent) and underwent all study procedures as specified in the original protocol, 
Amendment 1, and Amendment 2. 
Part B includes all data obtained under Amendment 3 (dated 10 March 2016) during 
which subjects successfully completing Study PVO-1A-201 (including any subject who 
participated in Part A of Study PVO-1A-202) as well as up to 20 new adult subjects 
were followed for up to 24 months. 
Part C includes all data obtained under Amendment 4 (dated 01 September 2017) and 
subsequent amendments during which subjects who participated in Part B will be 
followed for up to an additional 48 months. There will be no new subjects in Part C. 
Part C plus Part D total duration will not exceed 48 months. 
Part D 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 D. Subjects will follow assessments as outlined in Table 4 for as long 
as they are not 100% skeletally mature. Part C plus Part D total duration will not exceed 
48 months. 
 
Non-Flare-up-based Treatment 
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PROPRIETARY AND CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
 
All subjects will receive non-flare-up-based treatment of 5 mg palovarotene once daily 
(weight-adjusted doses for skeletally immature subjects). 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 every 6 months) will continue until these subjects achieve 100% skeletal 
maturity defined as growth plate closure at both knee and hand/wrist locations. 
Additional radiographic assessments will be performed every 3 months 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% skeletal maturity on their 
last radiographic assessment. 
Subjects will follow all assessments as outlined in Table 1 and Table 2. Subjects who 
cannot receive non-flare-up-based treatment will only undergo annual assessments 
(clinical laboratory tests will not be performed). In the event of a flare-up or traumatic 
event, these subjects will receive flare-up-based treatment and undergo all flare-up-
based assessments, including clinical laboratory tests and radiographs if they have not 
reached 100% skeletal maturity. 
Subjects from Part B Continuing Non-Flare-up-based Treatment into Part C 
Subjects who began non-flare-up-based treatment during Part B will continue the same 
visit schedule into Part C (includes Protocol Amendment 4 and subsequent 
amendments), and will receive non-flare-up-based treatment for up to an additional 48 
months. Therefore, these subjects may undergo non-flare-up-based treatment for up to 
72 months over the entire study. 
Subjects continuing into Part C will follow all procedures and undergo all assessments 
as specified in the Schedule of Assessments in Table 1. Site visits will occur at Months 
12, 24, 36, 48, 60 and 72. Non-flare-up Day 1 is the first day that non-flare-up-based 
treatment was initiated during Part B, and total duration of treatment will continue into 
Part C. 
Remote visits (eg, at home or at a local medical facility; and via telephone contact from 
clinical site personnel) will occur every 3 months unless the Investigator deems that a 
site visit is necessary; urine pregnancy tests will be performed each month for females 
of childbearing potential (FOCBP). 
Subjects from Part B Starting Non-Flare-up-based Treatment During Part C 
Subjects who will start non-flare-up-based treatment during Part C will receive non-
flare-up-based treatment for up to 48 months. These subjects will follow all procedures 
and undergo all assessments as specified in the Schedule of Assessments in Table 2. 
Site visits will occur at Part C Screening and/or Non-flare-up Day 1, and at Months 6, 
12, 24, 36 and 48. Non-flare-up Day 1 is the first day that non-flare-up-based treatment 
is initiated during Part C for these subjects. 
Remote visits (eg, at home or at a local medical facility; and via telephone contact from 
clinical site personnel) will occur every 3 months unless the Investigator deems that a 
site visit is necessary; urine pregnancy tests will be performed each month for FOCBP. 
Flare-up-based Treatment 
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 receive open-label palovarotene treatment as follows: 
• 
20 mg for 4 weeks (28 days) once daily. The first dose will be taken upon 
flare-up confirmation by the Investigator. To be followed by: 
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PROTOCOL SYNOPSIS 
 
• 
10 mg for 8 weeks (56 days) once daily, for a total flare-up treatment duration 
of 12 weeks (84 days); 10 mg treatment may be extended if the flare-up is 
ongoing and continue until the flare-up resolves. Dosing will be extended in 4-
week intervals and be based on clinical signs and symptoms as assessed 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. Note: all weight-
based flare-up dosing will cease when subjects achieve ≥90% skeletal maturity based 
on hand/wrist radiography, but radiographic assessment of the growth plate will 
continue until these subjects achieve 100% skeletal maturity (defined as growth plate 
closure) at both knee and hand/wrist locations. 
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. 
Should a subject experience an intercurrent flare-up, or other 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 equivalent]). 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 the flare-ups 
or traumatic events 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 follow all procedures and undergo all 
assessments as specified in the Schedule of Assessments in Table 3. 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 non-flare-up-based treatment with 5 mg palovarotene 
once daily (weight-adjusted doses for skeletally immature subjects). 
The pharmacokinetics (PK) of palovarotene dosing will be assessed at the first 3-month 
safety assessment during non-flare-up-based treatment; if samples cannot be or were 
not obtained during the first 3-month safety assessment, or if subjects are on flare-up-
based treatment, then PK blood samples for non-flare-up treatment can be obtained 
during any subsequent 3-month safety visit. 
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, PK blood samples can be 
obtained during any subsequent flare-up dosing cycle. Pharmacokinetic blood samples 
will be collected at pre-dose and 3, 6, 10, and 24 hours post-dose. Subjects who 
underwent a PK assessment for flare-up-based treatment under PVO-1A-202 Protocol 
Amendment 3 will not have flare-up PK assessed again. However, these subjects will 
require a non-flare-up treatment PK assessed at a 3-month safety visit  
As of 04 December 2019 all subjects < 14 years of age were required to interrupt study 
drug due to a partial clinical hold placed on the palovarotene clinical development 
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PROTOCOL SYNOPSIS 
 
program by the US FDA. Treatment will subsequently not be restarted in children <14 
years of age.  
 
Off Treatment Part D: No study drug will be administered in Part D.  For skeletally 
immature subjects in Part D, 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 D will end. The total duration of participation in Part 
C and Part D combined is a maximum of 4 years (±1 month). 
Number of Subjects 
A total of approximately 60 subjects will be enrolled: 
• 
Up to 40 subjects enrolled from Study PVO-1A-201. 
• 
Up to 20 new adult subjects enrolled during Part B. 
Total Number of 
Sites 
A total of approximately eight international investigational sites 
Study Population 
(Adult and Pediatric 
Cohorts – Part B) 
Inclusion Criteria 
1. Completion of Study PVO-1A-201 (through Study Day 84); or Adult Cohort 
subjects not enrolled in Study PVO-1A-201, have the confirmed R206H 
genetic mutation consistent with FOP, have had at least two acute symptomatic 
flare-ups in the past 2 years but no flare-up symptoms within the past 4 weeks, 
including at the time of enrollment, have a CAJIS score of 6 to 16, inclusive, 
and must be able to receive non-flare-up-based dosing. 
2. For the Adult Cohort, subjects under the age of 18 must have knee and 
hand/wrist radiographs confirming ≥ 90% skeletal maturity. 
3. Written, signed, and dated subject/parent informed consent; and, for subjects 
who are minors, age-appropriate assent (this must be performed according to 
local regulations). 
Exclusion Criteria 
1. Simultaneous participation in another clinical research study (except for 
Studies PVO-1A-201, PVO-1A-203, or PVO-1A-001) within 4 weeks prior to 
Part B Screening. 
2. Any reason that, in the opinion of the Investigator, would lead to the inability 
of the subject and/or family to comply with the protocol. 
Study Population for 
Non-Flare-up-based 
Treatment 
(Adult Cohort – Part 
B) 
Inclusion Criteria 
1. Females of child-bearing potential (FOCBP) 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 during treatment and for 1 month after treatment or, if 
sexually active, to use two highly effective methods of birth control during and 
for 1 month after treatment. Additionally, sexually active FOCBP subjects 
must already be using two highly effective methods of birth control 1 month 
before treatment is to start. Specific risks of the use of retinoids during 
pregnancy, and the agreement to remain abstinent or use two highly 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. 
2. Subjects must be accessible for treatment with palovarotene and follow-up. 
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. 
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PROTOCOL SYNOPSIS 
 
Exclusion Criteria 
1. Weight <20 kg. 
2. Intercurrent known or suspected non-healed fracture at any location. 
3. 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. 
4. Exposure to synthetic oral retinoids other than palovarotene in the past 30 days 
prior to Part B Screening (signature of the informed consent). 
5. Concurrent treatment with tetracycline or any tetracycline derivatives due to 
the potential increased risk of pseudotumor cerebri  
6. History of allergy or hypersensitivity to retinoids or lactose. 
7. Concomitant medications that are inhibitors or inducers of cytochrome P450 
(CYP450) 3A4 activity (see Section 5.6). 
8. Amylase or lipase >2x above the upper limit of normal (ULN) or with a 
history of chronic pancreatitis. 
9. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5x ULN. 
10. Fasting triglycerides >400 mg/dL with or without therapy. 
11. Female subjects who are breastfeeding. 
12. Subjects with uncontrolled cardiovascular, hepatic, pulmonary, 
gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, 
psychiatric, or other significant disease. 
13. Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior 
within the past month as defined by the C-SSRS. 
Study Population for 
Flare-up-based 
Treatment 
(Adult and Pediatric 
Cohorts – Part B) 
 
Inclusion Criteria 
1. Symptomatic onset of a flare-up within 7 days before the first dose of study 
drug and defined by the presence of at least two of the following symptoms: 
pain, soft tissue swelling, decreased ROM, stiffness, redness, and warmth. 
Symptoms must be reported by the subject, be consistent with their previous 
flare-ups, and include a subject-reported onset date, and flare-up must be 
confirmed by the Investigator. 
2. Flare-up is at an appendicular area (upper or lower extremity), abdomen, chest, 
neck, or lower back; and subject has received, is receiving, or is willing to 
receive treatment per standard of care, which may or may not include 
prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days. 
3. Females of child-bearing potential (FOCBP) 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 during treatment and for 1 month after treatment or, if 
sexually active, to use two highly effective methods of birth control during and 
for 1 month after treatment. Additionally, sexually active FOCBP subjects 
must already be using two highly effective methods of birth control 1 month 
before treatment is to start. Specific risks of the use of retinoids during 
pregnancy, and the agreement to remain abstinent or use two highly 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. 
4. Subjects must be accessible for treatment with palovarotene and follow-up. 
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. 
Exclusion Criteria 
1. Weight <20 kg. 
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PROPRIETARY AND CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
 
2. Intercurrent known or suspected non-healed fracture at any location. 
3. Complete immobilization of joint at site of flare-up. 
4. Inability of the subject to undergo imaging assessments using plain 
radiographs. 
5. 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. 
6. Exposure to synthetic oral retinoids other than palovarotene in the past 30 days 
prior to Flare-up Screening (signature of the informed consent). 
7. Concurrent treatment with tetracycline or any tetracycline derivatives due to 
the potential increased risk of pseudotumor cerebri. 
8. History of allergy or hypersensitivity to retinoids or lactose. 
9. Concomitant medications that are inhibitors or inducers of CYP450 3A4 
activity (see Section 5.6.1). 
10. Any subject with clinically significant elevations in amylase, lipase, AST, 
ALT, or fasting triglycerides during the most recent clinical laboratory 
assessment will require re-test prior to immediate flare-up-based dosing with 
palovarotene per the Investigator. If upon re-test, the laboratory value in 
question remains clinically significant abnormal, then the subject will not 
receive flare-up-based treatment for this flare-up. 
11. Female subjects who are breastfeeding. 
12. Subjects with uncontrolled cardiovascular, hepatic, pulmonary, 
gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, 
psychiatric, or other significant disease. 
13. Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior 
within the past month as defined by the C-SSRS. 
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. 
Study Population 
(All Subjects – Part 
C) 
Inclusion Criteria 
1. Prior participation in Part B of the current study (PVO-1A-202). 
2. Written, signed, and dated subject/parent informed consent; and, for subjects 
who are minors, age-appropriate assent (this must be performed according to 
local regulations). 
3. 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 risks 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. 
Exclusion Criteria 
1. 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. 
2. Currently using vitamin A or beta carotene, multivitamins containing vitamin 
A or beta carotene, herbal preparations containing vitamin A or beta carotene, 
or fish oil, and unable or unwilling to discontinue use of these products during 
palovarotene treatment. 
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30 November 2020 
PROPRIETARY AND CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
 
Study Population of 
Subjects Starting 
Non-Flare-up-based 
Treatment During 
Part C 
Inclusion Criteria 
1. Subjects must be accessible for treatment with palovarotene and follow-up. 
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. 
2. Subjects must be able to undergo low-dose WBCT scan, excluding head.  
Exclusion Criteria 
1. Amylase or lipase >2x above the upper limit of normal (ULN) or with a 
history of chronic pancreatitis. 
2. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5x ULN. 
3. Fasting triglycerides >400 mg/dL with or without therapy. 
4. 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). 
Investigational 
Product 
Palovarotene supplied as powder-filled hard gelatin capsules. The capsules may be 
swallowed whole or opened and the contents added onto specific food: apple sauce, 
pudding, or yogurt. 
Dose/Route/Regimen 
for Non-Flare-up-
based Treatment 
Palovarotene: 5 mg daily or weight-based equivalent for skeletally immature subjects 
(<90%, upon entry into the study) / taken orally with food / at approximately the same 
time each day. For 5 mg palovarotene, weight equivalent doses for 20 to <40 kg, 40 to 
<60 kg, and ≥60 kg will be 3 mg, 4 mg, and 5 mg, respectively. 
Dose/Route/Regimen 
for Flare-up-based 
Treatment 
Palovarotene initiated at the start of a flare-up: 20 mg for 4 weeks (28 days) once daily, 
10 mg for 8 weeks (56 days) once daily 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 and dose de-escalation for flare-up and non- 
flare-up-based dosing are: 
 
Weight 
Range 
Category 
20-mg 
Equiv-
alent 
15-mg 
Equiv-
alent* 
10-mg 
Equiv-
alent 
7.5-mg 
Equiv-
alent* 
5-mg Equiv-
alent* 
2.5-mg 
Equiv-
alent* 
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 equivalent, respectively. 
Comparator Product 
Dose/Route/Regimen 
Not Applicable – this is an open-label extension study. 
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30 November 2020 
PROPRIETARY AND CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
 
Assessments of 
Efficacy 
Primary Efficacy Endpoint 
1. Annualized change in new HO volume as assessed by low-dose WBCT scan, 
excluding head. The annualized change from Parts B and C will be compared 
to data collected from the NHS. 
Secondary Endpoints (Note: baseline is Non-flare-up Day 1.) Some subjects may be 
assessed for up to 72 months. 
1. Percent of subjects with new HO at Months 12, 24, 36, 48, 60, 72 and overall. 
2. Change from baseline in ROM as assessed by CAJIS at Months 6, 12, 18, 24, 
30, 36, 42, 48, 54, 60, 66 and 72. 
3. Change from baseline in physical function using age appropriate forms of the 
FOP-PFQ at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72. 
4. 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 at Months 6, 12, 18, 24, 30, 36, 42, 48, 
54, 60, 66 and 72. 
Assessments of 
Safety 
Safety evaluations will include AE and serious AE (SAE) reporting, electrocardiograms 
(for subjects receiving treatment), 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 years with open epiphyses at the last 
assessment will include knee (anterior/posterior [AP] view) and hand/wrist 
(posterior/anterior [PA] view) radiographs for assessment of epiphyseal growth plate; 
and standardized stadiometry and knee height for assessments of linear growth (in 
triplicate).  If there is evidence of premature growth plate closure (with or without 
linear growth deceleration) the Investigator may require that study drug 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 reads. Bilateral hip growth plate morphology will also be assessed 
for avascular necrosis (AVN) 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. 
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 
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30 November 2020 
PROPRIETARY AND CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
 
treatment-related adverse bone effects. The DMC Charter includes recommended safety 
stopping rules (see Section 7.6). 
Statistical Analysis 
Part C 
The primary efficacy endpoint for Part C is the annualized change in new HO volume 
(as assessed by low-dose WBCT scan, excluding head). The annualized change in Part 
C will be compared to data collected from a natural history study using a weighted 
linear mixed effects model with baseline HO volume divided by age as the only 
covariate and weights used to account for the different lengths of observed subject 
follow-up. A subject-specific random effect will be included to account for within- 
subject correlation. 
 
 
 
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PROPRIETARY AND CONFIDENTIAL 
 
Table 1. 
Schedule of Assessments During Non-Flare-up-based Treatment (Subjects 
from Part B Continuing Non-Flare-up-based Treatment into Part C) 
Assessment/Procedure 
Part C 
Consent/Assent1 
Remote Visit 
Every Month 
Remote Visit1,2 
(±1 week) 
Every 3 Months 
Remote Visit1,2,3 
(±2 weeks) 
Months 6, 18, 
30, 42, 54, 66 
Remote 
Visit1,2,4 
(±1 month) 
Months 12, 24, 
36, 48, 
60, 
72/EOT/EOS1,4,5 
Site Visit 
(±1 month) 
Informed consent/assent1 
X 
Inclusion/ exclusion 
X 
Knee and hand/wrist radiographs6 
X7 
X 
X 
Linear growth assessment 
(stadiometry, knee height; subjects 
<18 years of age)6 
X 
X 
Physical examination 
X 
Body weight 
X 
X 
X 
Electrocardiogram 
X 
Study drug dispensing 
As needed from Non-flare-up Day 1 through Month 72 
Study drug treatment 
Continuous from Non-flare-up Day 1 through Month 728 
Dispense/review subject diary 
Dispense diary as needed and review at every subject contact 
Vital signs 
X 
X 
X 
C-SSRS (age-appropriate) 
X 
X 
X 
Reassess for child bearing status 
(females only) and pregnancy 
prevention measures (females and 
males) 
X 
X 
X 
Hematology9 
X 
X 
Biochemistry (includes lipids, serum 
pregnancy test)9 
X 
X 
Urinalysis10 
X 
X 
Pregnancy test11 
X 
FOP-PFQ12 
X 
X 
PROMIS Global Health Scale12 
X 
X 
CAJIS 
X13 
X 
Low-dose WBCT scan, excluding 
head14 
X 
Prior/concomitant medications 
At every subject contact 
Adverse events 
At every subject contact 
Pharmacokinetic blood sample15 
Month 3 or later15 
Telephone contact3 
X 
1 
Consent may be obtained remotely via email or faxed. Visits can be combined with flare-up visits when appropriate. 
Subjects who began non-flare-up-based treatment during Part B will continue the same visit schedule into Part C 
(includes Protocol Amendment 4 and subsequent amendments). 
2 
Remote visits, except for knee and hand/wrist radiographs, will be performed at the subject’s home by qualified 
study personnel, at a local medical facility, or via video-conferencing or telephone contact, unless the Investigator 
deems that a site visit is necessary. Remote visits that occur every 3 months should align with the remote visits at 
Months 6, 18, 30, 42, 54 and 66. Monthly remote visits will only be conducted for FOCBP subjects. 
3 
At the time of a remote visit, subjects will be contacted by telephone every 3 months from the time of informed 
consent until study completion to assess AEs and concomitant medications. Every effort should be made to conduct 
the telephone contact on the same day as the remote visit completed every 3 months. However, the visit window of 
±2 weeks will allow for flexibility in scheduling if needed. 
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PROPRIETARY AND CONFIDENTIAL 
 
4 
Non-flare-up Day 1 is the first day that non-flare-up-based treatment was initiated during Part B, and total duration of 
treatment will continue into Part C. Subjects who began non-flare-up-based treatment during Part B will continue the 
same visit schedule into Part C, and will receive non-flare-up-based treatment for up to an additional 48 months. 
Therefore, these subjects may undergo non-flare-up-based treatment for up to 72 months over the entire study. 
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 D. 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 D. If the 
Part C EOS visit (at completion of the trial) is > 6 months from the last annual visit, this visit will serve as the 
EOT/EOS site visit, will include all annual assessments and will end their participation in the study. 
5 
Adult subjects who cannot receive non-flare-up-based treatment will only undergo annual assessments (clinical 
laboratory tests will not be performed). 
6 
Subjects with open epiphyseal growth plates at the most recent assessment will be evaluated at Months 6, 12, 18, 24, 
30, 36, 42, 48, 54, 60, 66 and 72. As the linear growth assessments cannot be performed remotely, all assessments 
scheduled at these time points will be performed at the clinical site. Limb/joint AEs in these subjects will be evaluated 
by clinical and radiographic assessments deemed appropriate by the Investigator. Once a subject has achieved 100% 
skeletal maturity (confirmed by radiography as complete closure of the growth plate), knee and hand/wrist radiographs 
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. In addition, once a subject is 18 years old, linear growth assessments in 
triplicate and knee height will no longer be required. 
7 
These additional knee and hand/wrist radiograph assessments will be performed every 3 months (±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% skeletal maturity on their last assessment. Radiographic assessments required because of flare-up status at the 
time of a remote visit will instead be conducted at the clinical site unless the Investigator determines they can be 
performed at a local medical facility. All remote assessments will be performed at the clinical site if the radiographs 
cannot be performed locally. 
8 
Continuous non-flare-up-based treatment unless flare-up-based treatment is initiated. 
9 
Analysis of samples can be completed at a local, qualified laboratory. The investigative site should notify the study 
team if the local laboratory cannot test all the analytes listed in Table 5. If the total thyroxine (Total T4), free T4, uric 
acid, gamma glutamyl transferase, inorganic phosphorous, very low-density lipoprotein, or globulin parameters are 
not available through the local laboratory, and alternative arrangements cannot be made, testing of these analytes may 
be omitted provided other subject-assessments of thyroid function (ie, thyroid-stimulating hormone), lipid metabolism 
(ie, triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol), and protein metabolism (ie, 
total protein and albumin) are available and confirmed to be stable as per the Investigator. Alternative arrangements to 
test the listed analytes are to be made if the Investigator, Medical Monitor, or sponsor determines that they have the 
potential to impact subject safety. In the event the local laboratory is unable to test any other analytes, they may be 
omitted in exceptional circumstances after consultation with the sponsor. Such exceptions will not be applied to any 
of the key safety analytes (see Section 7.2.6). 
10 
If urinalysis results are abnormal, then a microscopic evaluation will be completed. 
11 
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. 
12 
Age-appropriate versions of the FOP-PFQ and PROMIS Global Health Scale will be used. 
13 
CAJIS assessment may be performed remotely or by videoconferencing. 
14 
Baseline for low-dose WBCT scan, excluding head, was performed prior to the initiation of non-flare-up-based 
dosing during Part B. 
15 
Blood samples for PK assessment of non-flare-up dosing will be collected at the first 3-month safety assessment at 
pre-dose and 3, 6, 10, and 24 hours post-dose; if samples cannot be or were not obtained at the 3-month safety 
assessment, or if a subject is on flare-up-based treatment, then the PK blood sample for non-flare-up-based treatment 
can be obtained during any subsequent 3-month safety visit. 
AE = adverse event(s), CAJIS = Cumulative Analogue Joint Involvement Scale for FOP, C-SSRS = Columbia 
Suicide Severity Rating Scale, EOS = end of study, EOT = end of treatment, FOCBP = female of child-bearing 
potential, FOP-PFQ = Fibrodysplasia Ossificans Progressiva physical function questionnaire, PK = 
pharmacokinetic(s), PROMIS = Patient Reported Outcomes Measurement Information System, WBCT = whole 
body computed tomography. 
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PROPRIETARY AND CONFIDENTIAL 
 
 
Table 2. 
Schedule of Assessments During Non-Flare-up-based Treatment (Subjects 
Starting Non-Flare-up-based Treatment During Part C) 
Assessment/Procedure 
Part C 
Screening/ Non-
Flare-up Day 
11/Site Visit 
(-1 month) 
Every Month 
Remote 
Visit1,2 (±1 
week) 
Every 3 
Months Remote 
Visit1,2,3 (±2 
weeks) 
Months 18, 30, 
42 Remote 
Visit1,2 (±1 
month) 
Months 6, 12, 
24, 36, 
48/EOT/EOS1,4,5 
Site Visit 
(±1 
month) 
Informed consent/assent1 
X 
Inclusion/exclusion 
X 
Knee and hand/wrist radiographs 
for assessment of epiphyseal 
growth plate6 
X 
X7 
X 
X 
Linear and knee height growth 
assessments (<18 years of age)6 
X 
X 
X 
Physical examination 
X 
X 
Body weight 
X 
X 
X 
X 
Electrocardiogram 
X 
X 
Study drug dispensing 
As needed from Non-flare-up Day 1 through Month 48 
Study drug treatment 
Continuous from Non-flare-up Day 1 through Month 488 
Dispense/review subject diary 
Dispense diary as needed and review at every subject 
contact 
Vital signs 
X 
X 
X 
X 
C-SSRS (age-appropriate) 
X 
X 
X 
X 
Reassess for child bearing status 
(females only) and pregnancy 
prevention measures (females and 
males) 
X 
X 
X 
Hematology9 
X 
X 
X 
Biochemistry (includes lipids, 
serum pregnancy test)10 
X 
X 
X 
Urinalysis10 
X 
X 
X 
Pregnancy test11 
X 
FOP-PFQ12 
X 
X 
X 
PROMIS Global Health Scale12 
X 
X 
X 
CAJIS 
X 
X13 
X 
Low-dose WBCT scan, excluding 
head14 
X 
X14 
Prior/concomitant medications 
At every subject contact 
Adverse events 
At every subject contact 
Pharmacokinetic blood sample15 
Month 3 or later15 
Telephone contact3 
X 
1 
Consent may be obtained remotely via email or faxed. A visit will be scheduled as soon as possible after Protocol 
Amendment 5 is approved at the clinical site and non-flare-up-based treatment will be started during that visit (Non-
flare-up Day 1). Part C includes Protocol Amendment 4 and subsequent amendments. Visits can be combined with 
flare-up visits when appropriate. 
2 
Remote visits, except for knee and hand/wrist radiographs, will be performed at the subject’s home by qualified study 
personnel, at a local medical facility, or via video-conferencing or telephone contact unless the Investigator deems that 
a site visit is necessary. Remote visits that occur every 3 months should align with the remote visits at Months 18, 30 
and 42. Monthly remote visits will only be conducted for FOCBP subjects. 
3 
At the time of a remote visit, subjects will be contacted by telephone every 3 months from the time of informed consent 
until study completion to assess AEs and concomitant medications. Every effort should be made to conduct the 
telephone contact on the same day as the remote visit completed every 3 months. However, the visit window of ±2 
weeks will allow for flexibility in scheduling if needed. 
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PROPRIETARY AND CONFIDENTIAL 
 
4 
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 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 the Part C EOS visit (at completion of the trial) is > 6 months from the last annual visit, this visit will serve 
as the EOT/EOS site visit, will include all annual assessments and will end their participation in the study. 
5 
Adult subjects who cannot receive non-flare-up-based treatment will only undergo annual assessments (clinical 
laboratory tests will not be performed). 
6 
Subjects with open epiphyseal growth plates at the most recent assessment will undergo knee (AP view) and hand/wrist 
(PA view) radiographs and measurements of linear and knee height (in triplicate) at Part C Screening and/or Non-flare-
up Day 1. As the linear growth assessments cannot be performed remotely, all assessments scheduled at these time 
points will be performed at the clinical site. Subjects for whom radiographs were performed within the last 3 months 
will not need to repeat radiographs at Screening. Subjects with open epiphyseal growth plates at this assessment will 
also be evaluated at Months 6, 12, 18, 24, 30, 36, 42 and 48. Limb/joint AEs in these subjects will be evaluated by 
clinical and radiographic assessments deemed appropriate by the Investigator. Once a subject has achieved 100% 
skeletal maturity (confirmed by radiography), knee and hand/wrist radiographs 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. In addition, once a subject is 18 years old, linear growth assessments in triplicate and knee height will no 
longer be required. 
7 
These additional knee and hand/wrist radiograph assessments will be performed every 3 months (±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% skeletal maturity on their last assessment. These radiographic assessments required because of flare-up status at 
the time of a remote visit will instead be conducted at the clinical site unless the Investigator determines they can be 
performed at a local medical facility. All remote assessments will be performed at the clinical site if the radiographs 
cannot be performed locally. 
8 
Continuous non-flare-up-based treatment unless flare-up-based treatment is initiated. 
9 
 Analysis of samples can be completed at a local, qualified laboratory. The investigative site should notify the study team 
if the local laboratory cannot test all the analytes listed in Table 5. If the total thyroxine (Total T4), free T4, uric acid, 
gamma glutamyl transferase, inorganic phosphorous, very low-density lipoprotein, or globulin parameters are not 
available through the local laboratory, and alternative arrangements cannot be made, testing of these analytes may be 
omitted provided other subject-assessments of thyroid function (ie, thyroid-stimulating hormone), lipid metabolism (ie, 
triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol), and protein metabolism (ie, total 
protein and albumin) are available and confirmed to be stable as per the Investigator. Alternative arrangements to test the 
listed analytes are to be made if the Investigator, Medical Monitor, or sponsor determines that they have the potential to 
impact subject safety. In the event the local laboratory is unable to test any other analytes, they may be omitted in 
exceptional circumstances after consultation with the sponsor. Such exceptions will not be applied to any of the key 
safety analytes (see Section 7.2.6). 
10 
If urinalysis results are abnormal, then a microscopic evaluation will be completed. 
11 
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. 
12 
Age-appropriate versions of the FOP-PFQ and PROMIS Global Health Scale will be used. 
13 
CAJIS assessment may be performed remotely or by videoconferencing. 
14 
Baseline for low-dose WBCT scan, excluding head, will be at Part C Screening (ie, when the subject provides 
informed consent/assent for Study PVO-1A-202 Part C). The low-dose WBCT scans, excluding head, will only be 
performed during annual visits (not at the 6-month visit). 
15 
Blood samples for PK assessment of non-flare-up dosing will be collected at the first 3-month safety assessment at pre-
dose and 3, 6, 10, and 24 hours post-dose; if samples cannot be or were not obtained at the 3-month safety assessment, or 
if a subject is on flare-up-based treatment, then the PK blood sample for non-flare-up-based treatment can be obtained 
during any subsequent 3-month safety visit. 
 
AE = adverse event(s), AP = anterior/posterior, CAJIS = Cumulative Analogue Joint Involvement Scale for 
FOP, C-SSRS = Columbia Suicide Severity Rating Scale, EOS = end of study, EOT = end of treatment, FOP-
PFQ = Fibrodysplasia Ossificans Progressiva physical function questionnaire, P/A = posterior/anterior, PK = 
pharmacokinetic, PROMIS = Patient Reported Outcomes Measurement Information System, WBCT = whole 
body computed tomography. 
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Table 3. 
Schedule of Assessments for Flare-up-based Treatment (Subjects with a Flare-Up) 
Assessment/Procedure 
FLARE-UP CYCLE SAFETY ASSESSMENTS 
Remote Visits1,2 (±5 days) 
Flare-Up Cycle 
Safety Day 13 
Every 12 Weeks3 
Vital signs and body weight 
X 
X 
Hematology4,5 
X 
X 
Biochemistry (includes lipids)4,5 
X 
X 
Urinalysis4,5,6 
X 
X 
C-SSRS (age appropriate) 
X 
X 
Pregnancy testing7 
X 
Every 4 weeks 
Study drug dispensing 
As needed from Cycle Day 1 to end of treatment of last flare-up cycle8,9 
Study drug treatment 
Continuous from Cycle Day 1 to end of treatment of last flare-up cycle3,8,9 
Dispense/review subject diary 
Dispense diary as needed and review at every subject contact 
Flare-up(s) status and end date confirmation10 
X 
At every subject contact 
Prior/concomitant medications 
At every subject contact 
Adverse events 
At every subject contact 
Treatment/Assessment 
FLARE-UP TREATMENT8 AND PHARMACOKINETICS 
Flare-Up Day 
15,12,14 
High Dose 
Treatment 
Low Dose Treatment 
Flare-up (first flare-up or restart for intercurrent flare-up)10,11 
X 
Week 1 to 4 
(4 weeks) 
Week 4 to 12 
(8 weeks) 
4-Week Extension 
(if applicable) 
Pharmacokinetic blood sample 
X12 
X12 
Telephone contact13 
End of Week 12 
End of each 
4-week extension 
1 
All visit windows are ±5 days, except the End of Flare-Up Cycle Safety Assessments of the first flare-up, which is -5 days because a blood draw is required for 
pharmacokinetic analysis. 
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 the 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 non-flare-up-based treatment with 5 mg palovarotene once daily (weight-adjusted doses for skeletally immature subjects). It is possible that 
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subjects may experience more than one Flare-up Cycle during Part C of the study. Note that the Flare-up Cycle assessments will also be applicable to any treated 
high-risk traumatic event likely to lead to a flare-up. 
4 
Flare-up-based treatment can begin immediately after the Investigator confirms the presence of a flare-up 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). 
Analysis of samples can be completed at a local, qualified laboratory. The investigative site should notify the study team if the local laboratory cannot test all the 
analytes listed in Table 5. If the total thyroxine (Total T4), free T4, uric acid, gamma glutamyl transferase, inorganic phosphorous, very low-density lipoprotein, or 
globulin parameters are not available through the local laboratory, and alternative arrangements cannot be made, testing of these analytes may be omitted provided 
other subject- assessments of thyroid function (ie, thyroid-stimulating hormone), lipid metabolism (ie, triglycerides, low-density lipoprotein, high-density 
lipoprotein, and total cholesterol), and protein metabolism (ie, total protein and albumin) are available and confirmed to be stable as per the Investigator. Alternative 
arrangements to test the listed analytes are to be made if the Investigator, Medical Monitor, or sponsor determines that they have the potential to impact subject 
safety. In the event the local laboratory is unable to test any other analytes, they may be omitted in exceptional circumstances after consultation with the sponsor. 
Such exceptions will not be applied to any of the key safety analytes (see Section 7.2.6). 
5 
Subjects with normal or non-clinically significant abnormal safety laboratory results observed within 1 month of flare-up-based treatment will not need to have 
laboratory tests performed at Flare-up Cycle Safety Day 1. 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 the end of the cycle. 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. 
6 
If urinalysis results are abnormal, then a microscopic evaluation should be completed. 
7 
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. 
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 once 
daily followed by 8 weeks (56 days) of 10 mg palovarotene once daily (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 other 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 equivalent]). This may occur more than once during a Flare-up Cycle. 
10 
At each contact, flare-up status will be assessed 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 (upon confirmation by the Investigator). 
12 
Pharmacokinetics of palovarotene dosing will be assessed twice: 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 during Study Days 32 to 84, for the first treated flare-up only. If not possible for the first treated flare-up, PK blood samples can be obtained 
during any subsequent flare-up dosing cycle. Blood samples will be collected at pre-dose and 3, 6, 10, and 24 hours post-dose. Subjects who underwent a PK 
assessment for flare-up-based treatment under PVO-1A-202 Protocol Amendment 3 will not have flare-up PK assessed again. However, these subjects will require a 
non-flare-up treatment PK assessed at a 3-month safety visit. 
13 
Flare-up 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. 
 
Note: study procedures that require sedation will not be performed.  
C-SSRS = Columbia Suicide Severity Rating Scale, PK = pharmacokinetic(s) 
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Table 4. 
Schedule of Assessments for Part D 
 
 
 
Y1 and Y2 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 of age)4 
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 events2,6 
At every subject contact 
1     Year 1 (Y1) and Year 2 (Y2) visits following the last dose of study drug will be done within the total study 
duration from enrolment from Part A. Y1 to be completed in the window of ≥ 6 to < 18 months post last dose of 
study drug.  If Part A, B or C EOS date is within the Y1 window then the EOS will serve as the Y1 visit.   
If Part A, B or C EOS date is prior to Y1 window then Y1 should be scheduled ≥ 6 months from Part A, B or C 
EOS date but still within the Y1 window.  Y2 to be completed ≥18 – 24 months post last dose of study drug. If 
Part A, B or C EOS date is within the Y2 window then the EOS will serve as the Y2 visit.   
If Part A, B or C EOS date or Y1 date (if applicable) is prior to Y2 window then Y2 should be scheduled ≥ 6 
months from the Part A, B or C 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, B or C EOS more than 2 years prior to 
their consent for Part D, then these subjects will only complete Y2 following their consent for Part D.  
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 D informed consent is required prior to conducting Part D 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 D 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. 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
Protocol Signature Page ....................................................................................................... 2 
Protocol Amendment Summary of Changes ...................................................................... 3 
Groups Responsible for Study Contact .............................................................................. 6 
Protocol Synopsis .................................................................................................................. 7 
Table of Contents ................................................................................................................ 23 
List of Tables ....................................................................................................................... 26 
List of Figures ..................................................................................................................... 27 
List of Abbreviations .......................................................................................................... 28 
1. 
Introduction ............................................................................................ 30 
1.1 
Background ....................................................................................................... 30 
1.1.1 
Fibrodysplasia Ossificans Progressiva ............................................................ 30 
1.1.2 
Current Therapeutic Options for Fibrodysplasia Ossificans Progressiva ...... 30 
1.1.3 
Overview of Palovarotene ................................................................................. 31 
1.1.3.1 
Nonclinical Data ............................................................................................... 32 
1.1.3.2 
Clinical Data ..................................................................................................... 33 
2. 
Study Objectives .................................................................................... 36 
2.1 
Primary Objective ............................................................................................. 36 
2.2 
Secondary Objectives ........................................................................................ 36 
3. 
Study Design ........................................................................................... 37 
3.1 
Overview of the Study Design ........................................................................... 37 
3.2 
Study Rationale ................................................................................................. 41 
3.3 
Dose Justification ............................................................................................. 42 
3.4 
Appropriateness of Measurements ................................................................... 43 
3.4.1 
Imaging ............................................................................................................. 43 
3.4.2 
Measures of Functional Disability and General Health ................................. 43 
4. 
Study Endpoints ..................................................................................... 44 
4.1 
Primary Endpoints ............................................................................................ 44 
4.2 
Secondary Endpoints ........................................................................................ 44 
5. 
Selection of Study Population ............................................................... 44 
5.1 
Study Population (Adult and Pediatric Cohorts – Part B) .............................. 45 
5.1.1 
Inclusion Criteria .............................................................................................. 45 
5.1.2 
Exclusion Criteria ............................................................................................. 45 
5.2 
Study Population for Non-Flare-up-based Treatment (Adult Cohort – Part B)
 ........................................................................................................................... 45 
5.2.1 
Inclusion Criteria .............................................................................................. 45 
5.2.2 
Exclusion Criteria ............................................................................................. 46 
5.3 
Study Population for Flare-up-based Treatment (Adult and Pediatric Cohorts 
– Part B) ............................................................................................................ 46 
5.3.1 
Inclusion Criteria .............................................................................................. 46 
5.3.2 
Exclusion Criteria ............................................................................................. 47 
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5.4 
Study Population (All Subjects – Part C) ......................................................... 48 
5.4.1 
Inclusion Criteria .............................................................................................. 48 
5.4.2 
Exclusion Criteria ............................................................................................. 48 
5.5 
Study Population of Subjects Starting Non-Flare-up-based Treatment During 
Part C ................................................................................................................ 49 
5.5.1 
Inclusion Criteria.............................................................................................. 49 
5.5.2 
Exclusion Criteria ............................................................................................. 49 
5.6 
Prior and Concomitant Medications and Other Study Restrictions ............... 49 
5.6.1 
Prior and Concomitant Medications for Subjects Receiving Palovarotene ... 49 
5.6.2 
Other Restrictions ............................................................................................. 50 
5.7 
Subject Withdrawal or Early Termination from Study ................................... 51 
5.8 
Replacement of Subjects ................................................................................... 51 
6. 
Study Drug Administration .................................................................. 51 
6.1 
Identity of Study Drug ...................................................................................... 51 
6.2 
Packaging, Labeling, and Storage ................................................................... 52 
6.3 
Randomization and Blinding ........................................................................... 52 
6.4 
Administration .................................................................................................. 52 
6.5 
Dose Modification ............................................................................................. 53 
6.6 
Study Drug Accountability ............................................................................... 54 
6.7 
Assessment of Subject Compliance .................................................................. 54 
7. 
Study Procedures and Assessments ...................................................... 54 
7.1 
Screening, Recruitment, and Informed Consent ............................................. 54 
7.2 
Safety Assessments ............................................................................................ 55 
7.2.1 
Medical History and Flare-Up Assessment ..................................................... 55 
7.2.2 
Physical Examination ....................................................................................... 55 
7.2.3 
Body Weight and Linear Growth Assessments ................................................ 56 
7.2.4 
Vital Signs ......................................................................................................... 57 
7.2.5 
Electrocardiogram ............................................................................................ 57 
7.2.6 
Clinical Laboratory Tests ................................................................................. 57 
7.2.7 
Pregnancy Testing ............................................................................................ 60 
7.2.8 
Adverse Events .................................................................................................. 60 
7.2.9 
Concomitant Medications ................................................................................. 61 
7.3 
Special Safety Assessments ............................................................................... 61 
7.3.1 
Columbia-Suicide Severity Rating Scale.......................................................... 61 
7.3.2 
Knee and Hand/Wrist Radiographs ................................................................. 61 
7.3.3 
Bone Safety Management Plan ........................................................................ 62 
7.3.4 
Mucocutaneous Effects (Skin and Mucous Membrane Toxicity Profile) ...... 63 
7.3.5 
Serum Lipids ..................................................................................................... 63 
7.3.6 
Liver Enzymes ................................................................................................... 63 
7.3.7 
Lipase/Amylase ................................................................................................. 64 
7.3.8 
Central Nervous System.................................................................................... 64 
7.3.9 
Hearing and Visual Disturbances .................................................................... 64 
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7.3.10 
Teratogenicity ................................................................................................... 64 
7.4 
Efficacy Assessments ........................................................................................ 65 
7.4.1 
Low-Dose Whole Body Computed Tomography .............................................. 65 
7.4.2 
FOP-Physical Function Questionnaire ........................................................... 65 
7.4.3 
PROMIS Global Health Scale .......................................................................... 66 
7.4.4 
Cumulative Analogue Joint Involvement Scale ............................................... 66 
7.5 
Pharmacokinetics ............................................................................................. 67 
7.6 
Data Monitoring Committee ............................................................................. 67 
7.7 
Temporary Measures (Procedures Related to COVID-19 Pandemic) ............ 68 
8. 
Statistical and Analytical Plans ............................................................ 70 
8.1 
General Methods ............................................................................................... 71 
8.2 
Sample Size ....................................................................................................... 71 
8.3 
Study Populations ............................................................................................. 71 
8.4 
Baseline and Disease Characteristics (including Medical History) ................ 71 
8.5 
Subject Disposition ........................................................................................... 71 
8.6 
Extent of Exposure ........................................................................................... 71 
8.7 
Efficacy ............................................................................................................. 72 
8.7.1 
Primary Efficacy ............................................................................................... 72 
8.7.2 
Secondary Efficacy ........................................................................................... 72 
8.8 
Safety ................................................................................................................. 72 
8.8.1 
Adverse Events .................................................................................................. 73 
8.8.2 
Suicide Ideation ................................................................................................ 73 
8.8.3 
Clinical Laboratory Findings ........................................................................... 73 
8.9 
Pharmacokinetics ............................................................................................. 73 
8.10 
Pharmacodynamics........................................................................................... 73 
9. 
Procedural, Ethical, Regulatory, and Administrative Considerations
 
74 
9.1 
Adverse Event and Serious Adverse Event Documentation, Severity Grading, 
and Reporting ................................................................................................... 74 
9.1.1 
Adverse Event .................................................................................................... 74 
9.1.2 
Serious Adverse Event or Adverse Drug Reaction .......................................... 74 
9.1.3 
Adverse Event Documentation ......................................................................... 75 
9.1.4 
Severity of Adverse Events ................................................................................ 75 
9.1.5 
Causality Assessment ........................................................................................ 75 
9.1.6 
Action Taken With Study Drug ........................................................................ 76 
9.1.7 
Outcome of Adverse Event ............................................................................... 76 
9.1.8 
Reporting of Serious Adverse Event ................................................................ 76 
9.1.9 
Pregnancy ......................................................................................................... 77 
9.1.10 
Follow-Up of Adverse Events and Serious Adverse Events ............................ 77 
9.2 
Administrative Requirements ........................................................................... 77 
9.2.1 
Informed Consent Form ................................................................................... 77 
9.2.2 
Ethical Conduct of the Study ........................................................................... 78 
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9.2.3 
Ethics Board Approval ..................................................................................... 78 
9.2.4 
Subject Confidentiality ..................................................................................... 79 
9.2.5 
Amendments to the Protocol ............................................................................ 79 
9.2.6 
Protocol Deviations ........................................................................................... 79 
9.2.7 
Study Termination ............................................................................................ 80 
9.2.8 
Retention of Subject Records and Study Files ................................................. 80 
9.3 
Data Quality Assurance .................................................................................... 80 
9.4 
Monitoring ........................................................................................................ 81 
9.5 
Data Capture and Management ....................................................................... 81 
9.6 
Liability and Insurance .................................................................................... 81 
9.7 
Publication and Clinical Data Reporting ........................................................ 81 
9.8 
Coordinating Investigator ................................................................................ 82 
10. 
Investigator Agreement ......................................................................... 83 
11. 
References ............................................................................................... 84 
12. 
Appendices .............................................................................................. 86 
Appendix 1. 
Cumulative Analogue Joint Involvement Scale for FOP ................................ 86 
Appendix 2A. Adult FOP-Physical Function Questionnaire ................................................. 87 
Appendix 2B. Pediatric FOP-Physical Function Questionnaire ........................................... 89 
Appendix 2C. Pediatric FOP-Physical Function Questionnaire ........................................... 91 
Appendix 3. 
CYP450 3A4 Strong Inducers or Inhibitors: Exclusionary Medications ....... 93 
Appendix 4. 
Methods of Birth Control ................................................................................. 94 
Appendix 5A.  Adult Columbia-Suicide Severity Rating Scale (Subjects Ages 12 Years and 
Older) ................................................................................................................ 95 
Appendix 5B.  Pediatric Columbia-Suicide Severity Rating Scale (Subjects Ages 8 to 11 
Years) .............................................................................................................. 101 
Appendix 6. 
Retinoid-Specific Adverse Events to be Assessed for Severity by CTCAE 
Criteria (Version 4.03, 14 June 2010) ............................................................ 107 
Appendix 7A. PROMIS Global Health Scale ........................................................................ 108 
Appendix 7B. PROMIS Pediatric Global Health Scale ........................................................ 110 
Appendix 7C. PROMIS Pediatric Global Health Scale ........................................................ 111 
Appendix 8. 
Declaration of Helsinki .................................................................................. 112 
 
LIST OF TABLES 
 
Table 1. 
Schedule of Assessments During Non-Flare-up-based Treatment (Subjects from 
Part B Continuing Non-Flare-up-based Treatment into Part C) .......................... 16 
Table 2. 
Schedule of Assessments During Non-Flare-up-based Treatment (Subjects 
Starting Non-Flare-up-based Treatment During Part C) ..................................... 18 
Table 3. 
Schedule of Assessments for Flare-up-based Treatment (Subjects with a Flare-
Up) ........................................................................................................................... 20 
Table 4. 
Schedule of Assessments for Part D ....................................................................... 22 
Table 5. 
Weight-Adjusted Palovarotene Doses and Dose De-Escalation Doses ................. 39 
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Table 6. 
Clinical Laboratory Parameters ............................................................................. 59 
 
LIST OF FIGURES 
Figure 1 
Chemical Structure of Palovarotene ...................................................................... 52 
 
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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 
AVN 
avascular necrosis 
BMP 
bone morphogenetic protein 
CAJIS 
Cumulative Analogue Joint Involvement Scale for FOP  
CI 
confidence interval 
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  
CYP 
cytochrome P 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
EAP 
early access program 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FOCBP 
female of child-bearing potential 
FOP 
Fibrodysplasia Ossificans Progressiva  
FOP-PFQ 
FOP-Physical Function Questionnaire 
FOP-PFQ-P 
Pediatric FOP-PFQ 
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 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
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IRB 
Institutional Review Board 
LC-MS/MS   
Liquid chromatography–mass spectrometry 
LDL 
low-density lipoprotein 
LME 
linear mixed effects 
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 
PAS 
Pharmacokinetic Analysis Set 
PCS 
potentially clinically significant 
PK 
pharmacokinetic(s) 
PO 
per os 
PPS 
Per-Protocol Set 
PROMIS 
Patient Reported Outcomes Measurement Information System  
RAR 
retinoic acid receptor 
RARγ 
retinoic acid receptor gamma 
ROM 
range of motion 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
standard deviation 
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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1. 
INTRODUCTION 
 
1.1 
Background 
 
1.1.1 
Fibrodysplasia Ossificans Progressiva 
Fibrodysplasia Ossificans Progressiva (FOP) (OMIM #135100) is a rare, severely disabling 
disease characterized by heterotopic ossification (HO) in muscles, tendons, and ligaments often 
associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in 
early childhood and lead to progressive ankyloses of major joints with resultant loss of 
movement. Prognosis is poor and life expectancy is reduced. FOP is caused by an activating 
mutation in the bone morphogenetic protein (BMP) type I receptor, or activin receptor type IA 
(ACVR1), also known as activin-like-kinase 2 (ALK2) type I receptor. Most patients with FOP 
(approximately 97%) have the same point mutation, R206H. The International FOP Association, 
a US-based patient group organization, reports approximately 800 confirmed cases of FOP 
globally.1 The prevalence is estimated at approximately 1.36 per million individuals, with no 
geographic, ethnic, racial, or gender preference.2 FOP is misdiagnosed approximately 80% of 
the time resulting in great harm to patients.3 The preosseous flare-ups that characterize the 
disease have been misinterpreted as lymphedema, soft tissue sarcoma, or juvenile fibromatosis, 
often resulting in harmful diagnostic biopsies that exacerbate the progression of the disease, 
and/or unnecessary chemotherapeutic interventions. Individuals with FOP appear normal at birth 
except for the pathognomonic malformation of the great toes, which are typically short (lack a 
phalange) and deviated in hallux valgus.4 
 
Heterotopic ossification is episodic and cumulative throughout life, resulting in segments, 
sheets, and ribbons of extra bone developing throughout the body and across joints, 
progressively restricting movement. Rapidly growing bony spurs have been known to protrude 
through the skin causing pain and a risk of infections.5 Only the tongue, heart, and diaphragm 
muscle are spared for reasons that have yet to be elucidated. Asymmetric HO in the rib cage and 
subsequent contralateral growth can lead to a rapid progression in spinal deformity and cause 
respiratory insufficiency.  Ankyloses of the temporomandibular joints results in severe tooth 
decay and malnutrition. Periods of flare-up activity are interspersed with variable-length 
intervals of apparently quiescent disease in the absence of obvious clinical symptoms. In some 
subjects, the presence of substantial soft tissue edema and muscle necrosis observed in imaging 
performed within 7 days of flare-up symptom-onset suggests that the process that ultimately 
leads to new HO formation starts before clinical symptoms are reported. Fibrodysplasia 
Ossificans Progressiva 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) without clinical symptoms. 
 
The majority of FOP patients are confined to a wheelchair by the third decade of life, and 
require caregiver assistance to perform daily living activities. The median age of survival is 
approximately 56 years with mortality often resulting from complications of respiratory 
insufficiency.6,7 
1.1.2 
Current Therapeutic Options for Fibrodysplasia Ossificans Progressiva 
Currently there are no effective medical treatment options to prevent the formation of 
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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.10  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.11 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 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 chondrogenesis15 and that unliganded RAR transcriptional repressor activity 
is needed for chondrogenic differentiation.16,17 Inhibition of HO with non-selective retinoids or 
RARα receptor agonists has also been achieved but to a lesser degree.13 
 
RARγ is expressed in chondrogenic cells and chondrocytes18 where it also operates as an 
unliganded transcriptional repressor.19 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 (R206H) 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.20,21 
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 
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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.12 
 
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.22 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 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 
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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 
 
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); and 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:  
• 309 healthy volunteers received single or multiple doses between 0.02 and 50 mg for up 
to 4 weeks 
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• 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), increased 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. 
 
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. 
 
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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 4 weeks (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 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, PVO-
1A-202/Part C, that will include chronic or non-flare-up dosing for skeletally mature as 
well as skeletally immature subjects. This corresponds to Study PVO-1A-204 
Amendment 3 in France. 
• 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. Part D was added for skeletally immature subjects who stopped 
taking study drug for any reason before completion of Part A/B/C.  Part D includes 
yearly visits for up to a 2-year follow-up period following last dose. No dosing is to 
occur during Part D. 
 
Palovarotene Safety 
Consistent with other retinoids, the most commonly reported adverse events across all palovarotene 
dosing regimens in the FOP interventional studies were mucocutaneous and dermatologic events 
such as dry skin and lips, erythema, and pruritus. In general, the incidence, total number, duration 
and severity of mucocutaneous and dermatologic events increased with increasing palovarotene 
dose. These AEs generally resolved without sequelae after completion of palovarotene treatment. 
Musculoskeletal events such as arthralgia, pain in extremity, and condition aggravated (the Medical 
Dictionary for Regulatory Activities [MedDRA] preferred term used to capture reports of FOP flare-
ups) were also commonly reported. 
The majority of AEs in the palovarotene Phase 2 studies in FOP were mild or moderate in 
severity. 
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In the current study, and in the ongoing FOP Phase 2 study, subjects enrolled with open 
epiphyses undergo knee (anterior/posterior [AP] view) and hand/wrist radiographs 
(posterior/anterior [PA] view) for assessment of epiphyseal growth plate; and linear and knee 
height measurements for assessment of growth. The most common epiphyseal growth plate 
abnormality is growth recovery lines (dense metaphyseal lines) at both baseline and post-
baseline time points. Potential premature closure of the epiphysis is closely monitored, and data 
are reviewed quarterly by an independent Data Monitoring Committee (DMC). Premature 
epiphyseal closure has been observed in subjects in the interventional FOP studies that have 
been reported as serious adverse events. Analysis of the SAEs suggests that the risk of premature 
epiphyseal fusion is higher in subjects with open epiphyseal growth plates who have received 
the flare-up dosing regimen. The finding of premature epiphyseal closure has been seen across 
all ages although the potential impact on growth is likely to be greater in the youngest, most 
skeletally immature subjects, given limitations in time to attain a greater percent of their final 
adult height. 
 
2. 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
The primary objective is: 
 
• To evaluate the safety and efficacy of different palovarotene dosing regimens in subjects 
with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the 
formation of new heterotopic ossification (HO) as assessed by low-dose whole body 
computed tomography (WBCT) scan, excluding head. 
2.2 
Secondary Objectives 
• 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 (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. 
2.3 
Secondary Objective (Part D)  
• 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.  
 
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3. 
STUDY DESIGN 
3.1 
Overview of the Study Design 
This is a Phase 2, multicenter, open-label extension study that will explore different dosing 
regimens of palovarotene in adult and pediatric subjects with FOP. 
Part A includes all data obtained prior to Amendment 3 (dated 10 March 2016) during which 
pediatric and adult subjects successfully completing Study PVO-1A-201 were enrolled and 
followed for up to 36 months. Any subject experiencing an eligible flare-up under Part A received 
treatment with open-label palovarotene at a dose of 10 mg once daily for 14 days followed by 5 
mg once daily for 28 days (or weight-based equivalent) and underwent all study procedures as 
specified in the original protocol, Amendment 1, and Amendment 2. 
Part B includes all data obtained under Amendment 3 (dated 10 March 2016) during which 
subjects successfully completing Study PVO-1A-201 (including any subject who previously 
participated in Part A of Study PVO-1A-202) as well as up to 20 new adult subjects were 
followed for up to 24 months. 
Part C includes all data obtained under Amendment 4 (dated 01 September 2017) and 
subsequent amendments during which subjects who participated in Part B will be followed for 
up to an additional 48 months. There will be no new subjects in Part C. Part C plus Part D total 
duration will not exceed 48 months. 
Part D 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 D. Subjects will 
follow assessments as outlined in Table 4 for as long as they are not 100% skeletally mature. 
Part C plus Part D total duration will not exceed 48 months. 
 
All subjects will receive non-flare-up-based treatment of 5 mg palovarotene once daily (weight-
adjusted doses for skeletally immature subjects [ie, subjects under the age of 18 years with less 
than 90% skeletal maturity on hand/wrist radiography at Screening]). Note: all weight-based 
dosing will cease when subjects achieve ≥90% skeletal maturity based on hand/wrist 
radiography, but radiographic assessment of the growth plate (performed every 6 months) will 
continue until these subjects achieve 100% skeletal maturity (defined as growth plate closure) at 
both knee and hand/wrist locations. Additional radiographic assessments will be performed 
every 3 months 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% skeletal maturity 
on their last radiographic assessment. 
Subjects will follow all assessments as outlined in Table 1 and Table 2. Adult subjects who 
cannot receive non-flare-up-based treatment will only undergo annual assessments (clinical 
laboratory tests will not be performed). In the event of a flare-up or traumatic event, these 
subjects will receive flare-up-based treatment and undergo all flare-up-based assessments, 
including clinical laboratory tests and radiographs if they have not reached 100% skeletal 
maturity. 
 
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Adverse events will be assessed at every site and remote visit during both non-flare-up-based 
and flare-up-based 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. 
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. 
 
As of 04 December 2019, 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. 
 
Subjects from Part B Continuing Non-Flare-up-based Treatment into Part C 
 
Subjects who began non-flare-up-based treatment during Part B will continue the same visit 
schedule into Part C (includes Protocol Amendment 4 and subsequent amendments), and will 
receive non-flare-up-based treatment for up to an additional 48 months. Therefore, these subjects 
may undergo non-flare-up-based treatment for up to 72 months over the entire study. Subjects 
continuing into Part C will follow all procedures and undergo all assessments as specified in the 
Schedule of Assessments in Table 1. Site visits will occur at Months 12, 24, 36, 48, 60 and 72. 
Non-flare-up Day 1 is the first day that non-flare-up-based treatment was initiated during Part B, 
and total duration of treatment will continue into Part C. Non-flare-up Day 1 is the first day that 
non-flare-up-based treatment is initiated during Part B, and total duration of treatment will 
continue into Part C. 
Remote visits (eg, at home or at a local medical facility; and via telephone contact with clinical 
site personnel) will occur every 3 months unless the Investigator deems that a site visit is 
necessary; urine pregnancy tests will be performed each month for females of childbearing 
potential (FOCBP). 
Subjects from Part B Starting Non-Flare-up-based Treatment During Part C 
 
Subjects who will start non-flare-up-based treatment during Part C will receive non-flare-up-
based treatment for up to 48 months. These subjects will follow all procedures and undergo all 
assessments as specified in the Schedule of Assessments in Table 2. Site visits will occur at Part 
C Screening and/or Non-flare-up Day 1, and at Months 6, 12, 24, 36 and 48. Non-flare-up Day 1 
is the first day that non-flare-up-based treatment is initiated during Part C for these subjects. 
Remote visits (eg, at home or at a local medical facility; and via telephone contact with clinical 
site personnel) will occur every 3 months unless the Investigator deems that a site visit is 
necessary; urine pregnancy tests will be performed each month for FOCBP. 
 
Part D: 
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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 D. Subjects who were 
enrolled in Parts A, B or C who have discontinued the study and were skeletally immature at 
their last assessment will be invited back to participate in the off-treatment Part D safety follow-
up. These subjects will follow all procedures and undergo all assessments as specified in the 
Schedule of Assessments in Table 4. 
 
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. 
 
Flare-up-based Treatment 
 
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 receive 
open-label palovarotene treatment as follows: 
• 20 mg for 4 weeks (28 days) once daily. The first dose will be taken upon flare-up 
confirmation by the Investigator. 
 
To be followed by: 
 
• 
10 mg for 8 weeks (56 days) once daily, for a total flare-up treatment duration of 12 
weeks (84 days); 10 mg treatment may be extended if the flare-up is ongoing and continue until 
the flare-up resolves. Dosing will be extended in 4-week intervals and be based on clinical signs 
and symptoms as assessed by the Investigator. 
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. 
All dosing, be it non-flare-up or flare-up-based, 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 
5). Note: all weight-based dosing will cease when subjects achieve ≥90% skeletal maturity based 
on hand/wrist radiography, but radiographic assessment of the growth plate will continue until 
these subjects achieve 100% skeletal maturity (defined as growth plate closure) at both knee and 
hand/wrist locations. 
The weight-adjusted palovarotene doses and dose de-escalation doses are: 
 
Table 5. 
Weight-Adjusted Palovarotene Doses and Dose De-Escalation Doses 
Weight Range 
Category 
20-mg 
Equivalent 
15-mg 
Equivalent* 
10-mg 
Equivalent 
7.5-mg 
Equivalent* 
5-mg 
Equivalent* 
2.5-mg 
Equivalent* 
20 to <40 kg 
12.5 mg 
10 mg 
6 mg 
4 mg 
3 mg 
1.5 mg 
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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 equivalent, respectively. 
 
If the subject experiences intolerable side effects, the dose may be reduced to the next lower 
dose as shown in Table 5; 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 or marked 
worsening of the original flare-up), or if the Investigator confirms the presence of a 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 confirmation by the 
Investigator (ie, 4 weeks of 20 mg palovarotene followed by 8 weeks of 10 mg palovarotene [or 
weight-based equivalent]). 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 the 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 follow all procedures and undergo all 
assessments as specified in the Schedule of Assessments in Table 3. 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 non-flare-up-based treatment with 5 mg palovarotene once 
daily (weight-adjusted doses for skeletally immature subjects). 
The PK of palovarotene dosing will be assessed at the first 3-month safety assessment during 
non-flare-up-based treatment; if samples cannot be or were not obtained during the first 3-month 
safety assessment, or if subjects are on flare-up-based treatment, then PK blood samples for 
non-flare-up treatment can be obtained during any subsequent 3-month safety visit. 
 
Pharmacokinetics of palovarotene dosing 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, PK blood samples can be obtained 
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during any subsequent flare-up dosing cycle. Pharmacokinetic blood samples will be collected at 
pre-dose and 3, 6, 10, and 24 hours post-dose. Subjects who underwent a PK assessment for 
flare-up-based treatment under PVO-1A-202 Protocol Amendment 3 will not have flare-up PK 
assessed again. However, these subjects will require a non-flare-up treatment PK assessed at a 
3-month safety visit (Section 7.5). 
 
3.2 
Study Rationale 
Prior to Protocol Amendment 3, this study followed subjects who rolled over from Study PVO-
1A-201 and provided open-label active treatment to any subject who experienced a subsequent 
flare-up. This allowed for the collection of long-term efficacy and safety data of palovarotene 
(10 mg for 14 days, followed by 5 mg for 28 days), and provided active treatment to all subjects 
experiencing eligible flare-ups including those who were randomized to placebo during Study 
PVO-1A-201. 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. 
Fibrodysplasia Ossificans Progressiva 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 
Protocol Amendment 3, adult subjects initiated non-flare-up-based daily treatment with 
palovarotene, which is extended to the Pediatric Cohort subjects under Protocol Amendments 4 
and 5. In addition, subjects experiencing an eligible intercurrent flare-up will restart flare-up-
based dosing in order to continue exposure to palovarotene and provide an optimal treatment for 
all flare-ups that may occur during the study. 
 
As of 04 December 2019, 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 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. 
 
Given the serious identified risk of premature physeal closure, Part D was added 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 in Part A/B/C for skeletally immature 
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subjects who stopped treatment for any reason. 
3.3 
Dose Justification 
Fibrodysplasia Ossificans Progressiva 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 Investigator 
discretion for persistent flare-ups) for all subjects. The flare-up 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 
immunizations, mandibular blocks for dental work, muscle fatigue, blunt muscle trauma 
from bumps, bruises, 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 
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two-thirds of falls and resulted in permanent loss of movement in 93% of patients.10 
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 
current Phase 2 and Phase 3 studies has confirmed mucocutaneous adverse effects that are 
managed with prophylactic treatment or dose reduction. In addition, Phase 2 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 current Phase 2 and Phase 3 studies. Therefore, 
careful safety monitoring and dose modification procedures for intolerable side effects will be 
employed in the current study. 
3.4 
Appropriateness of Measurements 
 
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,23 magnetic 
resonance imaging (MRI),24 and radionuclide bone scan.25 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.26 
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 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 assess the 
primary and secondary endpoints will be low-dose WBCT scan (excluding head). 
In order to ensure consistency and standardization, interpretation of the acquired images will be 
performed by a central imaging laboratory. The clinical trial imaging methodology will be 
documented (eg, imaging charter and imaging guideline) prior to study initiation. 
3.4.2 
Measures of Functional Disability and General Health 
Two key measures of functional disability include: 
• The 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 
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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-PFQ is a disease-specific patient-reported outcome measure of physical 
impairment. The FOP-PFQ was developed by Clementia based on the Food and Drug 
Administration (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 2A. 
 
4. 
STUDY ENDPOINTS 
 
4.1 
Primary Endpoints 
The primary endpoint is the annualized change in new HO volume as assessed by low-dose 
WBCT scan, excluding head. The annualized change from Parts B and C will be compared to 
data collected from the NHS. 
 
4.2 
Secondary Endpoints 
Note: Baseline is Non-flare-up Day 1. Some subjects may be assessed for up to 72 months. 
 
1 
Percent of subjects with new HO at Months 12, 24, 36, 48, 60, 72 and overall. 
 
2 
Change from baseline in ROM as assessed by CAJIS at Months 6, 12, 18, 24, 30, 36, 
42, 48, 54, 60, 66 and 72. 
3 
Change from baseline in physical function using age appropriate forms of the FOP-
PFQ at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72. 
4 
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 at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 
72. 
 
5. 
SELECTION OF STUDY POPULATION 
The target study population consists of up to 40 adult and pediatric subjects with FOP who have 
completed Study PVO-1A-201 (through Study Day 84), as well as up to 20 new adult subjects 
who were enrolled during Part B. 
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5.1 
Study Population (Adult and Pediatric Cohorts – Part B) 
As of 04 December 2019 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. 
 
5.1.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
 
1 
Completion of Study PVO-1A-201 (through Study Day 84); or Adult Cohort 
subjects not enrolled in Study PVO-1A-201, have the confirmed R206H genetic 
mutation consistent with FOP, have had at least two acute symptomatic flare-ups in 
the past 2 years but no flare-up symptoms within the past 4 weeks, including at the 
time of enrollment, have a CAJIS score of 6 to 16, inclusive, and must be able to 
receive non-flare-up-based dosing. 
2 
For the Adult Cohort, subjects under the age of 18 must have knee and hand/wrist 
radiographs confirming ≥ 90% skeletal maturity. 
3 
Written, signed, and dated subject/parent informed consent; and, for subjects who 
are minors, age-appropriate assent (this must be performed according to local 
regulations). 
 
5.1.2 
Exclusion Criteria 
1 
Simultaneous participation in another clinical research study (except for Studies 
PVO-1A-201, PVO-1A-203, or PVO-1A-001) within the 4 weeks prior to Part B Screening. 
2 
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 
Study Population for Non-Flare-up-based Treatment (Adult Cohort – Part B) 
 
5.2.1 
Inclusion Criteria 
1 
Females of child-bearing potential (FOCBP) 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 during 
treatment and for 1 month after treatment or, if sexually active, to use two highly 
effective methods of birth control during and for 1 month after treatment. 
Additionally, sexually active FOCBP subjects must already be using two highly 
effective methods of birth control 1 month before treatment is to start. Specific risks 
of the use of retinoids during pregnancy, and the agreement to remain abstinent or 
use two highly effective methods of birth control will be clearly defined in the 
informed consent, and the subject or legally authorized representative (eg, parents, 
caregivers, or legal guardians) must specifically sign this section. 
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2 
Subjects must be accessible for treatment with palovarotene and follow-up. 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. 
 
5.2.2 
Exclusion Criteria 
1 
Weight <20 kg. 
 
2 
Intercurrent known or suspected non-healed fracture at any location. 
 
3 
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. 
 
4 
Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior 
to Part B Screening (signature of the informed consent). 
5 
Concurrent treatment with tetracycline or any tetracycline derivatives due to the 
potential increased risk of pseudotumor cerebri. 
6 
History of allergy or hypersensitivity to retinoids or lactose. 
 
7 
Concomitant medications that are inhibitors or inducers of cytochrome P450 
(CYP450) 3A4 activity (see Section 5.6). 
8 
Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of 
chronic pancreatitis. 
9 
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x 
ULN. 
10 
Fasting triglycerides >400 mg/dL with or without therapy. 
 
11 
Female subjects who are breastfeeding. 
 
12 
Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, 
endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant 
disease. 
13 
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). 
5.3 
Study Population for Flare-up-based Treatment (Adult and Pediatric Cohorts – 
Part B) 
5.3.1 Inclusion Criteria 
1 
Symptomatic onset of a flare-up within 7 days before the first dose of study drug and 
defined by the presence of at least two of the following symptoms: pain, soft tissue 
swelling, decreased ROM, stiffness, redness, and warmth. Symptoms must be 
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reported by the subject, be consistent with their previous flare-ups, and include a 
subject-reported onset date, and flare-up must be confirmed by the Investigator. 
2 
Flare-up is at an appendicular area (upper or lower extremity), abdomen, chest, 
neck, or lower back; and subject has received, is receiving, or is willing to receive 
treatment per standard of care, which may or may not include prednisone (2 mg/kg 
PO to a maximum dose of 100 mg daily) for 4 days. 
3 
Females of child-bearing potential (FOCBP) 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 during 
treatment and for 1 month after treatment or, if sexually active, to use two highly 
effective methods of birth control during and for 1 month after treatment. 
Additionally, sexually active FOCBP subjects must already be using two highly 
effective methods of birth control 1 month before treatment is to start. Specific risks 
of the use of retinoids during pregnancy, and the agreement to remain abstinent or 
use two highly 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. 
4 
Subjects must be accessible for treatment with palovarotene and follow-up. 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. 
5.3.2 Exclusion Criteria 
1 
Weight <20 kg. 
 
2 
Intercurrent known or suspected non-healed fracture at any location. 
 
3 
Complete immobilization of joint at site of flare-up. 
 
4 
The inability of the subject to undergo imaging assessments using plain radiographs. 
 
5 
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. 
6 
Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior 
to Flare-up Screening (signature of the informed consent). 
7 
Concurrent treatment with tetracycline or any tetracycline derivatives due to the 
potential increased risk of pseudotumor cerebri. 
 
8 
History of allergy or hypersensitivity to retinoids or lactose. 
 
9 
Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity 
(see Section 5.6). 
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10 
Any subject with clinically significant elevations in amylase, lipase, AST, ALT, or 
fasting triglycerides during the most recent clinical laboratory assessment will 
require re-test prior to immediate flare-up-based dosing with palovarotene per the 
Investigator. If upon re-test, the laboratory value in question remains clinically 
significant abnormal, then the subject will not receive flare-up-based treatment for 
this flare-up. 
 
11 
Female subjects who are breastfeeding. 
 
12 
Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, 
endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant 
disease. 
13 
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). 
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. 
5.4 
Study Population (All Subjects – Part C) 
5.4.1 Inclusion Criteria 
Subjects must meet the following inclusion criterion to be eligible for enrollment: 
 
1 
Prior participation in Part B of the current study (PVO-1A-202). 
 
2 
Written, signed, and dated subject/parent informed consent; and, for subjects who 
are minors, age-appropriate assent (this must be performed according to local 
regulations). 
3 
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 risks 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. 
5.4.2 Exclusion Criteria 
Subjects with the following exclusion criterion will not be eligible for enrollment: 
 
1 
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. 
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2 
Currently using vitamin A or beta carotene, multivitamins containing vitamin A or 
beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, 
and unable or unwilling to discontinue use of these products during palovarotene 
treatment. 
5.5 
Study Population of Subjects Starting Non-Flare-up-based Treatment During Part C 
5.5.1 Inclusion Criteria 
Subjects must meet the following inclusion criterion to be eligible for enrollment: 
 
1 
Subjects must be accessible for treatment with palovarotene and follow-up. 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. 
 
2 
Subjects must be able to undergo low-dose WBCT scan, excluding head. 
5.5.2 Exclusion Criteria 
Subjects with the following exclusion criterion will not be eligible for enrollment: 
 
1 
Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of 
chronic pancreatitis. 
2 
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x 
ULN. 
3 
Fasting triglycerides >400 mg/dL with or without therapy. 
 
4 
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). 
5.6 
Prior and Concomitant Medications and Other Study Restrictions 
5.6.1 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.27 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 (flare-up or non-flare-
up-based): 
• Vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal 
preparations containing vitamin A or beta carotene, or fish oil are not permitted from the 
day before the start of treatment until the last day of treatment. 
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• 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) or kinase inhibitors, such as imatinib, 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. 
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. 
 
5.6.2 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, 
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, 
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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. 
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. 
5.7 
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 subject’s safety is at risk. Additional details regarding study drug dose modification 
are provided in Section 6.5. 
 
If any subject enrolled in Part D chooses to enroll in another clinical trial, all reasonable efforts 
should be made by the study personnel to have the subject continue participation in Study PVO-
1A-202 until their final EOS 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 for non-flare-up-based treatment (Table 1 and Table 2), and if 
appropriate, for flare-up-based treatment (Table 3), including those assessments subsequent to 
early termination or study drug discontinuation. 
5.8 
Replacement of Subjects 
Subjects who drop-out will not be replaced. 
 
6. 
STUDY DRUG ADMINISTRATION 
6.1 
Identity of Study Drug 
Palovarotene is a white to off-white crystalline powder with the chemical name 4-[(E)-2- 
(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic 
acid. Palovarotene is an orally bioavailable RARγ selective agonist. The structure of 
palovarotene is shown in Figure 1. 
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Figure 1 
Chemical Structure of Palovarotene 
 
6.2 
Packaging, Labeling, and Storage 
Study drug supplies provided for this study will be manufactured under Good Manufacturing 
Practices and will be suitable for human use. Palovarotene will be provided in powder-filled 
opaque hard gelatin capsules using standard USP/EP grade excipients in the following dosage 
strengths: 10, 5, 4, 3, 2.5, 2, and 1.5 mg (see Section 3.1). Capsules will be packaged in 
appropriately sized bottles designed for maximum protection. 
Study drug will be stored in a secured area at the study site with limited access. All study drug is 
to be stored at room temperature (not above 30C/86F) and protected from light and humidity. 
6.3 
Randomization and Blinding 
This is an open-label study and does not involve randomization or blinding. 
 
6.4 
Administration 
All subjects will receive non-flare-up-based treatment of 5 mg palovarotene once daily (weight-
adjusted doses for skeletally immature subjects). The first day that subjects receive non-flare-up-
based treatment will be Non-Flare-Up Day 1. Details for handling, preparing, storing, and 
discarding study drug will be provided to subjects. 
Subjects who began non-flare-up-based treatment during Part B will continue the same visit 
schedule into Part C, and will receive non-flare-up-based treatment for up to an additional 48 
months. Subjects who will start non-flare-up-based treatment during Part C will receive non-
flare-up-based treatment for up to 48 months. Subjects who cannot receive non-flare-up-based 
treatment will only undergo annual assessments (clinical laboratory tests will not be performed). 
In the event of a flare-up, these subjects will receive flare-up-based treatment and undergo all 
flare-up-based assessments, including clinical laboratory tests. 
Flare-up-based treatment can begin immediately after the Investigator confirms the presence of a 
flare-up or the presence of a substantial high-risk traumatic event likely to lead to a flare-up. 
Subjects with normal or non-clinically significant abnormal safety laboratory results observed 
within 1 month of flare-up-based treatment will not need to have laboratory tests performed at 
Flare-up Day 1. 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 monthly. For subjects receiving flare-up-based treatment, Flare-up Day 1 is defined 
as the first day that flare-up-based treatment with study drug is administered. 
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Subjects will report potential flare-up symptoms or traumatic events to site personnel, and if 
confirmed by the Investigator as associated with a flare-up or, in the case of trauma, likely to 
lead to a flare-up, subjects will immediately begin flare-up-based treatment with palovarotene 20 
mg for 4 weeks (28 days) once daily followed by palovarotene 10 mg for 8 weeks (56 days) 
once daily (or weight-based equivalent), for a total duration of 12 weeks (84 days). 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 4-week extension treatment has been completed. Flare-up dosing will be weight-
adjusted for skeletally immature (<90%) subjects (Section 3.1). 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. Should a subject experience a new 
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 equivalent]). 
Once all flare-ups or traumatic events in a cycle have resolved and flare-up-based treatment has 
been completed, subjects will resume non-flare-up-based treatment with 5 mg palovarotene once 
daily (weight-adjusted doses for skeletally immature subjects). 
The dose of study drug taken each day will be documented in the subject dosing diary. 
 
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 5 (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 
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AEs observed or reported by the subject up to the end of the reporting period or the event 
stabilizes and 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. 
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. 
 
6.6 
Study Drug Accountability 
The Investigator has the ultimate responsibility for the study drug accountability at the study 
site. The Investigator or a designated individual (eg, pharmacist or another appropriate person) 
will maintain records of the study drug’s delivery to the study site and to the subject, the 
inventory at the site (used and unused product containers), the use by each subject, and the 
return to the sponsor or alternative disposition of unused medication. The study drug must be 
kept in a locked area that is monitored for temperature at least once per day. Access to study 
drug will be restricted to authorized study personnel and used only in accordance with the 
approved protocol. At the conclusion of the study, any remaining study drug supplies will be 
returned to the sponsor or its designee. The sponsor or its designee will ensure that a final report 
of study drug accountability is prepared and maintained by the Investigator. The Investigator 
agrees not to supply or administer study drug to any person except those subjects participating in 
this study. 
6.7 
Assessment of Subject Compliance 
Compliance will be based on the amount of study drug dispensed to the subject and returned to 
the site. 
 
7. 
STUDY PROCEDURES AND ASSESSMENTS 
Under Amendment 7 and subsequent amendments, subjects with open epiphyseal growth plates 
will undergo knee and hand/wrist radiographs (AP view) at the clinical site every 6 months. 
Additional knee and hand/wrist radiograph assessments will also be performed every 3 months 
(±2 weeks) in skeletally immature subjects who (1) received flare up dosing in the period of time 
since their last assessment; and (2) had not achieved 100% skeletal maturity on their last 
assessment. These radiographic assessments will not be performed remotely unless the 
Investigator determines they can be performed at a local medical facility. A description of the 
knee and hand/wrist radiograph assessments is provided in Section 7.3.2. 
7.1 
Screening, Recruitment, and Informed Consent 
Once the PVO-1A-202 Protocol Amendment 8 is approved at the clinical site, subjects currently 
enrolled in the study will be contacted, informed about the Amendment 8 changes, and given the 
opportunity to enroll under this amendment. 
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Subjects who began non-flare-up-based treatment during Part B will continue the same visit 
schedule into Part C, and will receive non-flare-up-based treatment for up to an additional 48 
months. Subjects who started non-flare-up-based treatment during Part C will receive non-flare-
up-based treatment for up to 48 months. 
 
Part D was added for skeletally immature subjects who stopped taking study drug for any reason 
before completion of Part A/B/C.  Part D includes yearly visits for up to a 2-year follow-up 
period following last dose. Maximum length of study is 72 months. No dosing will occur during 
Part D. 
Due to the burden of travel, subjects may undergo an Institutional Review Board (IRB)-
approved remote consent/assent process that will include a discussion with the site 
representative of the study requirements and risks. Signed consents will be emailed or faxed 
between site and subjects. Potential subjects/parents wishing to participate must sign the 
informed consent/assent per local requirements prior to undergoing any study-related 
procedures. Remote consent/assent will 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-202 Amendment 7, 
Investigators, in consultation with their site IRB/IEC, 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, Table 3, and Table 4, 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 and Flare-Up Assessment 
There will be no new subjects in Part C and a repeat medical history is not necessary. 
 
For subjects receiving flare-up-based treatment, the flare-up assessment will include subject-
reported current flare-up location, symptoms, and probable causes, documented on 
Flare-up Day 1. This will be recorded for each flare-up and intercurrent flare-up within a cycle. 
 
7.2.2 
Physical Examination 
For subjects from Part B continuing non-flare-up-based treatment into Part C, a physical 
examination of all body systems is to be documented at Months 12, 24, 36, 48, 60, and 72. 
For subjects from Part B starting non-flare-up-based treatment during Part C, a physical 
examination of all body systems is to be documented at Part C Screening and at Months 6, 12, 
24, 36, and 48. 
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For subjects in Part D, a physical examination of all body systems is to be documented at Year 1 
and Year 2 post last dose of study treatment. 
 
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 AEs. 
 
7.2.3 
Body Weight and Linear Growth Assessments 
For subjects from Part B continuing non-flare-up-based treatment into Part C, body weight will 
be documented every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 
51, 
54, 57, 60, 63, 66, 69 and 72). 
 
For subjects from Part B starting non-flare-up-based treatment during Part C, body weight will be 
documented at Part C Screening and every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 
33, 
36, 39, 42, 45 and 48). 
For subjects receiving flare-up-based treatment, body weight will 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 from Part B continuing non-flare-up-based treatment into Part C with open epiphyseal 
growth plates at the most recent assessment will have linear growth assessments (in triplicate) by 
stadiometer and knee height measurements (in triplicate) at Months 6, 12, 18, 24, 30, 36, 42, 48, 
54, 60, 66 and 72. 
 
Subjects from Part B starting non-flare-up-based treatment during Part C that are under the age 
of 18 years and who enrolled with open epiphyseal growth plates at the most recent assessment 
will have linear growth assessments (in triplicate) by stadiometer and knee height measurements 
(in triplicate) at Screening. Subjects with open epiphyseal growth plates will also be evaluated at 
Months 6, 12, 18, 24, 30, 36, 42, and 48. 
For subjects in Part D, body weight will be documented at Year 1 and Year 2 post last dose of 
study treatment. Subjects in Part D will have linear growth assessments (in triplicate) by 
stadiometer and knee height measurements (in triplicate) at Year 1 and Year 2 post last dose of 
study treatment. 
 
Once a subject is 18 years old, triplicate linear growth and knee height assessments will no 
longer be required. In Part D subjects will stop participation once they reach 18 years of age.  
Linear growth measurements will be performed by trained and qualified study personnel. The 
stadiometric measurement instructions will include practices that reduce measurement error 
including calibration of equipment, proper subject positioning, and measurement capture. 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. 
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7.2.4 
Vital Signs 
Vital signs (temperature, respiratory rate, blood pressure, and heart rate) will be assessed for all 
subjects. 
For subjects from Part B continuing non-flare-up-based treatment into Part C, vital signs 
(temperature, respiratory rate, blood pressure, and heart rate) will be assessed every 3 months 
(Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, and 
72). 
 
For subjects from Part B starting non-flare-up-based treatment during Part C, vital signs will be 
assessed at Part C Screening and every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 
36, 39, 42, 45 and 48). 
 
For subjects receiving flare-up-based treatment, vital signs will be assessed 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. 
 
For subjects in Part D, vital signs will be assessed at Year 1 and Year 2 post last dose of study 
treatment. 
 
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. 
7.2.5 
Electrocardiogram 
For subjects from Part B continuing non-flare-up-based treatment into Part C, a 12-lead 
electrocardiogram (ECG) will be performed at Months 12, 24, 36, 48, 60, and 72. 
For subjects from Part B starting non-flare-up-based treatment during Part C, an ECG will be 
performed at Part C Screening and at Months 6, 12, 24, 36 and 48. 
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. 
 
7.2.6 
Clinical Laboratory Tests 
Blood and urine samples will be collected for hematology, biochemistry (includes lipids), and 
urinalysis testing. 
For subjects from Part B continuing non-flare-up-based treatment into Part C, blood and urine 
samples will be collected every 6 months (Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 
72). 
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For subjects from Part B starting non-flare-up-based treatment during Part C, blood and urine 
samples will be collected at Part C Screening and every 6 months (Months 6, 12, 18, 24, 30, 36, 
42 and 48). 
 
For subjects receiving flare-up-based treatment, 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 safety laboratory results observed within 1 month 
of flare-up-based treatment will not need to have laboratory tests performed at Flare-up Day 1. 
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 monthly 
during non-flare-up-based 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 urinalysis results are abnormal, a microscopic 
evaluation will be completed. If results are needed promptly (eg, Screening for eligibility), 
analysis of samples can be completed at a local, qualified laboratory. 
The total blood volume drawn from a subject from Part B continuing non-flare-up-based 
treatment into Part C over the course of the entire study (up to 72 months) will range from 
approximately 60 mL (in the case of no flare-ups) to 170 mL (in the case of two expected flare-
ups treated per year, or a total of 12 flare-ups treated during the entire study). The total blood 
volume drawn from a subject from Part B starting non-flare-up-based treatment during Part C 
over the course of the entire study (up to 48 months) will range from approximately 42 mL (in 
the case of no flare-ups) to 120 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 and to determine if any laboratory value meets the safety 
monitoring/stopping rules outlined in the protocol (Section 7.3, Special Safety Assessments). 
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 by the home clinician, the subject/caregiver, 
the central laboratory, or the local laboratory facility about any protocol-specified safety 
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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 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. Every reasonable attempt should be made to adhere to 
the safety assessments specified in the protocol. The Investigator/designee should discuss with 
the home nursing team, subject, laboratory, and/or phlebotomy team, as applicable, to determine 
why assessments were not able to be performed successfully, or are missing, delayed, or 
unreportable and to identify methods to mitigate recurrence. 
If a local laboratory is utilized, the investigative site should notify the study team if the local 
laboratory cannot test all the analytes listed in Table 6. If the total thyroxine (Total T4), free T4, 
uric acid, gamma glutamyl transferase, inorganic phosphorous, very low-density lipoprotein, or 
globulin parameters are not available through the local laboratory, and alternative arrangements 
cannot be made, testing of these analytes may be omitted provided other subject-assessments of 
thyroid function (ie, thyroid-stimulating hormone), lipid metabolism (ie, triglycerides, 
low-density lipoprotein, high-density lipoprotein, and total cholesterol), and protein metabolism 
(ie, total protein and albumin) are available and confirmed to be stable as per the Investigator. 
Alternative arrangements to test the listed analytes are to be made if the Investigator, Medical 
Monitor, or sponsor determines that they have the potential to impact subject safety. In the event 
the local laboratory is unable to test any other analytes, they may be omitted in exceptional 
circumstances after consultation with the sponsor. Such exceptions will not be applied to any of 
the key safety analytes, as outlined below and in the clinical safety laboratory manual. 
For subjects with two or more consecutive missing assessments of key safety laboratory 
analytes, including triglycerides, ALT, AST, bilirubin, lipase, and amylase (as outlined in 
Section 7.3, Special Safety Assessments), blood collection for evaluation of missing analytes 
should be performed as soon as possible. If such analytes have not been evaluated over a 
prolonged period of time (>6 months during chronic treatment or >8 weeks during flare-up 
treatment), a successful repeat assessment should be performed within 1 month. If key safety 
laboratory tests cannot be evaluated within 1 month, the subject should be discussed with the 
Medical Monitor and the EC/IRB, as necessary. If the subject is unable to have venous 
specimens collected, use of microliter collection techniques and capillary specimens, where 
available, may be utilized to assess subject safety. Local laboratory results should be promptly 
documented in the appropriate eCRF. 
Table 6 presents the clinical laboratory parameters that will be assessed in this study. 
 
Table 6. 
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 
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Calcium 
Total thyroxine (T4) 
Inorganic phosphorous 
Free T4 
Glucose 
Thyroid-stimulating hormone 
Total bilirubin 
Amylase 
Total proteins 
Lipase 
Albumin 
 
Lipid Profile 
 
Triglycerides  
High-density lipoprotein (HDL) Low-density lipoprotein (LDL) 
Total cholesterol 
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 in Part A, B and C. 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 measures (females and males) every 3 months. 
7.2.8 
Adverse Events 
Adverse event monitoring will be conducted throughout the study for all subjects. Adverse 
events will be assessed at every site and remote visit during both non-flare-up-based and flare-
up-based treatment. The AE reporting period begins at the time of informed consent and 
continues through study completion. The SAE (including deaths) reporting period begins at the 
time of informed consent and continues through 30 days after study completion. 
The Investigator will follow-up on all AEs observed or reported by the subject up to the end of 
the reporting period or until the events stabilize and follow-up is no longer necessary. The 
Investigator will follow-up on SAEs until they are considered resolved or 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 
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events must be reported within 24 hours as described in Section 9.1.8. 
7.2.9 
Concomitant Medications 
Concomitant medications will be assessed at every site and remote visit during both non-flare-
up-based, flare-up-based treatment and in Part D. 
See Section 5.6 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 every 3 months using 
the age-appropriate C-SSRS and at all visits during the Flare-up Cycle Safety Assessments (see 
Appendix 5A). 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. Study personnel administering the questionnaire 
will receive formal training to ensure accuracy and consistency in application of the instrument. 
For subjects from Part B continuing non-flare-up-based treatment into Part C, assessment using 
the C-SSRS will occur every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 
45, 
48, 51, 54, 57, 60, 63, 66, 69 and 72). 
 
For subjects from Part B starting non-flare-up-based treatment during Part C, assessment using 
the C-SSRS will occur at Part C Screening and every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 
24, 
27, 30, 33, 36, 39, 42, 45 and 48). Any subject reporting a type 4 or 5 suicidal ideation or any 
suicidal behavior within 1 month prior to Part C Screening will not be eligible to receive study 
drug. 
Any subject experiencing a type 4 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, all subjects 
at the time of enrollment into Study PVO-1A-202 with open epiphyseal growth plates at 
Screening had knee (AP view) and hand/wrist (PA view) radiographs. 
For subjects from Part B continuing non-flare-up-based treatment into Part C with open  
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epiphyseal growth plates at the most recent assessment, knee (AP view, preferable on the left 
side) and hand/wrist (PA view, preferable on the left side) radiographs will be performed at the 
clinical site at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72. 
 
For subjects from Part B starting non-flare-up-based treatment during Part C with open 
epiphyseal growth plates at the most recent assessment, knee (AP view, preferable on the left 
side) and hand/wrist (PA view, preferable on the left side) radiographs will be performed at Part 
C Screening. Subjects for whom radiographs were performed within the last 3 months will 
not need to repeat radiographs at Screening. Subjects with open epiphyseal growth plates at this 
assessment will also be evaluated at Months 6, 12, 18, 24, 30, 36, 42 and 48 at the clinical site. 
Subjects who are skeletally immature at the time of study drug discontinuation and entering Part 
D (Y1 and Y2 post last dose of study treatment) will have follow-up knee (AP view) and 
hand/wrist radiographs (PA view, preferably on the left side) every year.  
Additional knee and hand/wrist radiograph assessments will also be performed every 3 months 
(±2 weeks) in skeletally immature subjects who (1) received flare-up dosing in the period of 
time since their last assessment; and (2) had not achieved 100% skeletal maturity on their last 
assessment. The 3-month radiographic assessments will be performed at the clinical site unless 
the Investigator determines they can be performed at a local medical facility. 
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. Limb/joint AEs in these subjects will be 
evaluated by clinical and radiographic assessments deemed appropriate by the Investigator. 
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 in Section 7.3.2, WBCT scans acquired from subjects under the age of 18 
years 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. 
Safety findings of these bone images may trigger additional follow-up images and/or dose 
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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 (see Section 7.2.6) 
for all subjects in Part C. 
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 (see Section 7.2.6) for all 
subjects in Part C. 
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. 
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Liver toxicity evaluation will follow the Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation (July 2009). 
7.3.7 
Lipase/Amylase 
Amylase and lipase will be monitored as part of the biochemistry testing (see Section 7.2.6) for 
all subjects in Part C. 
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 
Impaired hearing has been reported in subjects taking retinoids. 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) will be discontinued from treatment. 
 
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 
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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. 
 
7.4 
Efficacy Assessments 
Subjects who began non-flare-up-based treatment during Part B will continue the same visit 
schedule into Part C, and will receive non-flare-up-based treatment for up to an additional 48 
months. Therefore, these subjects may undergo non-flare-up-based treatment for up to 72 
months over the entire study. Subjects who will start non-flare-up-based treatment during Part C 
will receive non-flare-up-based treatment for up to 48 months. 
7.4.1 
Low-Dose Whole Body Computed Tomography 
For subjects from Part B continuing non-flare-up-based treatment into Part C, a low-dose WBCT 
scan (excluding head) will be performed during annual site visits at Months 12, 24, 36, 48, 60 
and 72. 
For subjects from Part B starting non-flare-up-based treatment during Part C, a low-dose WBCT 
scan (excluding head) will be performed at Part C Screening and during annual site visits at 
Months 12, 24, 36 and 48. 
For subjects in Part D, a low-dose WBCT scan (excluding head) will be performed during 
annual site visits at Y1 and Y2 post last dose of study treatment. 
Interpretation of the CT scan will document the absence or presence of HO across various body 
regions, volume of total body HO, and presence and volume of new HO at follow-up visits. 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 
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subject/parent before any other procedures are completed on those visit days. 
For subjects from Part B continuing non-flare-up-based treatment into Part C, age-appropriate 
forms of the FOP-PFQ will be administered every 6 months (Months 6, 12, 18, 24, 30, 36, 42, 
48, 54, 60, 66 and 72). 
 
For subjects from Part B starting non-flare-up-based treatment during Part C, age-appropriate 
forms of the FOP-PFQ will be administered at Part C Screening and every 6 months (Months 6, 
12, 18, 24, 30, 36, 42 and 48). 
To evaluate the effect of palovarotene on physical function, age-appropriate forms of the FOP-
PFQ will be administered. The adult form of the FOP-PFQ will be completed by subjects 15 
years of age and older (see Appendix 2A). Two 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 and a proxy-completed form developed for 5- to 14-year-olds (see Appendix 2B and 
Appendix 2C, 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. 
7.4.3 
PROMIS Global Health Scale 
For subjects from Part B continuing non-flare-up-based treatment into Part C, age-appropriate 
forms of the PROMIS Global Health Scale will be administered every 6 months (Months 6, 12, 
18, 24, 30, 36, 42, 48, 54, 60, 66 and 72). 
 
For subjects from Part B starting non-flare-up-based treatment during Part C, age-appropriate 
forms of the PROMIS Global Health Scale will be administered at Part C Screening and every 6 
months (Months 6, 12, 18, 24, 30, 36, 42 and 48). 
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. The adult form of the PROMIS Global Health Scale will be 
administered to subjects 15 years of age and older (see Appendix 7A). 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 7B and Appendix 7C, 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 
For subjects from Part B continuing non-flare-up-based treatment into Part C, CAJIS will be 
administered every 6 months (Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72). 
For subjects from Part B starting non-flare-up-based treatment during Part C, CAJIS will be 
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administered at Part C Screening and every 6 months (Months 6, 12, 18, 24, 30, 36, 42 and 48). 
Range of motion will be assessed by the Investigator using CAJIS (see Appendix 1). The CAJIS 
should be assessed by the same Investigator at each time point. The CAJIS assessment may be 
performed remotely or by videoconferencing. 
7.5 
Pharmacokinetics 
The PK of palovarotene dosing will be assessed in all subjects during non-flare-up and flare-up-
based treatments. 
During non-flare-up palovarotene treatment, PK blood samples will be collected at the first 3-
month safety assessment. If blood samples cannot be or were not obtained during the first 
3-month safety assessment, or if the subject is on flare-up-based treatment, then the non-flare-up 
treatment PK blood sample can be obtained during any subsequent 3-month safety visit. 
Pharmacokinetics of palovarotene dosing 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, PK blood samples can be obtained 
during any subsequent flare-up dosing cycle. 
Pharmacokinetic blood samples will be collected at pre-dose and 3, 6, 10, and 24 hours post-
dose. Subjects who underwent a PK assessment for flare-up-based treatment under 
PVO-1A-202 Protocol Amendment 3 will not have flare-up PK assessed again. However, these 
subjects will require a non-flare-up treatment PK assessed at a 3-month safety visit. 
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 blood 
sampling days will be recorded. 
Detailed instructions for collection, storage, labeling, and shipment of all samples will be 
provided in the Laboratory Manual. 
7.6 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will 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 
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will be developed by the Chairperson in collaboration with the sponsor and will be documented 
in the DMC Charter. 
7.7 
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-202 during the COVID-19 
pandemic and 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 C EOT/EOS and be invited to participate in Part D and 
undergo assessments outlined in Table 4. 
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):  
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 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 drug 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 
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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 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) 
 
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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, 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 documented in accordance with local regulations/EC requests and 
guidance. All contacts with subjects must be filed in the source records. 
 
A risk mitigation assessment will be performed for each subject at the site in order to determine 
how their participation may be impacted.  Sites must ensure that appropriate measures are 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 and sites to adequately monitor subject safety. 
 
8. 
STATISTICAL AND ANALYTICAL PLANS 
This study is intended to assess whether a non-flare-up-based dosing regimen, combined with 
higher doses during times of flare-ups, will result in a lower incidence of new HO formation. As 
this is an open-label study with no comparator arm, use of subject data from Study PVO-1A-001 
(Natural History Study [NHS]) will form the basis for a control arm. Additional analysis of the 
flare-up-based treatment regimen will be described in the Statistical Analysis Plan (SAP). 
A summary of the general methods and strategies for analysis is provided in the sections below. 
A more comprehensive SAP will be written that will describe the manner in which the analysis 
will be performed. 
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8.1 
General Methods 
For purposes of assessing the efficacy of the non-flare-up-based dosing regimen, low-dose 
WBCT imaging data from Part B (after Amendment 3) and Part C will be combined. 
8.2 
Sample Size 
The new HO volume data as assessed by low-dose WBCT scan, excluding head, from Part B 
(after Amendment 3) and Part C will be combined. The sample size was fixed by the number of 
subjects enrolled in Part B and was not based on power calculations. 
8.3 
Study Populations 
The following populations will be analyzed under Amendment 4 and subsequent amendments: 
 
• The Full Analysis Set (FAS) includes all enrolled subjects having a baseline HO volume 
measurement and at least one post-baseline HO volume measurement in the PVO-1A-202 
study. For efficacy comparisons to the NHS, the FAS will also include subjects enrolled 
in the NHS with available baseline and at least one post-baseline HO volume 
measurements. 
• The Per-Protocol Set (PPS) is a subset of the 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 PPS will also include subjects in the NHS with available 
baseline and at least one post-baseline HO volume measurements and with no major 
protocol deviations that are expected to interfere with assessments of the primary 
endpoint. 
• The Safety Analysis Set (SAS) includes all enrolled subjects receiving at least one dose 
of palovarotene in the PVO-1A-202 (after Amendment 3). For safety comparisons to the 
NHS, the SAS will also include subjects enrolled in the NHS with available post-baseline 
follow-up. 
• The Pharmacokinetic Analysis Set (PAS) is a subset of the SAS including subjects with 
evaluable pharmacokinetics data. 
8.4 
Baseline and Disease Characteristics (including Medical History) 
Baseline and disease characteristics will be tabulated descriptively (eg, number and percentage 
of subjects for each category for categorical parameters, and the number, mean, standard 
deviation, and range for continuous parameters). 
 
8.5 
Subject Disposition 
Subject disposition will be listed and summarized. 
 
8.6 
Extent of Exposure 
The extent (duration) of exposure will be determined from the date of first dose of study drug 
through the date of last dose of study drug. For times during which subjects are receiving 
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flare-up-based treatment, tabulation of the number of days at the higher dose(s) will be 
presented. An assessment of the proportion of subjects who are able to tolerate the higher doses 
will be performed. 
 
8.7 
Efficacy 
 
8.7.1 
Primary Efficacy 
The primary efficacy endpoint is the annualized change in new HO volume (as assessed by 
low-dose WBCT scan, excluding head). The primary efficacy analysis comparing the annualized 
change in new HO volume between subjects treated with palovarotene and untreated subjects 
from the NHS will be conducted using a weighted linear mixed effects (wLME) model. 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 the NHS and the current trial. 
Baseline HO volume divided by age will be the only covariate included in the model.  As HO 
volume is non-decreasing, the LME model will be fit 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. 
The estimated difference in the annualized change in new HO volume between subjects treated 
with palovarotene and untreated subjects and its associated Wald statistic will be used for 
hypothesis testing. Hypothesis testing will be performed using a two-sided, type I error rate of 
5%. 
8.7.2 
Secondary Efficacy 
Secondary efficacy variables for non-flare-up-based treatment will include the following: 
percent of subjects with new HO, change from baseline in ROM as assessed by CAJIS, change 
from baseline in physical function using age appropriate forms of the FOP-PFQ, and 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. 
The secondary efficacy endpoints will be summarized by visit and, where applicable, compared 
to the relevant time point from the NHS. 
8.8 
Safety 
The safety analysis will be descriptive in nature. Safety evaluations will include AE and SAE 
reporting, ECGs (for subjects receiving treatment), 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. 
Evaluation of subjects with open epiphyseal growth plates at the most recent assessment will 
include knee (AP view) and hand/wrist (PA view) radiographs for assessment of epiphyseal 
growth plate; and standardized stadiometry and knee height (in triplicate) for assessment of 
linear growth. Any limb/joint AEs reported by these subjects will be evaluated by clinical and 
radiographic assessments as deemed appropriate by the Investigator. 
 
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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. 
8.8.1 
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, 14 June 2010. 
Tabulations will include an overall incidence of at least one AE, incidence within body system, 
and incidence by preferred term. 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. 
 
8.8.2 
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 (see Appendix 5A). 
8.8.3 
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 non-flare-up-based 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. 
8.9 
Pharmacokinetics 
Plasma palovarotene concentrations will be summarized for the PAS population by descriptive 
statistics of n, arithmetic mean, standard deviation (SD), coefficient of variance, geometric 
mean, median, minimum, and maximum. 
 
8.10 
Pharmacodynamics 
Exploratory analyses will be performed to assess potential exposure relationships. 
 
 
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9. 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS    
9.1 
Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting 
 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product during the course of a study and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal product. 
Disease, signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the 
product are not considered AEs after administration of the study product unless they reoccur 
after the subject has recovered from the pre-existing condition or they represent an exacerbation 
in intensity or frequency. 
 
Only a clinically significant laboratory test abnormality, physical examination finding, or other 
objective finding should be reported as an AE, whether it represents an exacerbation or a new 
abnormality. 
 
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). 
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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. 
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. 
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9.1.6 
Action Taken With Study Drug 
The action taken to remedy the reported/observed AEs will be defined as follows: 
 
1 
None 
 
2 
Study drug dosage modified 
 
3 
Study drug dosage interrupted 
 
4 
Study drug permanently discontinued 
 
9.1.7 
Outcome of Adverse Event 
The outcome of the AEs will be recorded as follows: 
 
1 
Event resolved with no sequelae 
 
2 
Event resolved with sequelae 
 
3 
Event ongoing 
 
4 
Death 
 
9.1.8 
Reporting of Serious Adverse Event 
All SAEs must be reported within 24 hours to the Medpace Clinical Safety Group: 
 
Medpace SAE hotline – USA: 
Tel: 1.800.730.5779, ext. 2999 or 1.513.579.9911, ext. 2999 
Fax: 1.866.336.5320 
E-mail: safetynotification@medpace.com 
 
Medpace SAE hotline – Europe: 
Tel: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
E-mail: medpace-safetynotification@medpace.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. 
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The Investigator will notify the 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. 
 
9.1.10 
Follow-Up of Adverse Events and Serious Adverse Events 
The AE reporting period for the non-flare-up-based treatment and the flare-up-based treatment 
begins at the time of informed consent and continues through study completion, The SAE, 
including death, reporting period for the non-flare-up-based treatment and the flare-up-based 
treatment begins at the time of informed consent and continues through study completion 
(including Part D) + 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 the event 
stabilizes and 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. 
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. 
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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 8), inclusive of any 
subsequent amendment(s), and that are consistent with the International Council for 
Harmonisation (ICH) Good Clinical Practices (GCP), EU Directive 2001/20/EC, 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 
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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. 
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 
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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. 
• 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 
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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. 
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 
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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 Primary Investigators with 
their agreement. The Coordinating Investigator will approve the final clinical study report for 
Study PVO-1A-202. 
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10. 
INVESTIGATOR AGREEMENT 
I have read Protocol PVO-1A-202 Amendment 8, dated 30 November 2020: 
 
A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RARγ-
Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in 
Subjects with Fibrodysplasia Ossificans Progressiva (FOP). 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines 
for Good Clinical Practices and applicable regulatory requirements and to inform all 
who assist me in the conduct of this study of their responsibilities and obligations. 
 
 
 
 
 
 
 
 
Investigator (printed name) 
 
 
 
 
 
 
 
 
Investigator signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational site or name of institution and location (printed) 
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11. 
REFERENCES 
 
1. 
Lilijesthrom M, Bogard B. The Global Known FOP Population. In: FOP Drug Development 
Forum. Boston, MA; 2016. 
 
2. 
Shore EM, Feldman GJ, Xu M, Kaplan FS. The genetics of fibrodysplasia ossificans 
progressiva. Clin Rev Bone Miner Metab. 2005;3(3-4):201–204. 
 
3. 
Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic 
errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005;116(5):e654-661. 
doi:10.1542/peds.2005-0469 
 
4. 
Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. 
Orphanet J Rare Dis. 2011;6(80). doi:10.1186/1750-1172-6-80 
 
5. 
Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. The clinical features and 
natural history of 34 patients. J Bone Joint Surg Br. 1982;64(1):76-83. 
 
6. 
Kaplan F, Glaser D. Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans 
progressiva. 
Clin Rev Bone Miner Metab. 2005;3(3-4):213-216. doi:10.1385/BMM:3:3-4:213 
 
7. 
Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM. Early mortality and 
cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg 
Am. 2010;92(3):686-691. doi:10.2106/JBJS.I.00705 
 
8. 
Kaplan FS, Tabas JA, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of 
fibrodysplasia ossificans progressiva. An endochondral process. J Bone Joint Surg Am. 
1993;75(2):220-230. 
 
9. 
Kaplan FS, Le Merrer M, Glaser DL, et al. Fibrodysplasia ossificans progressiva. Best 
Pract Res Clin Rheumatol. 2008;22(1). doi:10.1016/j.berh.2007.11.007 
 
10. Glaser DL, Rocke DM, Kaplan FS. Catastrophic falls in patients who have 
fibrodysplasia ossificans progressiva. Clin Orthop. 1998;(346):110-116. 
 
11. Kaplan FS, Pignolo RJ, Shore EM. From mysteries to medicines: drug development for 
fibrodysplasia ossificans progressiva. Expert Opin Orphan Drugs. 2013;1(8):637-649. 
doi:10.1517/21678707.2013.825208 
 
12. Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nat Med. 
2011;17(4):420-421. doi:10.1038/nm0411-420 
 
13. Shimono K, Tung W-E, Macolino C, et al. Potent inhibition of heterotopic ossification by 
nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011;17(4):454-460. 
doi:10.1038/nm.2334 
 
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. Weston AD, Chandraratna RAS, Torchia J, Underhill TM. Requirement for RAR-mediated gene 
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repression in skeletal progenitor differentiation. J Cell Biol. 2002;158(1):39-51. 
doi:10.1083/jcb.200112029 
 
17. Weston AD, Blumberg B, Underhill TM. Active repression by unliganded retinoid receptors in 
development: less is sometimes more. J Cell Biol. 2003;161(2):223-228. 
doi:10.1083/jcb.200211117 
 
18. 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 
 
19. 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 
 
20. 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 
 
21. 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 
 
22. 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. 
 
23. 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. 
 
24. 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 
 
25. 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 
 
26. 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 
 
27. The International Consortium on Fibrodysplasia Ossificans Progressiva. The medical 
management of fibrodysplasia ossificans progressiva: current treatment considerations. Kaplan 
F., Shore EM, Pignolo RJ, eds. Clin Proc Int Consort FOP. 2011;4:1-100. 
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12. 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 3. CYP450 3A4 Strong Inducers or Inhibitors: Exclusionary Medications 
 
INDUCERS 
Half-life 
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 c 
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 
NA 
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: 
 
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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 7A. PROMIS Global Health Scale 
(Self-Completed for Subjects Age 15 Years and Older) 
 
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Appendix 7B. PROMIS Pediatric Global Health Scale 
(Self-Completed for Subjects Ages 8 to 14 Years) 
 
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Appendix 7C. PROMIS Pediatric Global Health Scale 
(Proxy-Completed for Subjects Ages Less Than 15 Years) 
 
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Appendix 8. Declaration of Helsinki 
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PROTOCOL AMENDMENT SUMMARY 
 
This sixth amendment to the protocol for Study PVO-1A-204 was finalized on 18 December 
2020. 
 
Location/Section Number 
Change 
Rationale 
Major changes that affected the clinical conduct of the study: 
Protocol Synopsis 
References to Parts B/C/D are to PVO-
1A-202 Parts B/C/D which 
corresponds to PVO-1A-204, ongoing 
in France. 
 
Part D was added for skeletally 
immature subjects who stopped taking 
study medication for any reason before 
completion of Part A/B/C.  Part D 
includes yearly visits for up to a 2-year 
follow-up period following last dose. 
No dosing will occur during Part D.  
Assessments obtained in Part D 
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 (AEs), and concomitant 
medications. 
Participation in Part D will continue as 
long as subjects remain skeletally 
immature. 
The up to 2-year period would begin 
the last day the subject stopped 
receiving study drug in Part A/B/C. 
The total duration of participation, in 
Part C and Part D, is a maximum of 4 
years.  
Secondary objective added for Part D 
to monitor longer-term safety in 
skeletally immature subjects off 
treatment.  
Safety will be summarized for Part D.  
To implement safety measures 
based on DMC recommendations. 
Preliminary data suggest that the 
risk of premature epiphyseal 
fusion is higher in subjects with 
open epiphyseal growth plates 
who have received the flare-up 
dosing regimen. Decreasing the 
interval between radiographic 
assessments will allow earlier 
detection of potential growth plate 
abnormalities in skeletally 
immature subjects treated with the 
palovarotene flare-up dosing 
regimen. A 2-year follow up is an 
adequate timeframe to assess 
growth and epiphyseal changes 
off palovarotene treatment. 
 
 
 
 
 
Tables 1, 2 and 4 
Section 3.1 Overview of Study 
Design 
Part D is also mentioned in 
1.1.3.2.2, 3.2, 5.7, 9.1.10 
Section 1.1.3.2.2  Palovarotene 
Phase 2 Interventional Studies 
Section 2.3 Secondary Objectives 
Section 3.2 Study Rationale 
Section 5.7 Subject Withdrawal or 
Early Termination from the Study
Section 7.2.2 Physical 
Examination 
Section 7.2.3 Body Weight and 
Linear Growth 
Section 7.2.4 Vital Sign 
Section 7.2.9 Concomitant 
Medications 
Section 7.3.2 Knee and 
Hand/Wrist Radiographs 
Section 7.4.1 Low-dose Whole 
Body Computed Tomography 
Section 9.1.10 Follow-up of 
Adverse Events and Serious 
Adverse Events 
 
 
Protocol Synopsis 
Tables 1 and 2 
Sections 2.3  Secondary 
Objectives  
Section 3.1 Overview of Study 
Design 
Section 4.2 Secondary Endpoints 
Section 7.1 Screening, 
Recruitment, and Informed 
Consent 
References to Parts B/C/D are to PVO-
1A-202 Parts B/C/D which 
corresponds to PVO-1A-204, ongoing 
in France. 
 
In Part C, subjects may continue on the 
study for up to an additional 12 
months. 
 
To allow for provision of study 
medication until commercial 
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Location/Section Number 
Change 
Rationale 
Section 7.2.2 Physical 
Examination 
Section 7.2.3 Body Weight and 
Linear Growth 
Section 7.2.4 Vital Signs 
Section 7.2.5 Electrocardiogram 
Section 7.2.6 Clinical Laboratory 
Test 
Section 7.3.1 Columbia-Suicide 
Severity Rating Scale 
Section 7.3.2 Knee and 
Hand/Wrist Radiographs 
Section 7.4 Efficacy Assessments 
Section 7.4.1 Low-dose Whole 
Body Computed Tomography 
Section 7.4.2 FOP-Physical 
Function Questionnaire 
Section 7.4.3 PROMIS Global 
Health Scale 
Section 7.4.4 Cumulative 
Analogue Joint Involvement Scale
Synopsis 
Section 3.1 Overview of Study 
Design 
Section 3.2 Study Rationale 
Section 5.1 Study Population 
(Adult and Pediatric Cohorts – 
Original Protocol and Amendment 
1) 
Section 6.4 Administration 
Section 7.1 Screening, 
Recruitment, and Informed 
Consent 
 
 
 
 
 
 
 
 
As of 04 December 2019, 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 D 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 
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 
palovarotene on bone mineral 
accrual. As such assessments were 
added to further characterize this 
risk in FOP subjects. 
Section 7.1 Screening, 
Recruitment, and Informed 
Consent 
Integrated protocol amendment 5 
addendum previously created to 
describe temporary measures applied 
during the COVID pandemic. 
To integrate protocol amendment 
5 for addendum. To assess 
years re-initiating treatment in 




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Location/Section Number 
Change 
Rationale 
assessment/procedure of low-dose 
WBCT scan, excluding head.  
 
Table 2  
Deleted the reference to footnote 14 for 
the assessment/procedure of Low-dose 
WBCT scan, excluding head. 
Integration of administrative 
change from PVO-1A-204 
Protocol Amendment 5 
Addendum #2. 
General 
Corrected minor errors and formatting 
irregularities. 
To provide a consistent 
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PROTOCOL SYNOPSIS 
Title 
A Phase 2, Open-Label, Efficacy and Safety Study of an 
-Specific Agonist 
(Palovarotene) to Prevent Heterotopic Ossification in Subjects with Fibrodysplasia 
Ossificans Progressiva (FOP). 
Sponsor 
Clementia Pharmaceuticals Inc. 
Objectives 
Primary Objective 
 
To evaluate the safety and efficacy of different palovarotene dosing regimens 
in subjects with FOP. Efficacy will be based on the ability of palovarotene to 
prevent the formation of new heterotopic ossification (HO) as assessed by 
low-dose whole body computed tomography (WBCT) scan, excluding head.
Secondary Objectives 
 
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 (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 D) 
 
To implement safety measures based on the Data Monitoring Committee 
(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 2, single-center, open-label study that will explore different dosing 
regimens of palovarotene in adult and pediatric subjects with FOP. References to 
Parts B/C/D are to PVO-1A-202 Parts B/C/D which corresponds to PVO-1A-204, 
ongoing in France. 
 
Under the original protocol and Amendment 1, subjects who successfully 
completed Study PVO-1A-201 as well as up to two new adult subjects were 
followed for up to 24 months. 
Subjects who participated under Amendment 1 will be followed for up to an 
additional 48 months. No new subjects will be enrolled. 
 
Non-Flare-up Based Treatment 
All subjects will receive non-flare-up based treatment of 5 mg palovarotene once 
daily (weight-adjusted doses for skeletally immature subjects [see table below and 
Table 5]). Note: all weight-based dosing, both non-flare-up-based and flare-up, will 
cease when subjects become skeletally mature, but radiographic assessment of the 
growth plate (performed every 6 months) will continue until these subjects achieve 
100% skeletal maturity as defined as growth plate closure at both knee and 
hand/wrist locations. 
Additional radiographic assessments will be performed every 3 months 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% skeletal maturity 
on their last radiographic assessment. 
Subjects will follow all assessments as outlined in Table 1, Table 2 and Table 3. 
Subjects who cannot receive non-flare-up based treatment will only undergo annual 
assessments (clinical laboratory tests will not be performed). In the event of a 
flare-up, these subjects will receive flare-up-based treatment and undergo all flare-
up based assessments, including clinical laboratory tests and radiographs if they 
have not reached 100% skeletal maturity. 
 


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18 December 2020 
Study Design (cont.) 
Subjects from Amendment 1 Continuing Non-Flare-Up Based Treatment 
Subjects who began non-flare-up based treatment prior to this amendment will 
continue the same visit schedule, and will receive non-flare-up based treatment for 
up to an additional 48 months. Therefore, these subjects may undergo non-flare-up 
based treatment for up to 72 months over the entire study. 
Subjects continuing Amendment 3 (dated 22 March 2018) and subsequent 
amendments will follow all procedures and undergo all assessments as specified in 
the Schedule of Assessments in Table 1, including low-dose WBCT scan 
(excluding head) at all annual site visits (Months 12, 24, 36, 48, 60 and 72). Non-
flare-up Day 1 is the first day that non-flare-up based treatment was initiated prior 
to Amendment 2, and total duration of treatment will continue under Amendment 3 
and subsequent amendments. 
Remote visits (eg, at home or at a local medical facility; and via telephone contact 
from clinical site personnel) will occur every 3 months unless the Investigator 
deems that a site visit is necessary; urine pregnancy tests will be performed each 
month for females of childbearing potential (FOCBP). 
Subjects from Amendment 1 Starting Non-Flare-Up Based Treatment 
Subjects who will start non-flare-up based treatment will receive non-flare-up based 
treatment for up to 48 months. These subjects will follow all procedures and 
undergo all assessments as specified in the Schedule of Assessments in Table 2, 
including low-dose WBCT scan (excluding head) at Screening for this amendment 
and at all annual site visits (Months 12, 24, 36 and 48). Non-flare-up Day 1 is the 
first day that non-flare-up based treatment is initiated under this amendment for 
these subjects. 
Remote visits (eg, at home or at a local medical facility; and via telephone contact 
from clinical site personnel) will occur every 3 months unless the Investigator 
deems that a site visit is necessary; urine pregnancy tests will be performed each 
month for FOCBP. 
Part D: 
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 D. Subjects who were enrolled in Parts A, B or C who have 
discontinued the study and were skeletally immature at their last assessment will be 
invited back to participate in the off-treatment Part D safety follow-up. These 
subjects will follow all procedures and undergo all assessments as specified in the 
Schedule of Assessments in Table 4. 
Flare-Up Based Treatment 
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 receive open-label palovarotene treatment as follows: 
 
20 mg for 4 weeks (28 days) once daily. The first dose will be taken upon 
flare-up confirmation by the Investigator. To be followed by: 
 
10 mg for 8 weeks (56 days) once daily, for a total flare-up treatment duration 
of 12 weeks (84 days); 10 mg treatment may be extended if the flare-up is 
ongoing and continue until the flare-up resolves. Dosing will be extended in 4-
week intervals and be based on clinical signs and symptoms as assessed by the 
Investigator. 
Subjects under the age of 18 years will receive weight-adjusted doses of 20 mg 
palovarotene (for 28 days) and 10 mg palovarotene (for 56 days) as shown in 
Table 5. (Note: all weight-based flare-up dosing will cease when subjects are 18 
years old, but radiographic assessment of the growth plate will continue until these 
subjects achieve 100% skeletal maturity at both knee and hand/wrist locations.) 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 10 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
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-204, AMENDMENT 6 
PAGE 11 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Study Design (cont.) 
Should a subject experience an intercurrent flare-up, or other 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 confirmation by 
the Investigator (ie, 4 weeks of 20 mg palovarotene followed by 8 weeks of 10 mg 
palovarotene [or weight-based equivalent]). 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 the 
flare-ups or traumatic events 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 follow all procedures and undergo 
all assessments as specified in the Schedule of Assessments in Table 3. 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 non-flare-up-based treatment with 5 mg 
palovarotene once daily (weight-adjusted doses for skeletally immature subjects). 
The pharmacokinetics of palovarotene dosing will be assessed at the first 3-month 
safety assessment during non-flare-up-based treatment; if samples cannot be 
obtained during the first 3-month safety assessment, or if subjects are on flare-up-
based treatment, then blood samples for non-flare-up treatment pharmacokinetics 
can be obtained during any subsequent 3-month safety visit. 
Pharmacokinetics of palovarotene dosing 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 pre-dose and 3, 6, 10, and 
24 hours post-dose. 
Subjects who underwent a pharmacokinetic assessment for flare-up-based treatment 
prior to Amendment 3 will not have flare-up pharmacokinetics assessed again. 
However, these subjects will need to have non-flare-up treatment pharmacokinetics 
assessed at a 3-month safety visit. 
As of 04 December 2019, 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. 
Off Treatment Part D: No study drug will be administered in Part D.  For skeletally 
immature subjects in Part D, 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 (AEs), and concomitant medications. 
Once subjects reach skeletal maturity their participation in Part D will end. The 
total duration of participation in Part C and Part D combined is a maximum of 4 
years (±1 month). 
 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 12 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Number of Subjects 
A total of approximately nine subjects will be enrolled: 
 
Up to seven subjects enrolled under Amendment 1 from Study PVO-1A-201. 
 
Up to two new adult subjects enrolled under Amendment 1 who did not 
previously participate in Study PVO-1A-201 or Study PVO-1A-202. 
Note: No new subjects will be enrolled under this amendment. 
Total Number of Sites 
One investigational site in France. 
Study Population 
(Adult and Pediatric 
Cohorts – Original 
Protocol and 
Amendment 1) 
Inclusion Criteria 
1. Completion of Study PVO-1A-201 (through Study Day 84), including any 
subject from Study PVO-1A-202); or Adult Cohort subjects not enrolled in 
Study PVO-1A-201, have the confirmed R206H genetic mutation consistent 
with FOP, have had at least two acute symptomatic flare-ups in the past 2 
years but no flare-up symptoms within the past 4 weeks (including at the time 
of enrollment), have a CAJIS score of 6 to 16, inclusive, and able to receive 
non-flare-up-based dosing. 
2. For the Adult Cohort, subjects under the age of 18 must have knee and 
 
3. Written, signed, and dated subject/parent informed consent; and, for subjects 
who are minors, age-appropriate assent (this must be performed according to 
local regulations). 
Exclusion Criteria 
1. Simultaneous participation in another clinical research study (except for 
Studies PVO-1A-201, PVO-1A-202, PVO-1A-203, or PVO-1A-001) within 4 
weeks prior to Screening. 
2. Any reason that, in the opinion of the Investigator, would lead to the inability 
of the subject and/or family to comply with the protocol. 
Study Population for 
Non-Flare-up-based 
Treatment 
(Adult Cohort –  
Original Protocol and 
Amendment 1) 
Inclusion Criteria 
1. Females of child-bearing potential (FOCBP) 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 during treatment and for 1 month after treatment or, if 
sexually active, to use two highly effective methods of birth control during and 
for 1 month after treatment. Additionally, sexually active FOCBP subjects 
must already be using two highly 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 highly 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. 
2. Subjects must be accessible for treatment with palovarotene and follow-up. 
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. 
Exclusion Criteria 
1. Weight <20 kg. 
2. Intercurrent known or suspected non-healed fracture at any location. 
3. 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. 
4. Exposure to synthetic oral retinoids other than palovarotene in the past 30 days 
prior to Screening (signature of the informed consent). 
5. Concurrent treatment with tetracycline or any tetracycline derivatives due to 
the potential increased risk of pseudotumor cerebri. 
6. History of allergy or hypersensitivity to retinoids or lactose 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 13 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Study Population for 
Non-Flare-up-based 
Treatment 
(Adult Cohort –  
Original Protocol and 
Amendment 1) (cont.) 
 
 
 
 
 
 
 
 
7. Concomitant medications that are inhibitors or inducers of cytochrome P450 
(CYP450) 3A4 activity). 
8. Amylase or lipase >2x above the upper limit of normal (ULN) or with a 
history of chronic pancreatitis. 
9. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5x ULN. 
10. Fasting triglycerides >400 mg/dL with or without therapy. 
11. Female subjects who are breastfeeding. 
12. Subjects with uncontrolled cardiovascular, hepatic, pulmonary, 
gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, 
psychiatric, or other significant disease. 
13. 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). 
Study Population for 
Flare-up-based 
Treatment 
(Adult and Pediatric 
Cohorts - Original 
Protocol and  
Amendment 1) 
 
Inclusion Criteria 
1. Symptomatic onset of a flare-up within 7 days before the first dose of study 
drug and defined by the presence of at least two of the following symptoms: 
pain, soft tissue swelling, decreased ROM, stiffness, redness, and warmth. 
Symptoms must be reported by the subject, be consistent with their previous 
flare-ups, and include a subject-reported onset date, and flare-up must be 
confirmed by the Investigator. 
2. Flare-up is at an appendicular area (upper or lower extremity), abdomen, chest, 
neck, or lower back; and subject has received, is receiving, or is willing to 
receive treatment per standard of care, which may or may not include 
prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days. 
3. Females of child-bearing potential (FOCBP) 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 during treatment and for 1 month after treatment or, if 
sexually active, to use two highly effective methods of birth control during and 
for 1 month after treatment. Additionally, sexually active FOCBP subjects 
must already be using two highly 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 highly 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. 
4. Subjects must be accessible for treatment with palovarotene and follow-up. 
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. 
Exclusion Criteria 
1. Weight <20 kg. 
2. Intercurrent known or suspected non-healed fracture at any location. 
3. Complete immobilization of joint at site of flare-up. 
4. Inability of the subject to undergo imaging assessments using plain 
radiographs. 
5. 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. 
6. Exposure to synthetic oral retinoids other than palovarotene in the past 30 days 
prior to Flare-up Screening (signature of the informed consent). 
7. Concurrent treatment with tetracycline or any tetracycline derivatives due to 
the potential increased risk of pseudotumor cerebri. 
8. History of allergy or hypersensitivity to retinoids or lactose. 
Concomitant medications that are inhibitors or inducers of CYP450 3A4 
activity (see Section 5.6.1). 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 14 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Study Population for 
Flare-up-based 
Treatment 
(Adult and Pediatric 
Cohorts - Original 
Protocol and  
Amendment 1) (cont.) 
9. Any subject with clinically significant elevations in amylase, lipase, AST, 
ALT, or fasting triglycerides during the most recent clinical laboratory 
assessment will require re-test prior to immediate flare-up-based dosing with 
palovarotene per the Investigator. If upon re-test, the laboratory value in 
question remains clinically significant abnormal, then the subject will not 
receive flare-up-based treatment for this flare-up. 
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 C-SSRS. 
13. Any reason that, in the opinion of the Investigator, would lead to the inability 
of the subject and/or family to comply with the protocol. 
Study Population  
(All Subjects - 
Amendment 2 and 
Amendment 3) 
Inclusion Criteria 
1. Prior participation in Amendment 1 of the current study (PVO-1A-204). 
2. Written, signed, and dated subject/parent informed consent; and, for subjects 
who are minors, age-appropriate assent (this must be performed according to 
local regulations). 
3. 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. 
Exclusion Criteria 
1. Any reason that, in the opinion of the Investigator, would lead to the inability 
of the subject and/or family to comply with the protocol. 
Study Population of 
Subjects Starting  
Non-Flare-up-based 
Treatment During 
Amendment 3 
Inclusion Criteria 
1. Subjects must be accessible for treatment with palovarotene and follow-up. 
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. 
2. Subjects must be able to undergo low-dose WBCT scan, excluding head. 
Exclusion Criteria 
1. Amylase or lipase >2x above the upper limit of normal (ULN) or with a history 
of chronic pancreatitis. 
2. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5x ULN. 
3. Fasting triglycerides >400 mg/dL with or without therapy. 
4. 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). 
Investigational Product 
Palovarotene supplied as powder-filled hard gelatin capsules. The capsules may be 
swallowed whole or opened and the contents added onto specific food: apple sauce, 
pudding, or yogurt. 
Dose/Route/Regimen  
for Non-Flare-Up  
Based Treatment 
Palovarotene: 5 mg daily or weight-based equivalent for skeletally immature 
subjects (upon entry into the study) / taken orally with food / at approximately the 
same time each day. For 5 mg palovarotene, weight equivalent doses for 20 to <40 
 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 15 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Dose/Route/Regimen  
for Flare-up-based 
Treatment 
Palovarotene initiated at the start of a flare-up for subjects 18 years of age and 
older: 20 mg for 4 weeks (28 days) once daily, 10 mg for 8 Weeks (56 days) once 
daily 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 
subjects under the age of 18 years / taken orally with food / at approximately the 
same time each day. 
The weight-adjusted palovarotene doses and dose de-escalation for flare-up and 
non-flare-up-based 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 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 
 
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 equivalent, respectively. 
 
Comparator Product 
Dose/Route/Regimen 
Not Applicable – this is an open-label study. 
Assessments of Efficacy Primary Efficacy Endpoint 
1. Annualized change in new HO volume as assessed by low-dose WBCT scan, 
excluding head. The annualized change from the original protocol, and 
Amendments 1 and 2, will be compared to data collected from the NHS. 
Secondary Endpoints (Note: baseline is Non-flare-up Day 1. Some subjects may be 
assessed for up to 72 months): 
1. Percent of subjects with new HO at Months 12, 24, 36, 48, 60, 72 and overall. 
2. Change from baseline in ROM as assessed by CAJIS at Months 6, 12, 18, 24, 
30, 36, 42, 48, 54, 60, 66, and 72. 
3. Change from baseline in physical function using age-appropriate forms of the 
FOP-PFQ at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72. 
4. 
old and mental function for subjects <15 years old using age-appropriate forms 
of the PROMIS Global Health Scale at Months 6, 12, 18, 24, 30, 36, 42, 48, 
54, 60, 66 and 72. 
Assessments of Safety 
Safety evaluations will include AE and serious AE (SAE) reporting, 
electrocardiograms (for subjects receiving treatment), 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 with open epiphyses at the last 
assessment will include knee (anterior/posterior [A/P]) and hand/wrist radiographs 
(posterior/anterior [P/A] view) for assessment of epiphyseal growth plate; and 
standardized stadiometry and knee height for assessments of linear growth (in 
triplicate). If there is evidence of premature growth plate closure (with or without 
linear growth deceleration) the Investigator may require that study drug 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 reads. 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. 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 16 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
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. 
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 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.  
Statistical Analysis 
(Amendment 3 and 
subsequent 
amendments) 
 
The primary efficacy endpoint implemented for Amendment 3 and subsequent 
amendments is the annualized change in new HO volume (as assessed by low-dose 
WBCT scan, excluding head). The annualized change will be compared to data 
collected from a natural history study using a weighted linear mixed effects model 
with baseline HO volume divided by age as the only covariate and weights used to 
account for the different lengths of observed subject follow-up. A subject-specific 
random effect will be included to account for within-subject correlation. 
 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 17 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Table 1 
Schedule of Assessments During Non-Flare-up-based Treatment  
(Subjects from Amendment 1 Continuing Non-Flare-up-based Treatment) 
 
 
 
Assessment/Procedure 
 
 
Amendment 3 
Consent/Assent1 
(Remote Visit) 
 
 
Every Month 
Remote 
Visit1,2, (±1 
week) 
 
 
Every 3 Months 
Remote Visit1,2,3 
(±2 weeks) 
Months 6, 18,
30, 42, 54, 66 
Remote 
Visit1,2,4 (±1 
month) 
Months 12, 24,
36, 48, 60 
72/EOT/EOS1,4,5 
Site Visit (±1 
month) 
Informed consent/assent1 
X 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
Knee and hand/wrist 
radiographs6 
 
 
X7 
X 
X 
Linear growth assessment 
(stadiometry, knee height; 
subjects 
<18 years of age)6 
 
 
 
 
X 
 
X 
Physical examination 
 
 
 
 
X 
Body weight 
 
 
X 
X 
X 
Electrocardiogram 
 
 
 
 
X 
Study drug dispensing 
As needed from Non-flare-up Day 1 through Month 72 
Study drug treatment 
Continuous from Non-flare-up Day 1 through Month 728 
Dispense/review subject diary 
Dispense diary as needed and review at every subject contact 
Vital signs 
 
 
X 
X 
X 
C-SSRS (age-appropriate) 
 
 
X 
X 
X 
Hematology9 
 
 
 
X 
X 
Biochemistry (includes lipids, 
serum pregnancy test)9 
 
 
 
X 
X 
Urinalysis10 
 
 
 
X 
X 
Pregnancy test11 
 
X 
 
 
 
FOP-PFQ12 
 
 
 
X 
X 
PROMIS Global Health Scale12
 
 
 
X 
X 
CAJIS 
 
 
 
X13 
X 
Low-dose WBCT scan, 
excluding head14 
 
 
 
 
X 
Prior/concomitant medications 
At every subject contact 
Adverse events 
At every subject contact 
Pharmacokinetic blood sample15
 
 
Month 3 only 
 
 
Telephone contact3 
 
 
X 
 
 
1 
Visits can be combined with flare-up visits when appropriate. 
2 
Remote visits, except for knee and hand/wrist radiographs, will be performed at the subject’s home by qualified study 
personnel, or at a local medical facility, or via video-conferencing or telephone contact, unless the Investigator deems 
that a site visit is necessary. Remote visits that occur every 3 months should align with the remote visits at Months 6, 18, 
30, 42, 54 and 66. Monthly remote visits will only be conducted for FOCBP subjects. 
3 
At the time of a remote visit, subjects will be contacted by telephone every 3 months from the time of informed consent 
until study completion to assess AEs and concomitant medications. Every effort should be made to conduct the telephone 
contact on the same day as the remote visit completed every 3 months. However, the visit window of ±2 weeks will allow 
for flexibility in scheduling if needed. 
4 
Non-flare-up Day 1 is the first day that non-flare-up-based treatment was initiated prior to Amendment 3, and total 
duration of treatment will continue into Amendment 3. Subjects who began non-flare-up-based treatment prior to 
Amendment 3 will continue this visit schedule into Amendment 3 and all subsequent amendments, and will receive non-
flare-up-based treatment for up to an additional 48 months. Therefore, these subjects may undergo non-flare-up-based 
treatment for up to 72 months over the entire study. 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 D. If the next annual visit is in more 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 18 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
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 D. If the Part C EOS visit (at completion of the trial) is >6 months from the last annual visit, this 
visit will serve as the EOT/EOS site visit, will include all annual assessments and will end their participation in the study. 
5 
Adult subjects who cannot receive non-flare-up-based treatment will only undergo annual assessments (clinical 
laboratory tests will not be performed). 
6 
Subjects with open epiphyseal growth plates at the most recent assessment will be evaluated at Months 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66 and 72. As the linear growth assessments cannot be performed remotely, all assessments scheduled 
at these time points will be performed at the clinical site. Limb/joint AEs in these subjects will be evaluated by clinical 
and radiographic assessments deemed appropriate by the Investigator. Once a subject has achieved 100% skeletal 
maturity (confirmed by radiography as complete closure of the growth plate), knee and hand/wrist radiographs 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. In addition, once a subject is 18 years old, linear growth assessments in triplicate and knee 
height will no longer be required. 
7 
These additional knee and hand/wrist radiograph assessments will be performed every 3 months (±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% 
skeletal maturity on their last assessment. Radiographic assessments required because of flare-up status at the time of a 
remote visit will instead be conducted at the clinical site unless the Investigator determines they can be performed at a 
local medical facility. All remote assessments will be performed at the clinical site if the radiographs cannot be performed 
locally. 
8 
Continuous non-flare-up-based treatment unless flare-up-based treatment is initiated. 
9 
Analysis of samples can be completed at a local, qualified laboratory. The investigative site should notify the study team 
if the local laboratory cannot test all the analytes listed in Table 6. If the total thyroxine (Total T4), free T4, uric acid, 
gamma glutamyl transferase, inorganic phosphorous, very low-density lipoprotein, or globulin parameters are not 
available through the local laboratory, and alternative arrangements cannot be made, testing of these analytes may be 
omitted provided other subject-assessments of thyroid function (ie, thyroid-stimulating hormone), lipid metabolism (ie, 
triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol), and protein metabolism (ie, total 
protein and albumin) are available and confirmed to be stable as per the Investigator. Alternative arrangements to test the 
listed analytes are to be made if the Investigator, Medical Monitor, or sponsor determines that they have the potential to 
impact subject safety. In the event the local laboratory is unable to test any other analytes, they may be omitted in 
exceptional circumstances after consultation with the sponsor. Such exceptions will not be applied to any of the key 
safety analytes (see Section 7.2.6). 
10 
If urinalysis results are abnormal, then a microscopic evaluation will be completed. 
11 
Pregnancy testing will be performed monthly for females of child-bearing potential. Urine pregnancy test will be 
performed only when a serum pregnancy test is not obtained. 
12 
Age-appropriate versions of the FOP-PFQ and PROMIS Global Health Scale will be used. 
13 
CAJIS assessment may be performed remotely or by videoconferencing. 
14 
Baseline for low-dose WBCT scan, excluding head, was performed under the original protocol or under Amendment 1 
(ie, prior to the initiation of non-flare-up-based dosing under Amendment 3). 
15 
Blood samples for pharmacokinetic assessment of non-flare-up dosing will be collected at the first 3-month safety 
assessment at predose and 3, 6, 10, and 24 hours post-dose; if samples cannot be obtained at the 3-month safety 
assessment, or if a subject is on flare-up-based treatment, then the blood sample for non-flare-up-based treatment 
pharmacokinetics can be obtained during any subsequent 3-month safety visit. 
Note: study procedures that require sedation will not be performed. 
 
AE = adverse event, CAJIS = Cumulative Analogue Joint Involvement Scale for FOP, C-SSRS = Columbia Suicide Severity 
Rating Scale, EOS = end of study, EOT = end of treatment; FOP-PFQ = Fibrodysplasia Ossificans Progressiva physical 
function questionnaire, PROMIS = Patient Reported Outcomes Measurement Information System, WBCT = whole body 
computed tomography. 
 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 19 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Table 2 
Schedule of Assessments During Non-Flare-up-based Treatment  
(Subjects from Amendment 1 Starting Non-Flare-up-based Treatment) 
 
 
 
Assessment/ Procedure 
Amendment 3 
Screening/ 
Non-Flare-Up 
Day 11/ 
Site Visit 
(-1 month) 
 
 
 
Non-Flare-Up 
Day 7 
(±3 days) 
 
 
 
Every Month 
Remote Visit1,2
(±1 week) 
 
 
Every 3 
Months 
Remote 
Visit1,2,3 
(±2 weeks) 
 
 
Months 18, 30 
42 
Remote Visit1,2
(±1 month) 
 
Months 6, 12, 
24, 36, 
48/EOT/ 
EOS1,4,5 
Site Visit  
(±1 month) 
Informed consent/assent1 
X 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
Knee and hand/wrist 
radiographs for assessment 
of epiphyseal growth plate6
 
X 
 
 
 
X7 
 
X 
 
X 
Linear and knee height 
growth assessments (<18 
years of age)6 
 
X 
 
 
 
 
X 
 
X 
Physical examination 
X 
 
 
 
 
X 
Body weight 
X 
 
 
X 
X 
X 
Electrocardiogram 
X 
X8 
 
 
 
X 
Study drug dispensing 
As needed from Non-flare-up Day 1 through Month 48 
Study drug treatment 
Continuous from Non-flare-up Day 1 through Month 489 
Dispense/review subject 
diary 
Dispense diary as needed and review at every subject contact 
Vital signs 
X 
 
 
X 
X 
X 
C-SSRS (age-appropriate) 
X 
 
 
X 
X 
X 
Hematology10 
X 
 
 
 
X 
X 
Biochemistry (includes 
lipids)10 
X 
 
 
 
X 
X 
Urinalysis 
X 
 
 
 
X 
X 
Pregnancy test12 
 
 
X 
 
 
 
FOP-PFQ13 
X 
 
 
 
X 
X 
PROMIS Global Health 
Scale13 
X 
 
 
 
X 
X 
CAJIS 
X 
 
 
 
X14 
X 
Low-dose WBCT scan, 
excluding head 
X 
 
 
 
 
X15 
Prior/concomitant 
medications 
At every subject contact 
Adverse events 
At every subject contact 
Pharmacokinetic blood 
sample16 
 
 
 
Month 3 only 
 
 
Telephone contact3 
 
 
 
X 
 
 
1 
A visit will be scheduled as soon as possible after Amendment 3 is approved at the clinical site and non-flare-up-based 
treatment will be started during that visit (Non-flare-up Day 1). Visits can be combined with flare-up visits when 
appropriate. 
2 
Remote visits, except for knee and hand/wrist radiographs, will be performed at the subject’s home by qualified study 
personnel, at a local medical facility, or via video-conferencing or telephone contact unless the Investigator deems that a 
site visit is necessary. Remote visits that occur every 3 months should align with the remote visits at Months 18, 30 and 
42. Monthly remote visits will only be conducted for FOCBP subjects. 
3 
At the time of a remote visit, subjects will be contacted by telephone every 3 months from the time of informed consent 
until study completion to assess AEs and concomitant medications. Every effort should be made to conduct the telephone 
contact on the same day as the remote visit completed every 3 months. However, the visit window of ±2 weeks will allow 
for flexibility in scheduling if needed. 
4 
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 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 20 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
6 months, the EOT will serve as their EOS assessments and will conclude their participation in the study. If the next 
annual visit is in more than six 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 the Part C EOS visit (at completion of the trial) is > 6 months from the last annual visit, this visit will serve 
as the EOT/EOS site visit, will include all annual assessments and will end their participation in the study. 
5 
Adult subjects who cannot receive non-flare-up-based treatment will only undergo annual assessments (clinical 
laboratory tests will not be performed). 
6 
Subjects with open epiphyseal growth plates at the most recent assessment will undergo knee (A/P) and hand/wrist 
radiographs (P/A view) and measurements of linear and knee height (in triplicate) at Amendment 3 Screening and/or 
Non-flare-up Day 1. As the linear growth assessments cannot be performed remotely, all assessments scheduled at these 
time points will be performed at the clinical site. Subjects for whom radiographs were performed within the last 3 months 
will not need to repeat radiographs at Screening. Subjects with open epiphyseal growth plates at this assessment will also 
be evaluated at Months 6, 12, 18, 24, 30, 36, 42 and 48. Limb/joint AEs in these subjects will be evaluated by clinical 
and radiographic assessments deemed appropriate by the Investigator. Once a subject has achieved 100% skeletal 
maturity (confirmed by radiography), knee and hand/wrist radiographs 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. In 
addition, once a subject is 18 years old, linear growth assessments in triplicate and knee height will no longer be required. 
7 
These additional knee and hand/wrist radiograph assessments will be performed every 3 months (±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% 
skeletal maturity on their last assessment. Radiographic assessments required because of flare-up status at the time of a 
remote visit will instead be conducted at the clinical site unless the Investigator determines they can be performed at a 
local medical facility. All remote assessments will be performed at the clinical site if the radiographs cannot be performed 
locally. 
8 
ECG may be performed at the subject’s home by qualified study personnel, at a local medical facility, or at the clinical 
site. 
9 
Continuous non-flare-up-based treatment unless flare-up-based treatment is initiated. 
10 
Analysis of samples can be completed at a local, qualified laboratory. The investigative site should notify the study team 
if the local laboratory cannot test all the analytes listed in Table 6. If the total thyroxine (Total T4), free T4, uric acid, 
gamma glutamyl transferase, inorganic phosphorous, very low-density lipoprotein, or globulin parameters are not 
available through the local laboratory, and alternative arrangements cannot be made, testing of these analytes may be 
omitted provided other subject-assessments of thyroid function (ie, thyroid-stimulating hormone), lipid metabolism (ie, 
triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol), and protein metabolism (ie, total 
protein and albumin) are available and confirmed to be stable as per the Investigator. Alternative arrangements to test the 
listed analytes are to be made if the Investigator, Medical Monitor, or sponsor determines that they have the potential to 
impact subject safety. In the event the local laboratory is unable to test any other analytes, they may be omitted in 
exceptional circumstances after consultation with the sponsor. Such exceptions will not be applied to any of the key 
safety analytes (see Section 7.2.6). 
11 
If urinalysis results are abnormal, then a microscopic evaluation will be completed. 
12 
Pregnancy testing will be performed monthly for females of child-bearing potential. Urine pregnancy test will be 
performed only when a serum pregnancy test is not obtained. 
13 
Age-appropriate versions of the FOP-PFQ and PROMIS Global Health Scale will be used. 
14 
CAJIS assessment may be performed remotely or by videoconferencing. 
15 
Baseline for low-dose WBCT scan, excluding head, will be at Amendment 3 Screening (ie, when the subject provides 
informed consent/assent for Amendment 3). The low-dose WBCT scans, excluding head, will only be performed during 
annual visits (not at the 6-month visit). 
16 
Blood samples for pharmacokinetic assessment of non-flare-up dosing will be collected at 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, or if the subject is on flare-up-based treatment, then the blood sample for non-flare-up-based treatment 
pharmacokinetics can be obtained during any subsequent 3-month safety visit. 
Note: study procedures that require sedation will not be performed. 
 
AE = adverse event, A/P = anterior/posterior, CAJIS = Cumulative Analogue Joint Involvement Scale for FOP, C-SSRS = 
Columbia Suicide Severity Rating Scale, EOS = end of study, EOT = end of treatment, FOP-PFQ = Fibrodysplasia 
Ossificans Progressiva physical function questionnaire, P/A = posterior/anterior; PK = pharmacokinetic(s), PROMIS = 
Patient Reported Outcomes Measurement Information System, WBCT = whole body computed tomography. 
 




PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 22 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
protein and albumin) are available and confirmed to be stable as per the Investigator. Alternative arrangements to test the 
listed analytes are to be made if the Investigator, Medical Monitor, or sponsor determines that they have the potential to 
impact subject safety. In the event the local laboratory is unable to test any other analytes, they may be omitted in 
exceptional circumstances after consultation with the sponsor. Such exceptions will not be applied to any of the key 
safety analytes (see Section 7.2.6). 
6 
Subjects with normal or non-clinically significant abnormal safety laboratory results observed within 1 month of flare-
up based treatment will not need to have laboratory tests performed at Flare-up Cycle Safety Day 1. 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 the end of the cycle. However, if a 
pregnancy test was performed within 4 weeks prior to the start of treatment for a flare-up/trauma, treatment of the flare-
up/trauma will not be delayed pending repeat pregnancy testing. 
7 
If urinalysis results are abnormal, then a microscopic evaluation should be completed. 
8 
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. 
9 
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 once daily followed by 8 weeks (56 days) of 10 mg palovarotene once daily (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. 
10 
Should a subject experience an intercurrent flare-up, or other 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 
equivalent]). This may occur more than once during a Flare-up Cycle. 
11     At each contact, flare-up status will be assessed 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. 
12 
Flare-up Day 1 is the first day of treatment for a flare-up/substantial high-risk traumatic event (upon confirmation by the 
Investigator). 
13 
Pharmacokinetics of palovarotene dosing will be assessed twice: 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 during Study Days 32 to 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 cycle. Blood samples will be collected at pre- dose and 3, 6, 10, and 24 hours post-dose. 
Subjects who underwent a flare-up dosing pharmacokinetic assessment prior to Amendment 3 will not have flare-up 
treatment pharmacokinetics assessed again under Amendment 3 or subsequent amendments. However, these subjects 
will require a pharmacokinetic assessment for non-flare-up palovarotene dosing at a 3-month safety visit. 
14 
Flare-up 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. 
 
C-SSRS = Columbia Suicide Severity Rating Scale, PK = pharmacokinetic(s) 
 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 23 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Table 4 
Schedule of Assessments for Part D 
Assessment/Procedure 
Y1 and Y2 Post Treatment 
Site Visit1 
Informed consent2,3 
X 
Knee and hand/wrist radiographs4,5 
X 
Linear and knee height growth assessments 
(<18 years of age)4 
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 events2,6 
At every subject contact 
1 
Year 1 (Y1) and Year 2 (Y2) visits following the last dose of study drug will be done within the 
total study duration from enrolment from Part A. 
to < 18 months post last dose of study medication.   
If Part A, B or C EOS date is within the Y1 window then the EOS will serve as the Y1 visit.   
If Part A, B or C EOS date is prior to Y1 window then Y1 should be sc
Part A, B or C EOS date but still within the Y1 window.   
– 24 months post last dose of study medication. 
If Part A, B or C EOS date is within the Y2 window then the EOS will serve as the Y2 visit.   
If Part A, B or C EOS date or Y1 date (if applicable) is prior to Y2 window then Y2 should be 
within the Y2 window. 
If subjects had their last dose of study medication and completed Part A, B or C EOS more than 2 
years prior to their consent for Part D, then these subjects will only complete Y2 following their 
consent for Part D.  
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 D informed consent is required prior to conducting Part D 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 D 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. 
Note: References to Parts B/C/D are to PVO-1A-202 Parts B/C/D which corresponds to PVO-
1A-204, ongoing in France. 
AE = adverse event; WBCT = whole-body computed tomography; Y = year; 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 24 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................... 2 
PROTOCOL AMENDMENT SUMMARY ....................................................................... 3 
GROUPS RESPONSIBLE FOR STUDY CONTACT ..................................................... 7 
PROTOCOL SYNOPSIS .................................................................................................... 8 
LIST OF ABBREVIATIONS ............................................................................................ 29 
1 
INTRODUCTION .................................................................................................... 32 
1.1 
Background ............................................................................................................... 32 
1.1.1 
Fibrodysplasia Ossificans Progressiva ................................................... 32 
1.1.2 
Current Therapeutic Options for Fibrodysplasia Ossificans Progressiva
.................................................................................................................. 32 
1.1.3 
Overview of Palovarotene ....................................................................... 33 
1.1.3.1 
Nonclinical Data ...................................................................................... 34 
1.1.3.2 
Clinical Data ............................................................................................ 35 
2 
STUDY OBJECTIVES ............................................................................................. 38 
2.1 
Primary Objective ..................................................................................................... 38 
2.2 
Secondary Objectives ............................................................................................... 38 
2.3 
Secondary Objective (Part D) .................................................................................. 38 
3 
STUDY DESIGN ....................................................................................................... 38 
3.1 
Overview of the Study Design .................................................................................. 38 
3.2 
Study Rationale ......................................................................................................... 42 
3.3 
Dose Justification ...................................................................................................... 42 
3.4 
Appropriateness of Measurements .......................................................................... 44 
3.4.1 
Imaging.................................................................................................... 44 
3.4.2 
Measures of Functional Disability and General Health ....................... 44 
4 
STUDY ENDPOINTS ............................................................................................... 45 
4.1 
Primary Endpoints ................................................................................................... 45 
4.2 
Secondary Endpoints ................................................................................................ 45 
5 
SELECTION OF STUDY POPULATION ............................................................ 45 
5.1 
Study Population (Adult and Pediatric Cohorts – Original Protocol and 
Amendment 1) ........................................................................................................... 45 
5.1.1 
Inclusion Criteria .................................................................................... 45 
5.1.2 
Exclusion Criteria ................................................................................... 46 
5.2 
Study Population for Non-Flare-Up Based Treatment (Adult Cohort - Original 
Protocol and Amendment 1) .................................................................................... 46 
5.2.1 
Inclusion Criteria .................................................................................... 46 
5.2.2 
Exclusion Criteria ................................................................................... 46 
5.3 
Study Population for Flare-up Based Treatment (Adult and Pediatric Cohorts - 
Original Protocol and Amendment 1) ..................................................................... 47 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 25 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
5.3.1 
Inclusion Criteria .................................................................................... 47 
5.3.2 
Exclusion Criteria ................................................................................... 47 
5.4 
Study Population (All Subjects – Amendments 2 and 3)....................................... 48 
5.4.1 
Inclusion Criteria .................................................................................... 48 
5.4.2 
Exclusion Criteria ................................................................................... 49 
5.5 
Study Population of Subjects Starting Non-Flare-Up Based Treatment During 
Amendment 3 ............................................................................................................ 49 
5.5.1 
Inclusion Criteria .................................................................................... 49 
5.5.2 
Exclusion Criteria ................................................................................... 49 
5.6 
Prior and Concomitant Medications and Other Study Restrictions .................... 49 
5.6.1 
Prior 
and 
Concomitant 
Medications 
for 
Subjects 
Receiving 
Palovarotene ............................................................................................ 49 
5.6.2 
Other Restrictions ................................................................................... 50 
5.7 
Subject Withdrawal or Early Termination from Study ........................................ 51 
5.8 
Replacement of Subjects .......................................................................................... 51 
6 
STUDY DRUG ADMINISTRATION ..................................................................... 51 
6.1 
Identity of Study Drug .............................................................................................. 51 
6.2 
Packaging, Labeling, and Storage ........................................................................... 51 
6.3 
Randomization and Blinding ................................................................................... 52 
6.4 
Administration .......................................................................................................... 52 
6.5 
Dose Modification ..................................................................................................... 53 
6.6 
Study Drug Accountability ...................................................................................... 53 
6.7 
Assessment of Subject Compliance ......................................................................... 54 
7 
STUDY PROCEDURES AND ASSESSMENTS ................................................... 54 
7.1 
Screening, Recruitment, and Informed Consent ................................................... 54 
7.2 
Safety Assessments .................................................................................................... 55 
7.2.1 
Medical History ....................................................................................... 55 
7.2.2 
Physical Examination ............................................................................. 55 
7.2.3 
Body Weight and Linear Growth Assessments ...................................... 55 
7.2.4 
Vital Signs ............................................................................................... 56 
7.2.5 
Electrocardiogram .................................................................................. 56 
7.2.6 
Clinical Laboratory Tests ........................................................................ 57 
7.2.7 
Pregnancy Testing................................................................................... 59 
7.2.8 
Adverse Events ........................................................................................ 59 
7.2.9 
Concomitant Medications ....................................................................... 60 
7.3 
Special Safety Assessments ...................................................................................... 60 
7.3.1 
Columbia-Suicide Severity Rating Scale ................................................ 60 
7.3.2 
Knee and Hand/Wrist Radiographs ........................................................ 60 
7.3.3 
Bone Safety Management Plan .............................................................. 61 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 26 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
7.3.4 
Mucocutaneous Effects (Skin and Mucous Membrane Toxicity Profile)
.................................................................................................................. 61 
7.3.5 
Serum Lipids ........................................................................................... 62 
7.3.6 
Liver Enzymes ......................................................................................... 62 
7.3.7 
Lipase/Amylase........................................................................................ 62 
7.3.8 
Central Nervous System .......................................................................... 63 
7.3.9 
Hearing and Visual Disturbances .......................................................... 63 
7.3.10 
Teratogenicity .......................................................................................... 63 
7.4 
Efficacy Assessments ................................................................................................ 64 
7.4.1 
Low-Dose Whole Body Computed Tomography .................................... 64 
7.4.2 
FOP-Physical Function Questionnaire ................................................. 64 
7.4.3 
PROMIS Global Health Scale ................................................................ 65 
7.4.4 
Cumulative Analogue Joint Involvement Scale ..................................... 65 
7.5 
Pharmacokinetics ...................................................................................................... 65 
7.6 
Data Monitoring Committee .................................................................................... 66 
7.7 
Temporary Measures (Procedures Related to COVID-19 Pandemic) ................ 66 
8 
STATISTICAL AND ANALYTICAL PLANS ...................................................... 69 
8.1 
General Methods ....................................................................................................... 69 
8.2 
Sample Size ................................................................................................................ 69 
8.3 
Study Populations ..................................................................................................... 69 
8.4 
Baseline and Disease Characteristics (including Medical History) ...................... 70 
8.5 
Subject Disposition ................................................................................................... 70 
8.6 
Extent of Exposure .................................................................................................... 70 
8.7 
Efficacy ...................................................................................................................... 70 
8.7.1 
Primary Efficacy ..................................................................................... 70 
8.7.2 
Secondary Efficacy ................................................................................. 71 
8.8 
Safety .......................................................................................................................... 71 
8.8.1 
Adverse Events ........................................................................................ 71 
8.8.2 
Suicide Ideation....................................................................................... 71 
8.8.3 
Clinical Laboratory Findings ................................................................. 72 
8.9 
Pharmacokinetics ...................................................................................................... 72 
8.10 Pharmacodynamics ................................................................................................... 72 
9 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS ................................................................................................ 72 
9.1 
Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ................................................................................................................... 72 
9.1.1 
Adverse Event .......................................................................................... 72 
9.1.2 
Serious Adverse Event or Adverse Drug Reaction................................. 72 
9.1.3 
Adverse Event Documentation ............................................................... 73 
9.1.4 
Severity of Adverse Events ...................................................................... 73 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 27 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
9.1.5 
Causality Assessment .............................................................................. 73 
9.1.6 
Action Taken With Study Drug .............................................................. 74 
9.1.7 
Outcome of Adverse Event ...................................................................... 74 
9.1.8 
Reporting of Serious Adverse Event ....................................................... 74 
9.1.9 
Pregnancy ................................................................................................ 75 
9.1.10 
Follow-Up of Adverse Events and Serious Adverse Events .................. 75 
9.2 
Administrative Requirements .................................................................................. 75 
9.2.1 
Informed Consent Form ......................................................................... 75 
9.2.2 
Ethical Conduct of the Study .................................................................. 76 
9.2.3 
Ethics Board Approval ............................................................................ 76 
9.2.4 
Subject Confidentiality ............................................................................ 77 
9.2.5 
Amendments to the Protocol ................................................................... 77 
9.2.6 
Protocol Deviations ................................................................................. 77 
9.2.7 
Study Termination ................................................................................... 77 
9.2.8 
Retention of Subject Records and Study Files ....................................... 78 
9.3 
Data Quality Assurance ............................................................................................ 78 
9.4 
Monitoring ................................................................................................................. 78 
9.5 
Data Capture and Management .............................................................................. 79 
9.6 
Liability and Insurance ............................................................................................ 79 
9.7 
Publication and Clinical Data Reporting ................................................................ 79 
9.8 
Coordinating Investigator ........................................................................................ 79 
10 
INVESTIGATOR AGREEMENT .......................................................................... 80 
11 
REFERENCES .......................................................................................................... 81 
APPENDICES .................................................................................................................... 83 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments During Non-Flare-up-based Treatment  (Subjects 
from Amendment 1 Continuing Non-Flare-up-based Treatment) ............. 17 
Table 2 
Schedule of Assessments During Non-Flare-up-based Treatment  (Subjects 
from Amendment 1 Starting Non-Flare-up-based Treatment) .................. 19 
Table 3 
Schedule of Assessments for Flare-up-based Treatment (Subjects with a 
Flare-Up) .......................................................................................................... 21 
Table 4 
Schedule of Assessments for Part D ............................................................... 23 
Table 5 
Weight-Adjusted Palovarotene Doses and Dose De-escalation ................... 40 
Table 6 
Clinical Laboratory Parameters .................................................................... 59 
 
LIST OF FIGURES 


PROTOCOL PVO-1A-204, AMENDMENT 6 
PAGE 28 
 
 
 
CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Figure 1 
Chemical Structure of Palovarotene .............................................................. 51 
 
LIST OF APPENDICES 
Appendix 1. 
Cumulative Analogue Joint Involvement Scale for FOP ............... 83 
Appendix 2A. 
Adult FOP-Physical Function Questionnaire (Self-Completed for 
Subjects Age 15 Years and Older) ................................................... 84 
Appendix 2B. 
Pediatric FOP-Physical Function Questionnaire  (Self-Completed 
for Subjects Ages 8 to 14 Years) ...................................................... 86 
Appendix 2C. 
Pediatric FOP-Physical Function Questionnaire  (Proxy-
Completed for Subjects Ages 5 to 14 Years) ................................... 88 
Appendix 3. 
CYP450 3A4 Strong Inducers or Inhibitors: Exclusionary 
Medications ........................................................................................ 90 
Appendix 4. 
Methods of Birth Control ................................................................. 91 
Appendix 5A. 
Adult Columbia-Suicide Severity Rating Scale  (Subjects Ages 12 
Years and Older) ............................................................................... 92 
Appendix 5B. 
Pediatric Columbia-Suicide Severity Rating Scale  (Subjects Ages 
8 to 11 Years) ..................................................................................... 98 
Appendix 6. 
Retinoid-Specific Adverse Events to Be Assessed For Severity By  
CTCAE Criteria (Version 4.03, 14 June 2010) ............................. 104 
Appendix 7A. 
Promis Global Health Scale (Self-Completed for Subjects Age 15 
Years and Older) ............................................................................. 105 
Appendix 7B. 
Promis Pediatric Global Health Scale (Self-Completed for 
Subjects Ages 8 to 14 Years) .......................................................... 107 
Appendix 7C. 
Promis Pediatric Global Health Scale (Proxy-Completed for 
Subjects Ages Less Than 15 Years) ............................................... 108 
Appendix 8. 
Declaration of Helsinki ................................................................... 109 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ACVR1/ALK2 
activin receptor type IA/activin-like kinase 2  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
A/P 
anterior/posterior view 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AVN 
avascular necrosis 
BMP 
bone morphogenetic protein 
CAJIS 
Cumulative Analogue Joint Involvement Scale for FOP 
CI 
confidence interval 
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  
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
EAP 
early access program 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FOCBP 
female of child-bearing potential 


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Abbreviation 
Definition 
FOP 
Fibrodysplasia Ossificans Progressiva  
FOP-PFQ 
FOP-Physical Function Questionnaire 
FOP-PFQ-P 
Pediatric FOP-PFQ 
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 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LDL 
low-density lipoprotein 
LME 
linear mixed effects 
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 
P/A 
posterior/anterior view 
PAS 
Pharmacokinetic Analysis Set 
PCS 
potentially clinically significant 
PK 
pharmacokinetic(s) 
PO 
per os 
PPS 
Per-Protocol Set 
PROMIS 
Patient Reported Outcomes Measurement Information System  
RAR 
retinoic acid receptor 
 
retinoic acid receptor gamma 


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Abbreviation 
Definition 
ROM 
range of motion 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Set 
SD 
standard deviation 
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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1 
INTRODUCTION 
1.1 
Background 
1.1.1 
Fibrodysplasia Ossificans Progressiva 
Fibrodysplasia Ossificans Progressiva (FOP) (OMIM #135100) is a rare, severely disabling 
disease characterized by heterotopic ossification (HO) in muscles, tendons, and ligaments often 
associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in 
early childhood and lead to progressive ankyloses of major joints with resultant loss of 
movement. Prognosis is poor and life expectancy is reduced. FOP is caused by an activating 
mutation in the bone morphogenetic protein (BMP) type I receptor, or activin receptor type IA 
(ACVR1), also known as activin-like-kinase 2 (ALK2) type I receptor. Most patients with FOP 
(approximately 97%) have the same point mutation, R206H. The International FOP 
Association, a US-based patient group organization, reports approximately 800 confirmed cases 
of FOP globally.1 The prevalence is estimated at approximately 1.36 per million individuals, 
with no geographic, ethnic, racial, or gender preference.2  FOP is misdiagnosed approximately 
80% of the time resulting in great harm to patients.3 The preosseous flare-ups that characterize 
the disease have been misinterpreted as lymphedema, soft tissue sarcoma, or juvenile 
fibromatosis, often resulting in harmful diagnostic biopsies that exacerbate the progression of 
the disease, and/or unnecessary chemotherapeutic interventions. Individuals with FOP appear 
normal at birth except for the pathognomonic malformation of the great toes, which are 
typically short (lack a phalange) and deviated in hallux valgus.4 
Heterotopic ossification is episodic and cumulative throughout life, resulting in segments, 
sheets, and ribbons of extra bone developing throughout the body and across joints, 
progressively restricting movement. Rapidly growing bony spurs have been known to protrude 
through the skin causing pain and a risk of infections.5 Only the tongue, heart, and diaphragm 
muscle are spared for reasons that have yet to be elucidated. Asymmetric HO in the rib cage 
and subsequent contralateral growth can lead to a rapid progression in spinal deformity and 
cause respiratory insufficiency. Ankyloses of the temporomandibular joints results in severe 
tooth decay and malnutrition. Periods of flare-up activity are interspersed with variable-length 
intervals of apparently quiescent disease in the absence of obvious clinical symptoms. In some 
subjects, the presence of substantial soft tissue edema and muscle necrosis observed in imaging 
performed within 7 days of flare-up symptom-onset suggests that the process that ultimately 
leads to new HO formation starts before clinical symptoms are reported. Fibrodysplasia 
Ossificans Progressiva 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) without clinical symptoms. 
The majority of FOP patients are confined to a wheelchair by the third decade of life, and 
require caregiver assistance to perform daily living activities. The median age of survival is 
approximately 56 years with mortality often resulting from complications of respiratory 
insufficiency.6,7 
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. 


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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.10  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.11 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 
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. 
 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 chondrogenesis15 and that unliganded RAR transcriptional repressor 
activity is needed for chondrogenic differentiation.16,17 Inhibition of HO with non-selective 
 been achieved but to a lesser degree.13 
18 where it also operates as an 
unliganded transcriptional repressor.19 
-based anti-HO therapy could 
be very effective because it would target both chondrogenic cells and chondrocytes. It has been 
-translational 
regulation of BMP signaling by inhibiting Smad phosphorylation and promoting proteasome-
could directly prevent the activating (R206H) 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- -catenin signaling.20,21 
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– -
 agonists affect both BMP and Wnt-
-catenin signaling and interfere with the building of the cartilaginous scaffold, thereby 
disrupting the bridge and derailing HO.12 


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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 non-flare-up-based 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.22 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 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 


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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); and 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:  
• 
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.   
• 
7 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 


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18 December 2020 
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. 
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- , 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 4 weeks (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 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 


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18 December 2020 
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 non-
flare-up-based 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 “non-flare-
up-based/flare-up” regimen is the dosing regimen employed in Study PVO-1A 202/Part 
C that will include non-flare-up-based dosing for skeletally mature as well as skeletally 
immature subjects. This corresponds to the current study, PVO-1A-204 Amendment 3 in 
France, that also includes non-flare-up-based dosing (weight-adjusted for skeletally 
immature subjects). 
• 
Study PVO-1A-202/Part C (corresponds to Study PVO-1A-204 in France, ongoing) 
extends the non-flare-up-based/flare-up palovarotene regimen to all subjects, including 
skeletally immature children.  
• 
Study PVO-1A-202/Part D (corresponds to Study PVO-1A-204 in France, ongoing) is 
adding annual post last dose of study treatment assessments for up to 2 years in subjects 
who were skeletally immature at the time of study treatment discontinuation in order to 
obtain longer-term safety data. 
1.1.3.2.3 Palovarotene Safety 
Consistent with other retinoids, the most commonly reported adverse events across all 
palovarotene dosing regimens in the FOP interventional studies were mucocutaneous and 
dermatologic events such as dry skin and lips, erythema, and pruritus. In general, the incidence, 
total number, duration and severity of mucocutaneous and dermatologic events increased with 
increasing palovarotene dose. These AEs generally resolved without sequelae after completion 
of palovarotene treatment. Musculoskeletal events such as arthralgia, pain in extremity, and 
condition aggravated (the Medical Dictionary for Regulatory Activities [MedDRA] preferred 
term used to capture reports of FOP flare-ups) were also commonly reported. 
The majority of AEs in the palovarotene Phase 2 studies in FOP were mild or moderate in 
severity. 
In the current study, and in the ongoing FOP Phase 2 study, subjects enrolled with open 
epiphyses undergo knee (anterior/posterior [AP] view) and hand/wrist radiographs 
(posterior/anterior [PA] view) for assessment of epiphyseal growth plate; and linear and knee 
height measurements for assessment of growth. The most common epiphyseal growth plate 
abnormality is growth recovery lines (dense metaphyseal lines) at both baseline and 
post-baseline time points. Potential premature closure of the epiphysis is closely monitored and 
data are reviewed quarterly by an independent Data Monitoring Committee (DMC). Premature 
epiphyseal closure has been observed in subjects in the interventional FOP studies that have 
been reported as serious adverse events. Analysis of the SAEs suggests that the risk of 
premature epiphyseal fusion is higher in subjects with open epiphyseal growth plates who have 
received the flare-up dosing regimen. The finding of premature epiphyseal closure has been 
seen across all ages although the potential impact on growth is likely to be greater in the 
youngest, most skeletally immature subjects, given limitations in time to attain a greater percent 
of their final adult height. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is: 
 
• 
To evaluate the safety and efficacy of different palovarotene dosing regimens in subjects 
with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the 
formation of new heterotopic ossification (HO) as assessed by low-dose whole body 
computed tomography (WBCT) scan, excluding head. 
2.2 
Secondary Objectives 
• 
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 (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. 
2.3 
Secondary Objective (Part D) 
• 
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.  
 
3 
STUDY DESIGN 
3.1 
Overview of the Study Design 
This is a Phase 2, single-center, open-label study that will explore different dosing regimens of 
palovarotene in adult and pediatric subjects with FOP. References to Parts B/C/D are to PVO-
1A-202 Parts B/C/D which corresponds to PVO-1A-204, ongoing in France. 
Under the original protocol and Amendment 1, subjects who successfully completed 
Study PVO-1A-201 as well as up to two new adult subjects were followed for up to 24 months. 
Subjects who participated under Amendment 1 will be followed for up to an additional 
48 months. No new subjects will be enrolled under this amendment. 
All subjects will receive non-flare-up based treatment of 5 mg palovarotene once daily (weight-
adjusted doses for skeletally immature subjects). Note: all weight-based dosing will cease when 
subjects become skeletally mature, but radiographic assessment of the growth plate will 
continue until these subjects achieve 100% skeletal maturity at both knee and hand/wrist 
locations performed at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 72. Additional 
radiographic assessments will be performed at Months 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63, 
66, or 69 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% skeletal maturity on 
their last radiographic assessment. 


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Subjects will follow all assessments as outlined in Table 1 and Table 2. Adult subjects who 
cannot receive non-flare-up based treatment will only undergo annual assessments (clinical 
laboratory tests will not be performed). In the event of a flare-up or traumatic event, these 
subjects will receive flare-up-based treatment and undergo all flare-up-based assessments, 
including clinical laboratory tests and radiographs if they have not reached 100% skeletal 
maturity. 
Adverse events will be assessed at every site and remote visit during both non-flare-up based 
and flare-up-based 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. 
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. 
As of 04 December 2019, 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. 
 
Subjects from Amendment 1 Continuing Non-Flare-Up Based Treatment 
Subjects who began non-flare-up based treatment under Amendment 1 will continue this visit 
schedule, and will receive non-flare-up based treatment for up to an additional 48 months. 
Therefore, these subjects may undergo non-flare-up based treatment for up to 72 months over 
the entire study. 
These subjects will follow all procedures and undergo all assessments as specified in the 
Schedule of Assessments in Table 1, including low-dose WBCT scan (excluding head) at all 
annual site visits (Months 12, 24, 36, 48, 60 and 72). Non-flare-up Day 1 is the first day that 
non-flare-up based treatment was initiated, and total duration of treatment will include 
participation under this amendment. 
Remote visits (eg, at home or at a local medical facility; and via telephone contact from clinical 
site personnel) will occur every 3 months unless the Investigator deems that a site visit is 
necessary; urine pregnancy tests will be performed each month for females of childbearing 
potential (FOCBP). 
 
Subjects from Amendment 1 Starting Non-Flare-Up Based Treatment 
Subjects from Amendment 1 who will start non-flare-up based treatment will receive 
non-flare-up based treatment for up to 48 months. These subjects will follow all procedures and 
undergo all assessments as specified in the Schedule of Assessments in Table 2, including 
low-dose WBCT scan (excluding head) at Amendment 3 Screening and at all annual site visits 
(Months 12, 24, 36 and 48). Non-flare-up Day 1 is the first day that non-flare-up based 
treatment is initiated under Amendment 3 for these subjects. 


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18 December 2020 
Remote visits (eg, at home or at a local medical facility; and via telephone contact from clinical 
site personnel) will occur every 3 months unless the Investigator deems that a site visit is 
necessary; urine pregnancy tests will be performed each month for FOCBP. 
 
Part D: 
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 D. Subjects who 
were enrolled in Parts A, B or C who have discontinued the study and were skeletally immature 
at their last assessment will be invited back to participate in the off-treatment Part D safety 
follow-up. These subjects will follow all procedures and undergo all assessments as specified 
in the Schedule of Assessments in Table 4. 
 
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. 
 
Flare-Up Based Treatment 
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 
receive open-label palovarotene treatment as follows: 
• 
20 mg for 4 weeks (28 days) once daily. The first dose will be taken upon flare-up 
confirmation by the Investigator. To be followed by: 
• 
10 mg for 8 weeks (56 days) once daily, for a total flare-up treatment duration of 
12 weeks (84 days); 10 mg treatment may be extended if the flare-up is ongoing and 
continue until the flare-up resolves. Dosing will be extended in 4-week intervals and be 
based on clinical signs and symptoms as assessed by the Investigator. 
Subjects under the age of 18 years will receive weight-adjusted doses of 20 mg palovarotene 
(for 28 days) and 10 mg palovarotene (for 56 days) as shown in Table 5. (Note: all weight-based 
flare-up dosing will cease when subjects are 18 years old, but radiographic assessment of the 
growth plate will continue until these subjects achieve 100% skeletal maturity at both knee and 
hand/wrist locations.) 
 
Table 5 
Weight-Adjusted Palovarotene Doses and Dose De-escalation 
Weight Range 
Category 
20-mg 
Equivalent 
15-mg 
Equivalent* 
10-mg 
Equivalent 
7.5-mg 
Equivalent* 
5-mg 
Equivalent* 
2.5-mg 
Equivalent* 
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 
 
20 mg 
15 mg 
10 mg 
7.5 mg 
5 mg 
2.5 mg 


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18 December 2020 
* In the event of dose de-escalation from 20-mg, 10-mg, or 5-mg equivalent, respectively. 
 
If the subject experiences intolerable side effects, the dose may be reduced to the next lower 
dose as shown in Table 5; if the subject is already receiving the lowest possible dose, then study 
drug will be discontinued. Treatment may be extended after the 84-day treatment period (flare-
up based dosing) if the flare-up is ongoing and continue until the flare-up resolves. Dosing will 
be extended in 4-week intervals based on clinical signs and symptoms as assessed by the 
Investigator, with remote visits performed every 2 weeks while on treatment. 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 or marked 
worsening of the original flare-up), or if the Investigator confirms the presence of a 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 confirmation by the 
Investigator (ie, 4 weeks of 20 mg palovarotene followed by 8 weeks of 10 mg palovarotene 
[or weight-based equivalent]). 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 the 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 follow all procedures and undergo all 
assessments as specified in the Schedule of Assessments in Table 3. 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 non-flare-up based treatment with 5 mg palovarotene 
once daily (weight-adjusted doses for skeletally immature subjects as shown in Table 5). 
Pharmacokinetics of palovarotene dosing will 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, pharmacokinetics blood samples can 
be obtained during any subsequent flare-up dosing cycle. Pharmacokinetic blood samples will 
be collected at pre-dose and 3, 6, 10, and 24 hours post-dose. Subjects who underwent a prior 
flare-up pharmacokinetic assessment will not have flare-up treatment pharmacokinetics 


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18 December 2020 
assessed again. However, these subjects will require a pharmacokinetic assessment during non-
flare-up palovarotene treatment at a 3-month safety assessment (see Section 7.5). 
3.2 
Study Rationale 
Study PVO-1A-202 followed subjects who rolled over from Study PVO-1A-201 and provided 
open-label active treatment to any subject who experienced a subsequent flare-up. This allowed 
for the collection of long-term efficacy and safety data of palovarotene (10 mg for 14 days, 
followed by 5 mg for 28 days), and provided active treatment to all subjects experiencing 
eligible flare-ups including those who were randomized to placebo during Study PVO-1A-201. 
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. 
Fibrodysplasia Ossificans Progressiva 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 non-flare-up-based 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 non-flare-up-based/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 and Amendment 1, adult subjects initiated non-flare-up 
based daily treatment with palovarotene, which was extended to the Pediatric Cohort subjects 
under Protocol Amendment 2. In addition, subjects experiencing an eligible intercurrent flare-
up will restart flare-up based dosing in order to continue exposure to palovarotene and provide 
an optimal treatment for all flare-ups that may occur during the study. 
As of 04 December 2019, 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 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. 
Given the serious identified risk of premature physeal closure, Part D was added 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 in Part A/B/C for skeletally immature 
subjects, who stopped treatment for any reason. 
3.3 
Dose Justification 
Fibrodysplasia Ossificans Progressiva 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 


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18 December 2020 
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 non-flare-up-based 
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 non-flare-up-based/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 non-flare-up-based/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 non-flare-up-based 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 Investigator discretion for persistent 
flare-ups) for all subjects. The flare-up dosage will be adjusted for weight in subjects 
under the age of 18 years. 
• 
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 
immunizations, mandibular blocks for dental work, muscle fatigue, blunt muscle trauma 
from bumps, bruises, 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.10 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 


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18 December 2020 
current Phase 2 and 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 current Phase 2 and Phase 3 studies. Therefore, careful safety 
monitoring and dose modification procedures for intolerable side effects will be employed in 
the current study. 
 
3.4 
Appropriateness of Measurements 
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,23 
magnetic resonance imaging (MRI),24 and radionuclide bone scan.25 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.26 
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 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 assess the primary 
and secondary endpoints will be low-dose WBCT scan (excluding head). 
In order to ensure consistency and standardization, interpretation of the acquired images will 
be performed by a central imaging laboratory. The clinical trial imaging methodology will be 
documented (eg, imaging charter and imaging guideline) prior to study initiation. 
 
3.4.2 
Measures of Functional Disability and General Health 
Two key measures of functional disability include: 
 
• 
The 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-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 


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18 December 2020 
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. 
 
4 
STUDY ENDPOINTS 
4.1 
Primary Endpoints 
The primary endpoint is: 
 
(1) 
Annualized change in new HO volume as assessed by low-dose WBCT scan, excluding 
head. The annualized change from the original protocol, and Amendments 1 and 3, will 
be compared to data collected from the NHS. 
4.2 
Secondary Endpoints 
Note: Baseline is Non-flare-up Day 1. Some subjects may be assessed for up to 72 months. 
 
(1) 
Percent of subjects with new HO at Months 12, 24, 36, 48, 60, 72 and overall. 
(2) 
Change from baseline in ROM as assessed by CAJIS at Months 6, 12, 18, 24, 30, 36, 42, 
48, 54, 60, 66 and 72. 
(3) 
Change from baseline in physical function using age-appropriate forms of the FOP-PFQ 
at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, and 72. 
(4) 
mental function for subjects <15 years old using age-appropriate forms of the PROMIS 
Global Health Scale at Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72. 
 
5 
SELECTION OF STUDY POPULATION 
The target study population consists of up to nine subjects with FOP who have completed Study 
PVO-1A-201 (through Study Day 84), including subjects from Study PVO-1A-202, as well as 
up to two new subjects who did not participate in Study PVO-1A-201 or Study PVO-1A-202. 
No new subjects will be enrolled under this amendment. References to Parts B/C/D are to PVO-
1A-202 Parts B/C/D which corresponds to PVO-1A-204, ongoing in France. 
5.1 
Study Population (Adult and Pediatric Cohorts – Original Protocol and 
Amendment 1) 
As of 04 December 2019, 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. 
5.1.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 


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18 December 2020 
 
(1) 
Completion of Study PVO-1A-201 (through Study Day 84), including any subject from 
Study PVO-1A-202; or Adult Cohort subjects not enrolled in Study PVO-1A-201, have 
the confirmed R206H genetic mutation consistent with FOP, have had at least two acute 
symptomatic flare-ups in the past 2 years but no flare-up symptoms within the past 4 
weeks (including at the time of enrollment), have a CAJIS score of 6 to 16, inclusive, 
and able to receive non-flare-up based dosing. 
(2) 
For the Adult Cohort, subjects under the age of 18 must have knee and hand/wrist 
 maturity. 
(3) 
Written, signed, and dated subject/parent informed consent; and, for subjects who are 
minors, age-appropriate assent (this must be performed according to local regulations). 
5.1.2 
Exclusion Criteria 
(1) 
Simultaneous participation in another clinical research study (except for Studies 
PVO-1A-201, PVO-1A-202, PVO-1A-203, or PVO 1A-001) within the 4 weeks prior to 
Screening. 
(2) 
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 
Study Population for Non-Flare-Up Based Treatment (Adult Cohort - Original 
Protocol and Amendment 1) 
5.2.1 
Inclusion Criteria 
(1) 
Females of child-bearing potential (FOCBP) 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 during treatment 
and for 1 month after treatment or, if sexually active, to use two highly effective methods 
of birth control during and for 1 month after treatment. Additionally, sexually active 
FOCBP subjects must already be using two highly 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 highly effective methods of birth 
control will be clearly defined in the informed consent, and the subject or legally 
authorized representative (eg, parents, caregivers, or legal guardians) must specifically 
sign this section. 
(2) 
Subjects must be accessible for treatment with palovarotene and follow-up. 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. 
5.2.2 
Exclusion Criteria 
(1) 
Weight <20 kg. 
(2) 
Intercurrent known or suspected non-healed fracture at any location. 
(3) 
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. 
(4) 
Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior to 
Screening (signature of the informed consent). 


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18 December 2020 
(5) 
Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential 
increased risk of pseudotumor cerebri. 
(6) 
History of allergy or hypersensitivity to retinoids or lactose. 
(7) 
Concomitant medications that are inhibitors or inducers of cytochrome P450 (CYP450) 
3A4 activity (see Appendix 3). 
(8) 
Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic 
pancreatitis. 
(9) 
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5x ULN. 
(10) Fasting triglycerides >400 mg/dL with or without therapy. 
(11) Female subjects who are breastfeeding. 
(12) Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, 
endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant 
disease. 
(13) 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). 
5.3 
Study Population for Flare-up Based Treatment (Adult and Pediatric Cohorts - 
Original Protocol and Amendment 1) 
5.3.1 
Inclusion Criteria 
(1) 
Symptomatic onset of a flare-up within 7 days before the first dose of study drug and 
defined by the presence of at least two of the following symptoms: pain, soft tissue 
swelling, decreased ROM, stiffness, redness, and warmth. Symptoms must be reported 
by the subject, be consistent with their previous flare-ups, and include a subject-reported 
onset date, and flare-up must be confirmed by the Investigator. 
(2) 
Flare-up is at an appendicular area (upper or lower extremity), abdomen, chest, neck, or 
lower back; and subject has received, is receiving, or is willing to receive treatment per 
standard of care, which may or may not include prednisone (2 mg/kg PO to a maximum 
dose of 100 mg daily) for 4 days. 
(3) 
Females of child-bearing potential (FOCBP) 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 during treatment 
and for 1 month after treatment or, if sexually active, to use two highly effective methods 
of birth control during and for 1 month after treatment. Additionally, sexually active 
FOCBP subjects must already be using two highly 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 highly 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. 
(4) 
Subjects must be accessible for treatment with palovarotene and follow-up. 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. 
5.3.2 
Exclusion Criteria 
(1) 
Weight <20 kg. 


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(2) 
Intercurrent known or suspected non-healed fracture at any location. 
(3) 
Complete immobilization of joint at site of flare-up. 
(4) 
The inability of the subject to undergo imaging assessments using plain radiographs. 
(5) 
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. 
(6) 
Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior to 
Flare-up Screening (signature of the informed consent). 
(7) 
Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential 
increased risk of pseudotumor cerebri. 
(8) 
History of allergy or hypersensitivity to retinoids or lactose. 
(9) 
Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity (see 
Appendix 3). 
(10) Any subject with clinically significant elevations in amylase, lipase, AST, ALT, or 
fasting triglycerides during the most recent clinical laboratory assessment will require 
re-test prior to immediate flare-up-based dosing with palovarotene per the Investigator. 
If upon re-test, the laboratory value in question remains clinically significant abnormal, 
then the subject will not receive flare-up-based treatment for this flare-up. 
(11) Female subjects who are breastfeeding. 
(12) Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, 
endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant 
disease. 
(13) 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). 
(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. 
5.4 
Study Population (All Subjects – Amendments 2 and 3) 
5.4.1 
Inclusion Criteria 
Subjects must meet the following inclusion criterion to be eligible for enrollment: 
 
(1) 
Prior participation in Amendment 1 of the current study (PVO-1A-204). 
(2) 
Written, signed, and dated subject/parent informed consent; and, for subjects who are 
minors, age-appropriate assent (this must be performed according to local regulations). 
(3) 
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 


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authorized representatives (eg, parents, caregivers, or legal guardians) must specifically 
sign this section. 
5.4.2 
Exclusion Criteria 
Subjects with the following exclusion criterion will not be eligible for enrollment: 
 
(1) 
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. 
5.5 
Study Population of Subjects Starting Non-Flare-Up Based Treatment During 
Amendment 3 
5.5.1 
Inclusion Criteria 
Subjects must meet the following inclusion criterion to be eligible for enrollment: 
 
(1) 
Subjects must be accessible for treatment with palovarotene and follow-up. 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. 
(2) 
Subjects must be able to undergo low-dose WBCT scan, excluding head. 
5.5.2 
Exclusion Criteria 
Subjects with the following exclusion criterion will not be eligible for enrollment: 
 
(1) 
Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic 
pancreatitis. 
(2) 
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x 
ULN. 
(3) 
Fasting triglycerides >400 mg/dL with or without therapy. 
(4) 
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). 
5.6 
Prior and Concomitant Medications and Other Study Restrictions 
5.6.1 
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.27 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 (flare-up or 
non-flare-up based): 
• 
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. 


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18 December 2020 
• 
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) or kinase inhibitors, such as imatinib, 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 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. 
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. 
5.6.2 
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, 
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. 
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 


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18 December 2020 
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. 
5.7 
Subject Withdrawal or Early Termination from Study 
Subjects can voluntarily withdraw from the study at any time for any reason. All reasonable 
efforts 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 subject’s safety is at risk. Additional details regarding study drug dose 
modification are provided in Section 6.5. 
If any subject enrolled in Part D chooses to enroll in another clinical trial, all reasonable efforts 
should be made by the study personnel to have the subject continue participation in Study PVO-
1A-204 until their final EOS 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 for non-flare-up based treatment (Table 1 and Table 2), and if 
appropriate, for flare-up based treatment (Table 3), including those assessments subsequent to 
early termination or study drug discontinuation. 
5.8 
Replacement of Subjects 
Subjects who drop out will not be replaced. 
 
6 
STUDY DRUG ADMINISTRATION 
6.1 
Identity of Study Drug 
Palovarotene is a white to off-white crystalline powder with the chemical name 4-[(E)-2- 
(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic 
palovarotene is shown in Figure 1. 
 
Figure 1 Chemical Structure of Palovarotene 
 
 
6.2 
Packaging, Labeling, and Storage 
Study drug supplies provided for this study will be manufactured under Good Manufacturing 
Practices and will be suitable for human use. Palovarotene will be provided in powder-filled 
opaque hard gelatin capsules using standard USP/EP grade excipients in the following dosage 
strengths: 10, 5, 4, 3, 2.5, 2, and 1.5 mg (see Section 3.1). Capsules will be packaged in 
appropriately sized bottles designed for maximum protection. 


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Study drug will be stored in a secured area at the study site with limited access. All study drug 
is to be stored at room temperature (not above 30 C/86 F) and protected from light and 
humidity. 
6.3 
Randomization and Blinding 
This is an open-label study and does not involve randomization or blinding. 
6.4 
Administration 
All subjects will receive non-flare-up based treatment of 5 mg palovarotene once daily (weight-
adjusted doses for skeletally immature subjects). The first day that subjects receive non-flare-
up based treatment will be Non-Flare-Up Day 1. Details for handling, preparing, storing, and 
discarding study drug will be provided to subjects. 
Subjects who began non-flare-up based treatment under Amendment 1 will continue this visit 
schedule, and will receive non-flare-up based treatment for up to an additional 48 months. 
Subjects who will start non-flare-up based treatment will receive non-flare-up based treatment 
for up to 48 months. Subjects who cannot receive non-flare-up based treatment will only 
undergo annual assessments (clinical laboratory tests will not be performed). In the event of a 
flare-up, these subjects will receive flare-up-based treatment and undergo all flare-up based 
assessments, including clinical laboratory tests. 
Flare-up based treatment can begin immediately after the Investigator confirms the presence of 
a flare-up or the presence of a substantial high-risk traumatic event likely to lead to a flare-up. 
Subjects with normal or non-clinically significant abnormal safety laboratory results observed 
within 1 month of flare-up based treatment will not need to have laboratory tests performed at 
Flare-up Day 1. 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 monthly. For subjects receiving flare-up based treatment, Flare-up Day 1 is defined 
as the first day that flare-up based treatment with study drug is administered. 
Subjects will report potential flare-up symptoms or traumatic events to site personnel, and if 
confirmed by the Investigator as associated with a flare-up or, in the case of trauma, likely to 
lead to a flare-up, subjects will immediately begin flare-up based treatment with palovarotene 
20 mg for 4 weeks (28 days) once daily followed by palovarotene 10 mg for 8 weeks (56 days) 
once daily (or weight-based equivalent), for a total duration of 12 weeks (84 days). 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 4-week extension treatment has been completed. Flare-up dosing will be weight-
adjusted for subjects under the age of 18 years (Section 3.1). 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.  Should a subject experience a new 
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 equivalent]). 
Once all flare-ups or traumatic events in a cycle have resolved and flare-up based treatment has 
been completed, subjects will resume non-flare-up based treatment with 5 mg palovarotene 
once daily (weight-adjusted doses for skeletally immature subjects). 


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18 December 2020 
The dose of study drug taken each day will be documented in the subject dosing diary. 
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 5 (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 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. 
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. 
6.6 
Study Drug Accountability 
The Investigator has the ultimate responsibility for the study drug accountability at the study 
site. The Investigator or a designated individual (eg, pharmacist or another appropriate person) 
will maintain records of the study drug’s delivery to the study site and to the subject, the 
inventory at the site (used and unused product containers), the use by each subject, and the 
return to the sponsor or alternative disposition of unused medication. The study drug must be 
kept in a locked area that is monitored for temperature at least once per day. Access to study 
drug will be restricted to authorized study personnel and used only in accordance with the 
approved protocol. At the conclusion of the study, any remaining study drug supplies will be 
returned to the sponsor or its designee. The sponsor or its designee will ensure that a final report 
of study drug accountability is prepared and maintained by the Investigator. The Investigator 


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18 December 2020 
agrees not to supply or administer study drug to any person except those subjects participating 
in this study. 
6.7 
Assessment of Subject Compliance 
Compliance will be based on the amount of study drug dispensed to the subject and returned to 
the site. In addition, subjects with flare-up-based treatment will be provided diaries to record 
the date study drug was taken. The diaries will be collected by the study personnel at the end 
of the dosing period. 
 
7 
STUDY PROCEDURES AND ASSESSMENTS 
Under Amendment #5 and subsequent amendments, subjects with open epiphyseal growth 
plates will undergo knee (A/P) and hand/wrist radiographs (P/A view) at the clinical site every 
6 months. Additional knee and hand/wrist radiograph assessments will also be performed every 
3 months (±2 weeks) in skeletally immature subjects who (1) received flare up dosing in the 
period of time since their last assessment; and (2) had not achieved 100% skeletal maturity on 
their last assessment. These radiographic assessments will not be performed remotely unless 
the Investigator determines they can be performed at a local medical facility. A description of 
the knee and hand/wrist radiograph assessments is provided in Section 7.3.2. 
References to Parts B/C/D are to PVO-1A-202 Parts B/C/D which corresponds to PVO-1A-
204, ongoing in France. 
7.1 
Screening, Recruitment, and Informed Consent 
Once the PVO-1A-204 Protocol Amendment 6 is approved at the clinical site, subjects currently 
enrolled in the study will be contacted, informed about the Amendment 6 changes, and given 
the opportunity to enrol under this amendment. PVO-1A-202 Parts B/C/D corresponds to PVO-
1A-204, ongoing in France. 
Subjects who began non-flare-up based treatment during the original protocol or Amendment 1 
will continue this visit schedule, and will receive non-flare-up based treatment for up to an 
additional 48 months. Subjects who started non-flare-up based treatment under Amendment 3 
will receive non-flare-up based treatment for up to 48 months. 
Potential subjects/parents wishing to participate must sign the informed consent/assent per local 
requirements prior to undergoing any study-related procedures. 
Part D was added for skeletally immature subjects who stopped taking study medication for any 
reason before completion of Part A/B/C.  Part D includes yearly visits for up to a 2-year follow-
up period following last dose. Maximum length of study is 72 months. No dosing will occur 
during Part D. 
As per the global addendum (dated 15Apr2020) to Study PVO-1A-202 Amendment 5, 
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. 


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18 December 2020 
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, Table 3 and Table 4, as appropriate, unless a subject is unable 
to undergo a procedure due to safety concerns (eg, risk of flare) or physical limitation (pain or 
locked position). 
7.2.1 
Medical History 
No new subjects will be enrolled under Amendment 5 and a repeat medical history is not 
necessary. 
For subjects receiving flare-up-based treatment, the flare-up assessment will include 
subject-reported current flare-up location, symptoms, and probable causes, documented on 
Flare-up Day 1. 
7.2.2 
Physical Examination 
For subjects from Amendment 1 continuing non-flare-up based treatment, a physical 
examination of all body systems is to be documented at Months 12, 24, 36, 48, 60 and 72. 
 
For subjects from Amendment 1 starting non-flare-up based treatment, a physical examination 
of all body systems is to be documented at Amendment 2 Screening and at Months 6, 12, 24, 
36 and 48. 
For subjects in Part D, a physical examination of all body systems is to be documented at Year 
1 and Year 2 post last dose of study treatment. 
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 AEs. 
7.2.3 
Body Weight and Linear Growth Assessments 
For subjects from Amendment 1 continuing non-flare-up based treatment, body weight will be 
documented every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 
51, 54, 57, 60, 63, 66, 69 and 72). 
For subjects from Amendment 1 starting non-flare-up based treatment, body weight will be 
documented at Amendment 3 Screening and every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 
27, 30, 33, 36, 39, 42, 45 and 48). 
For subjects receiving flare-up-based treatment, body weight will 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 from Amendment 1 continuing non-flare-up based treatment with open epiphyseal 
growth plates at the most recent assessment will have linear growth assessments (in triplicate) 
by stadiometer and knee height measurements (in triplicate) at Months 6, 12, 18, 24, 30, 36, 42, 
48, 54, 60, 66, and 72. 
Subjects from Amendment 1 starting non-flare-up based treatment that are under the age of 
18 years and who enrolled with open epiphyseal growth plates at the most recent assessment 
will have linear growth assessments (in triplicate) by stadiometer and knee height 


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18 December 2020 
measurements (in triplicate) at Screening. Subjects with open epiphyseal growth plates at this 
assessment will also be evaluated at Months 6, 12, 18, 24, 30, 36, 42 and 48. 
For subjects in Part D, body weight will be documented at Year 1 and Year 2 post last dose of 
study treatment. Subjects in Part D will have linear growth assessments (in triplicate) by 
stadiometer and knee height measurements (in triplicate) at Year 1 and Year 2 post last dose of 
study treatment. 
Once a subject is 18 years old, triplicate linear growth and knee height assessments will no 
longer be required. In Part D subjects will stop participation once they reach 18 years of age. 
Linear growth measurements will be performed by trained and qualified study personnel. The 
stadiometric measurement instructions will include practices that reduce measurement error 
including calibration of equipment, proper subject positioning, and measurement capture. 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. 
7.2.4 
Vital Signs 
Vital signs (temperature, respiratory rate, blood pressure, and heart rate) will be assessed for all 
subjects. 
For subjects from Amendment 1 continuing non-flare-up based treatment, vital signs 
(temperature, respiratory rate, blood pressure, and heart rate) will be assessed every 3 months 
(Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 
72). 
For subjects from Amendment 1 starting non-flare-up based treatment, vital signs will be 
assessed at Amendment 3 Screening and every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 
30, 33, 36, 39, 42, 45, and 48). 
For subjects receiving flare-up based treatment, vital signs will be assessed 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. 
For subjects in Part D, vital signs will be assessed at Year 1 and Year 2 post last dose of study 
treatment. 
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. 
7.2.5 
Electrocardiogram 
For subjects from Amendment 1 continuing non-flare-up based treatment, a 12-lead 
electrocardiogram (ECG) will be performed at Months 12, 24, 36, 48, 60, and 72. 
For subjects from Amendment 1 starting non-flare-up based treatment, an ECG will be 
performed at Amendment 3 Screening, Non-flare-up Day 7, and at Months 6, 12, 24, 36, and 
48. 


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18 December 2020 
For subjects receiving flare-up based treatment, an ECG will be performed at Flare-up Cycle 
Safety Day 1, Flare-up Cycle Safety Day 7, and at the End of Flare-up Cycle Safety 
Assessments. 
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. 
7.2.6 
Clinical Laboratory Tests 
Blood and urine samples will be collected for hematology, biochemistry (includes lipids), and 
urinalysis testing. 
For subjects from Amendment 1 continuing non-flare-up based treatment, blood and urine 
samples will be collected every 6 months (Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 
72). 
For subjects from Amendment 1 starting non-flare-up based treatment, blood and urine samples 
will be collected at Amendment 3 Screening and every 6 months (Months 6, 12, 18, 24, 30, 36, 
42 and 48). 
For subjects receiving flare-up-based treatment, blood and urine samples will be collected at 
Flare-up 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 safety laboratory results observed within 1 month of 
flare-up-based treatment will not need to have laboratory tests performed at Flare-up Day 1. 
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 
monthly during non-flare-up based 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 urinalysis results are abnormal, a microscopic 
evaluation will be completed. If results are needed promptly (eg, Screening for eligibility), 
analysis of samples can be completed at a local, qualified laboratory. 
The total blood volume drawn from a subject from Amendment 1 continuing non-flare-up based 
treatment over the course of the entire study (up to 72 months) will range from approximately 
60 mL (in the case of no flare-ups) to 170 mL (in the case of two flare-ups treated per year, or 
a total of 12 flare-ups treated during the entire study). The total blood volume drawn from a 
subject from Amendment 1 starting non-flare-up based treatment during Amendment 2 over the 
course of the entire study (up to 48 months) will range from approximately 42 mL (in the case 


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18 December 2020 
of no flare-ups) to 120 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 
laboratory data for that timepoint, or reassessed at the next scheduled timepoint based on the 
subject’s current clinical status (eg, AEs, vital signs) and previous laboratory measures. 
If a local laboratory is utilized, the investigative site should notify the study team if the local 
laboratory cannot test all the analytes listed in Table 6. If the total thyroxine (Total T4), free 
T4, uric acid, gamma glutamyl transferase, inorganic phosphorous, very low-density 
lipoprotein, or globulin parameters are not available through the local laboratory, and 
alternative arrangements cannot be made, testing of these analytes may be omitted provided 
other subject-assessments of thyroid function (ie, thyroid-stimulating hormone), lipid 
metabolism (ie, triglycerides, low-density lipoprotein, high-density lipoprotein, and total 
cholesterol), and protein metabolism (ie, total protein and albumin) are available and confirmed 
to be stable as per the Investigator. 
Alternative arrangements to test the listed analytes are to be made if the Investigator, Medical 
Monitor, or sponsor determines that they have the potential to impact subject safety. In the event 
the local laboratory is unable to test any other analytes, they may be omitted in exceptional 
circumstances after consultation with the sponsor. Such exceptions will not be applied to any 
of the key safety analytes, as outlined below and in the clinical safety laboratory manual. 
For subjects with two or more consecutive missing assessments of key safety laboratory 
analytes, including triglycerides, ALT, AST, bilirubin, lipase, and amylase (as outlined in 
Section 7.3, Special Safety Assessments), blood collection for evaluation of missing analytes 
should be performed as soon as possible. If such analytes have not been evaluated over a 
prolonged period of time (>6 months during non-flare-up-based treatment or >8 weeks during 
flare-up treatment), a successful repeat assessment should be performed within 1 month. If key 
safety laboratory tests cannot be evaluated within 1 month, the subject should be discussed with 
the Medical Monitor and the EC/IRB, as necessary. If the subject is unable to have venous 
specimens collected, use of microliter collection techniques and capillary specimens, where 
available, may be utilized to assess subject safety. Local laboratory results should be promptly 
documented in the appropriate eCRF. 
Table 6 presents the clinical laboratory parameters that will be assessed in this study. 
 


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18 December 2020 
Table 6 
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 
High-density lipoprotein (HDL) 
Total cholesterol 
Low-density lipoprotein (LDL) 
 
Very low-density lipoprotein (VLDL) 
Hematology: 
 
Hemoglobin 
Platelets 
Hematocrit 
White blood cell count (including differentials) 
Red blood cell count 
Neutrophils 
Packed cell volume 
Lymphocytes 
Mean corpuscular volume 
Monocytes 
Mean corpuscular hemoglobin 
Eosinophils 
Mean corpuscular hemoglobin concentration 
Basophils 
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 females of child bearing potential receiving palovarotene, a blood or urine pregnancy test 
(with sensitivity of at least 50 mIU/mL) will be conducted monthly in Parts A, B and C. 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. 
7.2.8 
Adverse Events 
Adverse event (AE) monitoring will be conducted throughout the study for all subjects. Adverse 
events will be assessed at every site and remote visit during both non-flare-up-based and flare-
up-based treatment. The AE, serious adverse event (SAE) and death reporting period begins at 
the time of informed consent and continues through study completion.  Adverse events, SAEs, 
and deaths will be assessed at every site and remote visit during non-flare-up-based treatment, 
flare-up-based treatment, Part C or SC and EOT/EOS + 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. Limb/joint AEs reported by 


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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 (SAEs) must be reported within 24 hours as described in Section 9.1.8. 
7.2.9 
Concomitant Medications 
Concomitant medications will be assessed at every site and remote visit during both non-flare-
up based and flare-up-based treatment and in Part D. 
See Section 5.6.1 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 every 3 months 
using the age-appropriate C-SSRS and at all visits during the Flare-up Cycle Safety 
Assessments (see Appendix 5). 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. Study personnel administering the 
questionnaire will receive formal training to ensure accuracy and consistency in application of 
the instrument. 
For subjects from Amendment 1 continuing non-flare-up based treatment, assessment using the 
C-SSRS will occur every 3 months (Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 
45, 48, 51, 54, 57, 60, 63, 66, 69 and 72). 
For subjects from Amendment 1 starting non-flare-up based treatment, assessment using the 
C-SSRS will occur at Amendment 3 Screening and every 3 months (Months 3, 6, 9, 12, 15, 18, 
21, 24, 27, 30, 33, 36, 39, 42, 45 and 48). Any subject reporting a type 4 or 5 suicidal ideation 
or any suicidal behavior within 1 month prior to Amendment 3 Screening will not be eligible 
to receive study drug. 
Any subject experiencing a type 4 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 counselling as appropriate. 
7.3.2 
Knee and Hand/Wrist Radiographs 
Due to the potential for palovarotene to cause adverse effects on long-bone growth, all subjects 
at the time of enrolment into Study PVO-1A-204 with open epiphyseal growth plates at 
Screening had knee (A/P) and hand/wrist radiographs (P/A). 
For subjects from Amendment 1 continuing non-flare-up based treatment with open epiphyseal 
growth plates at the most recent assessment, knee (A/P) and hand/wrist radiographs (P/A view, 
preferable on the left side) will be performed at the clinical site at Months 6, 12, 18, 24, 30, 36, 
42, 48, 54, 60, 66 and 72. 


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18 December 2020 
For subjects from Amendment 1 starting non-flare-up based treatment with open epiphyseal 
growth plates at the most recent assessment, knee (A/P) and hand/wrist radiographs (P/A) view, 
preferable on the left side) will be performed at Amendment 3 Screening. Subjects for whom 
radiographs were performed within the last 3 months will not need to repeat radiographs at 
Screening. Subjects with open epiphyseal growth plates at this assessment will also be evaluated 
at the clinical site at Months 6, 12, 18, 24, 30, 36, 42 and 48 at the clinical site. 
Subjects who are skeletally immature at the time of study drug discontinuation and entering 
Part D (Y1 and Y2 post last dose of study treatment) will have follow-up knee (A/P view) and 
hand/wrist radiographs (P/A view, preferably on the left side) every year.  
Additional knee and hand/wrist radiograph assessments will also be performed every 3 months 
(±2 weeks) in skeletally immature subjects who (1) received flare-up dosing in the period of 
time since their last assessment; and (2) had not achieved 100% skeletal maturity on their last 
assessment. The 3-month radiographic assessments will be performed at the clinical site unless 
the Investigator determines they can be performed at a local medical facility. 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. Limb/joint AEs in these subjects will be 
evaluated by clinical and radiographic assessments deemed appropriate by the Investigator. 
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 and will be followed under Amendment 3 and 
subsequent amendments of Study PVO-1A-204. Of note, in addition to the knee and hand/wrist 
radiographs described in Section 7.3.2, WBCT scans acquired from subjects under the age of 
18 years 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. 
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), 


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18 December 2020 
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 (see Section 7.2.6) 
for all subjects in Part C. 
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 (see Section 7.2.6) for all 
subjects in Part C. 
During palovarotene treatment, drug therapy should be discontinued if any of the following 
occur: 
• 
 ULN 
• 
Jaundice is observed 
• 
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). 
7.3.7 
Lipase/Amylase 
Amylase and lipase will be monitored as part of the biochemistry testing (see Section 7.2.6) for 
all subjects in Part C. 
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. 


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18 December 2020 
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 
Impaired hearing has been reported in subjects taking retinoids. 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) will be discontinued from treatment. 
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 


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18 December 2020 
hormone deficiency. In some cases, death has occurred with other retinoids with certain of the 
abnormalities previously noted. 
7.4 
Efficacy Assessments 
Subjects who began non-flare-up based treatment during Amendment 1 will continue this visit 
schedule, and will receive non-flare-up based treatment for up to an additional 48 months. 
Therefore, these subjects may undergo non-flare-up based treatment for up to 72 months over 
the entire study.  Subjects who will start non-flare-up based treatment will receive non-flare-up 
based treatment for up to 48 months. 
7.4.1 
Low-Dose Whole Body Computed Tomography 
For subjects from Amendment 1 continuing non-flare-up based treatment, a low-dose WBCT 
scan (excluding head) will be performed during annual site visits at Months 12, 24, 36, 48, 60 
and 72. 
For subjects from Amendment 1 starting non-flare-up based treatment, a low-dose WBCT scan 
(excluding head) will be performed at Amendment 3 Screening and during annual site visits at 
Months 12, 24, 36 and 48. 
For subjects in Part D, a low-dose WBCT scan (excluding head) will be performed during 
annual site visits at Y1 and Y2 post last dose of study treatment. 
Interpretation of the CT scan will document the absence or presence of HO across various body 
regions, volume of total body HO, and presence and volume of new HO at follow-up visits. 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. 
For subjects from Amendment 1 continuing non-flare-up based treatment, age-appropriate 
forms of the FOP-PFQ will be administered every 6 months (Months 6, 12, 18, 24, 30, 36, 42, 
48, 54, 60, 66 and 72). 
For subjects from Amendment 1 starting non-flare-up based treatment, age-appropriate forms 
of the FOP-PFQ will be administered at Amendment 3 Screening and every 6 months (Months 
6, 12, 18, 24, 30, 36, 42 and 48). 
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. 
To evaluate the effect of palovarotene on physical function, age-appropriate forms of the FOP-
PFQ will be administered. The adult form of the FOP-PFQ will be completed by subjects 15 
years of age and older (see Appendix 2A). Two 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 and a proxy-completed form developed for 5- to 14-year-olds (see Appendix 2B and 
Appendix 2C, respectively). 


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18 December 2020 
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 
For subjects from Amendment 1 continuing non-flare-up based treatment, age-appropriate 
forms of the PROMIS Global Health Scale will be administered every 6 months (Months 6, 12, 
18, 24, 30, 36, 42, 48, 54, 60, 66, and 72). 
For subjects from Amendment 1 starting non-flare-up based treatment, age-appropriate forms 
of the PROMIS Global Health Scale will be administered at Amendment 3 Screening and every 
6 months (Months 6, 12, 18, 24, 30, 36, 42 and 48). 
age and mental health in subjects <15 years, age-appropriate forms of the PROMIS Global 
Health Scales will be administered. The adult form of the PROMIS Global Health Scale will 
be administered to subjects 15 years of age and older (see Appendix 7A). 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 7B and Appendix 7C, 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 
For subjects from Amendment 1 continuing non-flare-up based treatment, CAJIS will be 
administered every 6 months (Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66 and 72). 
For subjects from Amendment 1 starting non-flare-up based treatment, CAJIS will be 
administered at Amendment 3 Screening and every 6 months (Months 6, 12, 18, 24, 30, 36, 42 
and 48). 
Range of motion will be assessed by the Investigator using CAJIS (see Appendix 1). The CAJIS 
should be assessed by the same Investigator at each time point. The CAJIS assessment may be 
performed remotely or by videoconferencing. 
7.5 
Pharmacokinetics 
The pharmacokinetics of palovarotene dosing will be assessed in all subjects during non-
flare-up and flare-up-based treatments. 
During non-flare-up palovarotene treatment, pharmacokinetic blood samples will be collected 
at the first 3-month safety assessment. If blood samples cannot be obtained during the first 3-
month safety assessment, or if the subject is on flare-up-based treatment, then the non-flare-up 
treatment pharmacokinetic blood sample can be obtained during any subsequent 3-month safety 
visit. 
Pharmacokinetics of palovarotene dosing 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. 


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PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
Pharmacokinetic blood samples will be collected at pre-dose and 3, 6, 10, and 24 hours post-
dose. Subjects who underwent a prior flare-up dosing pharmacokinetic assessment will not 
require a repeat assessment of flare-up dosing pharmacokinetics. However, these subjects will 
require a pharmacokinetic assessment for non-flare-up palovarotene dosing at a 3-month safety 
visit. 
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 
pharmacokinetic blood sampling days will be recorded. 
Detailed instructions for collection, storage, labeling, and shipment of all samples will be 
provided in the Laboratory Manual. 
7.6 
Data Monitoring Committee 
A DMC will 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 8.6).  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. 
7.7 
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-204 during the COVID-19 
pandemic and 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 C EOT/EOS and be invited to participate 
in Part D and undergo assessments outlined in Table 4. 


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18 December 2020 
(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):  
(a) 
Non-flare-up-based 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 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. 
Non-flare-up-based 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. 
Non-flare-up-based 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  


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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 
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, ECG.  


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(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 
documented in accordance with local regulations/EC requests and guidance. All contacts 
with subjects must be filed in the source records. 
 
A risk mitigation assessment will be performed for each subject at the site in order to determine 
how their participation may be impacted.  Sites must ensure that appropriate measures are 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 and sites to adequately monitor subject safety. 
 
8 
STATISTICAL AND ANALYTICAL PLANS 
This study is intended to assess whether a non-flare-up based dosing regimen, combined with 
higher doses during times of flare-ups, will result in a lower incidence of new HO formation. 
As this is an open-label study with no comparator arm, use of subject data from Study PVO-1A-
001 (Natural History Study [NHS]) will form the basis for a control arm. Additional analysis 
of the flare-up-based treatment regimen will be described in the Statistical Analysis Plan (SAP). 
A summary of the general methods and strategies for analysis is provided in the sections below. 
A more comprehensive SAP will be written that will describe the manner in which the analysis 
will be performed. 
References to Parts B/C/D are to PVO-1A-202 Parts B/C/D which corresponds to PVO-1A-
204, ongoing in France. 
8.1 
General Methods 
For purposes of assessing the efficacy of the non-flare-up based dosing regimen, low-dose 
WBCT imaging data obtained under the original protocol and all amendments will be 
combined. 
8.2 
Sample Size 
The new HO volume data as assessed by low dose WBCT scan, excluding head, from the 
original protocol and all amendments will be combined. The sample size was fixed by the 
number of subjects enrolled in the original protocol and Amendment 1 and was not based on 
power calculations. 
8.3 
Study Populations 
The following populations will be analyzed under Amendment 3 (and all subsequent 
amendments): 
• 
The Full Analysis Set (FAS) includes all enrolled subjects having a baseline 
• 
HO volume measurement and at least one post-baseline HO volume measurement. For 
efficacy comparisons to the NHS, the FAS will also include subjects enrolled in the NHS 
with available baseline and at least one post-baseline HO volume measurements. 


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• 
The Per-Protocol Set (PPS) is a subset of the 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 PPS will also include subjects in the NHS with available 
baseline and at least one post-baseline HO volume measurements and with no major 
protocol deviations that are expected to interfere with assessments of the primary 
endpoint. 
• 
The Safety Analysis Set (SAS) includes all enrolled subjects receiving at least one dose 
of palovarotene during Amendment 2. For safety comparisons to the NHS, the SAS will 
also include subjects enrolled in the NHS with available post-baseline follow-up. 
• 
The Pharmacokinetic Analysis Set (PAS) is a subset of the SAS including subjects with 
evaluable pharmacokinetics data. 
8.4 
Baseline and Disease Characteristics (including Medical History) 
Baseline and disease characteristics will be tabulated descriptively (eg, number and percentage 
of subjects for each category for categorical parameters, and the number, mean, standard 
deviation, and range for continuous parameters). 
8.5 
Subject Disposition 
Subject disposition will be listed and summarized. 
8.6 
Extent of Exposure 
The extent (duration) of exposure will be determined from the date of first dose of study drug 
through the date of last dose of study drug. For times during which subjects are receiving flare-
up based treatment, tabulation of the number of days at the higher dose(s) will be presented. An 
assessment of the proportion of subjects who are able to tolerate the higher doses will be 
performed. 
8.7 
Efficacy 
8.7.1 
Primary Efficacy 
The primary efficacy endpoint is the annualized change in new HO volume (as assessed by low-
dose WBCT scan, excluding head). The primary efficacy analysis comparing the annualized 
change in new HO volume between subjects treated with palovarotene and untreated subjects 
from the NHS will be conducted using a weighted linear mixed effects (wLME) model. 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 the NHS and the current trial. 
Baseline HO volume divided by age will be the only covariate included in the model.  As HO 
volume is non-decreasing, the LME model will be fit 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. 
The estimated difference in the annualized change in new HO volume between subjects treated 
with palovarotene and untreated subjects and its associated Wald statistic will be used for 
hypothesis testing. Hypothesis testing will be performed using a two-sided, type I error rate of 
5%. 


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8.7.2 
Secondary Efficacy 
Secondary efficacy variables for non-flare-up based treatment will include the following: 
percent of subjects with new HO, change from baseline in ROM as assessed by CAJIS, change 
from baseline in physical function using age-appropriate forms of the FOP-PFQ, and change 
ental function 
for subjects <15 years old using age-appropriate forms of the PROMIS Global Health Scale. 
The secondary efficacy endpoints will be summarized by visit and, where applicable, compared 
to the relevant time point from the NHS. 
8.8 
Safety 
The safety analysis will be descriptive in nature. Safety evaluations will include AE and SAE 
reporting, ECGs (for subjects receiving treatment), 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. 
Evaluation of subjects with open epiphyseal growth plates at the most recent assessment will 
include knee (A/P) and hand/wrist radiographs (P/A view) for assessment of epiphyseal growth 
plate; and standardized stadiometry and knee height (in triplicate) for assessment of linear 
growth. 
Any limb/joint AEs reported by these subjects will be evaluated by clinical and radiographic 
assessments as deemed appropriate by the Investigator. 
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. 
8.8.1 
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, 14 June 2010. 
Tabulations will include an overall incidence of at least one AE, incidence within body system, 
and incidence by preferred term. 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. 
8.8.2 
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 (see Appendix 5). 


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18 December 2020 
8.8.3 
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 non-flare-up based 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. 
8.9 
Pharmacokinetics 
Plasma palovarotene concentrations will be summarized for the PAS by descriptive statistics of 
n, arithmetic mean, standard deviation (SD), coefficient of variance, geometric mean, median, 
minimum, and maximum. 
8.10 
Pharmacodynamics 
Exploratory analyses will be performed to assess potential exposure/biomarker relationships. 
 
9 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
9.1 
Adverse Event and Serious Adverse Event Documentation, Severity Grading, 
and Reporting 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product during the course of a study and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal product. 
Disease, signs, symptoms, and/or laboratory abnormalities already existing prior to the use of 
the product are not considered AEs after administration of the study product unless they reoccur 
after the subject has recovered from the pre-existing condition or they represent an exacerbation 
in intensity or frequency. 
Only a clinically significant laboratory test abnormality, physical examination finding, or other 
objective finding should be reported as an AE, whether it represents an exacerbation or a new 
abnormality. 
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. 


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• 
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.  The site will be provided with 
specific criteria for the coding of AEs. 
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, 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 


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18 December 2020 
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: 
(1) 
None 
(2) 
Study drug dosage modified 
(3) 
Study drug dosage interrupted 
(4) 
Study drug permanently discontinued 
9.1.7 
Outcome of Adverse Event 
The outcome of the AEs will be recorded as follows: 
(1) 
Event resolved with no sequelae 
(2) 
Event resolved with sequelae 
(3) 
Event ongoing 
(4) 
Death 
9.1.8 
Reporting of Serious Adverse Event 
All SAEs must be reported within 24 hours to the Medpace Clinical Safety Group: 
 
Medpace SAE hotline – USA: 
Tel: 
 
Fax: 
 
E-mail: 
 
 
Medpace SAE hotline – Europe: 
Tel: 
 
Fax: 
 
E-mail: 
 
 
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. 
PPD
PPD
PPD
PPD
PPD
PPD


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18 December 2020 
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. 
9.1.10 
Follow-Up of Adverse Events and Serious Adverse Events 
The AE, SAE and death reporting period for the non-flare-up based treatment and the flare-up-
based treatment begins at the time of informed consent and continues through study completion, 
including Part D + 30 days. References to Parts B/C/D are to PVO-1A-202 Parts B/C/D which 
corresponds to PVO-1A-204, ongoing in France. 
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. 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. 
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. 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. 


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One signed and dated copy of the ICF will be given 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, the Investigator, 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 8), inclusive of 
any subsequent amendment(s), and that are consistent with the ICH GCP, EU Directive 
2001/20/EC, 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. 


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18 December 2020 
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. 
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. 


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18 December 2020 
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. 
• 
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. 
The participating site, 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 the site receives 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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18 December 2020 
9.5 
Data Capture and Management 
The sponsor or designee will provide the study site 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 the Investigator 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 the participating study center. Subsequently, the individual Investigator may 
publish results from the study in compliance with their agreement with the sponsor. 
9.8 
Coordinating Investigator 
The Coordinating Investigator will be designated by the Sponsor prior to database lock. The 
Coordinating Investigator will approve the final clinical study report for Study PVO-1A-204. 


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18 December 2020 
10 
INVESTIGATOR AGREEMENT 
I have read Protocol PVO-1A-204 (France-Specific) Amendment 6, dated 18 December 2020: 
 
A Phase 2, Open-Label, Efficacy and Safety Study of an 
-Specific Agonist (Palovarotene) to 
Prevent Heterotopic Ossification in Subjects with Fibrodysplasia Ossificans Progressiva (FOP). 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good 
Clinical Practices and applicable regulatory requirements and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations. 
 
 
 
 
 
 
 
Investigator (printed name) 
 
 
 
 
 
 
 
 
 
Investigator signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational site or name of institution and location (printed) 


PROTOCOL PVO-1A-204, AMENDMENT 6 
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18 December 2020 
11 
REFERENCES 
 
(1) 
Lilijesthrom M, Bogard B. The Global Known FOP Population. In: FOP Drug 
Development Forum. Boston, MA; 2016. 
(2) 
Shore EM, Feldman GJ, Xu M, Kaplan FS. The genetics of fibrodysplasia ossificans 
progressiva. Clin Rev Bone Miner Metab. 2005;3(3-4):201–204. 
(3) 
Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic 
errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005;116(5):e654-661. 
doi:10.1542/peds.2005-0469 
(4) 
Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and 
genetic aspects. Orphanet J Rare Dis. 2011;6(80). doi:10.1186/1750-1172-6-80 
(5) 
Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. The clinical features and 
natural history of 34 patients. J Bone Joint Surg Br. 1982;64(1):76-83. 
(6) 
Kaplan F, Glaser D. Thoracic insufficiency syndrome in patients with fibrodysplasia 
ossificans progressiva. 
Clin 
Rev Bone 
Miner 
Metab. 
2005;3(3-4):213-216. 
doi:10.1385/BMM:3:3-4:213 
(7) 
Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM. Early mortality 
and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J 
Bone Joint Surg Am. 2010;92(3):686-691. doi:10.2106/JBJS.I.00705 
(8) 
Kaplan FS, Tabas JA, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology 
of fibrodysplasia ossificans progressiva. An endochondral process. J Bone Joint Surg 
Am. 1993;75(2):220-230. 
(9) 
Kaplan FS, Le Merrer M, Glaser DL, et al. Fibrodysplasia ossificans progressiva. Best 
Pract Res Clin Rheumatol. 2008;22(1). doi:10.1016/j.berh.2007.11.007 
(10) Glaser DL, Rocke DM, Kaplan FS. Catastrophic falls in patients who have fibrodysplasia 
ossificans progressiva. Clin Orthop. 1998;(346):110-116. 
(11) Kaplan FS, Pignolo RJ, Shore EM. From mysteries to medicines: drug development for 
fibrodysplasia ossificans progressiva. Expert Opin Orphan Drugs. 2013;1(8):637-649. 
doi:10.1517/21678707.2013.825208 
(12) Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nat Med. 
2011;17(4):420-421. doi:10.1038/nm0411-420 
(13) Shimono K, Tung W-E, Macolino C, et al. Potent inhibition of heterotopic ossification 
by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011;17(4):454-460. 
doi:10.1038/nm.2334 
(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) Weston AD, Chandraratna RAS, Torchia J, Underhill TM. Requirement for RAR-
mediated gene repression in skeletal progenitor differentiation. J Cell Biol. 
2002;158(1):39-51. doi:10.1083/jcb.200112029 


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CLEMENTIA PHARMACEUTICALS INC.  
PROPRIETARY AND CONFIDENTIAL 
18 December 2020 
(17) Weston AD, Blumberg B, Underhill TM. Active repression by unliganded retinoid 
receptors in development: less is sometimes more. J Cell Biol. 2003;161(2):223-228. 
doi:10.1083/jcb.200211117 
(18) 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 
(19) 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 
(20) 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 
(21) 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 
(22) 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. 
(23) 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. 
(24) 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 
(25) 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 
(26) 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 
(27) The International Consortium on Fibrodysplasia Ossificans Progressiva. The medical 
management of fibrodysplasia ossificans progressiva: current treatment considerations. 
Kaplan F., Shore EM, Pignolo RJ, eds. Clin Proc Int Consort FOP. 2011;4:1-100. 





SAP_001.pdf: 
Statistical Analysis Plan 
 
A Phase 2, Open-Label Extension, Efficacy and Safety Study of a 
RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous 
Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP) 
 
Study Number:  PVO-1A-202 Part A 
 
Original Protocol: 04 June 2014 
Amendment 1: 30 September 2014 
Amendment 2: 22 June 2015 
Amendment 3: 10 March 2016 
  
  
Statistical Analysis Plan Version: Final v2 
Statistical Analysis Plan Date: 03 April 2017 
 
 
Clementia Pharmaceuticals Inc. 
4150 Saint Catherine Street West, Suite 550 
Montreal, Quebec, H3Z 2Y5 
Canada 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Clementia Pharmaceuticals Inc. is strictly prohibited except to the extent required under applicable laws 
or regulations.  Persons to whom the information is disclosed must be informed that the information is confidential  
 
 




STATISTICAL ANALYSIS PLAN, PROTOCOL PVO-1A-202 PART A 
PALOVAROTENE 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
03 APRIL 2017 
PROPRIETARY AND CONFIDENTIAL 
Table of Contents 
Table of Contents .............................................................................................................................3 
List of Tables ...................................................................................................................................5 
List of Abbreviations .......................................................................................................................6 
1 Introduction ................................................................................................................................7 
2 Overview ....................................................................................................................................7 
2.1 Study Objectives ..................................................................................................................7 
2.1.1 Primary Objective ..........................................................................................................7 
2.1.2 Secondary Objectives .....................................................................................................7 
2.2 Study Population ..................................................................................................................8 
2.3 Study Design ........................................................................................................................8 
2.4 Study Treatment ...................................................................................................................8 
2.5 Randomization and Blinding ...............................................................................................9 
3 General .......................................................................................................................................9 
3.1 Adjustments for Covariates..................................................................................................9 
3.2 Handling of Dropouts or Missing Data ................................................................................9 
3.3 Interim Analyses ................................................................................................................10 
3.4 Multicenter Studies ............................................................................................................10 
3.5 Multiple Comparison/Multiplicity .....................................................................................10 
3.6 Examination of Subgroups .................................................................................................10 
3.7 Study Day and Flare-up Study Day ...................................................................................10 
4 Analysis Populations ................................................................................................................10 
4.1 Enrolled Population ...........................................................................................................10 
4.2 Untreated Population .........................................................................................................10 
4.3 Treated Population .............................................................................................................10 
4.4 Efficacy Population ............................................................................................................11 
4.5 Per Protocol Population .....................................................................................................11 
5 Treatment Period and Non-Treatment Period ..........................................................................11 
6 Subject Data .............................................................................................................................11 
6.1 Subject Disposition and Analysis Populations ..................................................................11 
6.2 Eligibility Criteria ..............................................................................................................12 
6.3 Protocol Deviations ............................................................................................................12 


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6.4 Demographic and Other Baseline Characteristics .............................................................12 
6.5 Medical History .................................................................................................................12 
6.6 Flare-ups Starting During Part A .......................................................................................12 
6.7 Concomitant Medications ..................................................................................................12 
6.8 Duration of Exposure .........................................................................................................13 
6.9 Duration of Participation in Part A ....................................................................................14 
6.10 Compliance ........................................................................................................................14 
7 Efficacy Data ...........................................................................................................................14 
7.1 Primary Efficacy ................................................................................................................15 
7.2 Secondary/Exploratory Efficacy ........................................................................................15 
7.2.1 Volume of HO and HO Grades ....................................................................................15 
7.2.2 Area of HO and HO Scores .........................................................................................16 
7.2.3 New or Enlarged HO and Severity of New HO ...........................................................17 
7.2.4 Presence of Soft Tissue Swelling (Edema) and/or Cartilage Formation, Severity of 
Edema, and Volume of Edema ...............................................................................................18 
7.2.5 Active Range of Motion ...............................................................................................18 
7.2.6 Cumulative Analogue Joint Involvement Scale ...........................................................20 
7.2.7 Global Assessment of Movement ................................................................................20 
7.2.8 FOP-Physical Function Questionnaire (FOP-PFQ) .....................................................20 
7.2.9 PROMIS Global Health ...............................................................................................22 
7.2.10 Flare-up Pain and Swelling ..........................................................................................23 
7.2.11 Assistive Devices and Adaptations for Daily Living ...................................................24 
7.2.12 Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers ..................................24 
7.2.13 Duration of Active Symptomatic Flare-up ..................................................................25 
8 Safety Data ...............................................................................................................................26 
8.1 Adverse Events ..................................................................................................................26 
8.2 Safety Laboratory Assessment ...........................................................................................27 
8.3 Vital Signs ..........................................................................................................................28 
8.4 Body Weight ......................................................................................................................28 
8.5 Knee and Hand/Wrist Radiograph .....................................................................................28 
8.6 Linear Growth Assessment ................................................................................................29 


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8.7 Electrocardiogram ..............................................................................................................29 
8.8 Physical Examination.........................................................................................................31 
8.9 Columbia-Suicide Severity Rating Scale ...........................................................................31 
9 References ................................................................................................................................32 
Appendices .....................................................................................................................................33 
Appendix 1.  PROMIS T-Score Conversions ................................................................................33 
 
List of Tables 
Table 1.  
Arcs of Motion ........................................................................................................... 19 
Table 2.  
Sample Derivations for the Percentage of Worst Score for the FOP-PFQ ................. 22 
Table 3.  
Rescaled PROMIS Global Health Scale Scores ......................................................... 23 
Table 4.  
Potentially Clinically Significant Safety Laboratory Values ..................................... 27 
Table 5.  
Potentially Clinically Significant Vital Sign Values .................................................. 28 
Table 6.  
Abnormal Electrocardiogram Categories ................................................................... 30 
Table 7.  
Potentially Clinical Significant Electrocardiogram Values ........................................ 31 
 
 
 
 


STATISTICAL ANALYSIS PLAN, PROTOCOL PVO-1A-202 PART A 
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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
CAJIS 
Cumulative Analogue Joint Involvement Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
FAS 
Full Analysis Set 
FOP 
Fibrodysplasia Ossificans Progressiva 
FOP-PFQ 
FOP-Physical Function Questionnaire 
FPS-R 
Faces Pain Scale-Revised 
HO 
heterotopic ossification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NRS 
numeric rating scales 
PCS 
potentially clinically significant 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
RARγ 
retinoic acid receptor gamma 
ROM 
range of motion 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
ULN 
upper limit of normal 
US 
ultrasound 
 
 
 


STATISTICAL ANALYSIS PLAN, PROTOCOL PVO-1A-202 PART A 
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1 
Introduction 
This Statistical Analysis Plan (SAP) describes the detailed analyses to be performed for Study 
PVO-1A-202 Part A.  These analyses are based on Amendment 2 of the protocol dated 
22 June 2015 and Amendment 3 of the protocol dated 10 March 2016.  The analyses to be 
performed for Study PVO-1A-202 Part B will be described in a separate SAP.  Note that 
analyses related to the Follow-up Component objectives as described in Section 2.1 will be 
addressed in the Part B SAP.  
2 
Overview 
2.1 
Study Objectives 
2.1.1 Primary Objective 
The primary objectives are: 
 To evaluate the long-term safety and efficacy of prior palovarotene treatment in FOP 
subjects who completed Study PVO-1A-201 (Follow-up Component; up to 12 months). 
 To evaluate the safety and efficacy of palovarotene in FOP subjects experiencing up to 
two, new, distinct flare-ups (Flare-up Component; up to 36 months).  Efficacy will be 
based on the ability of palovarotene to prevent heterotopic ossification (HO) at the new, 
distinct flare-up site as assessed by low-dose computed tomography (CT) scan (or plain 
radiographs for subjects unable to undergo CT scan). 
2.1.2 Secondary Objectives 
The secondary objectives for the Follow-up Component are:  
 To evaluate the amount of HO at the original flare-up site by plain radiograph. 
 To evaluate active range of motion (ROM) by goniometer at the original flare-up site. 
 To evaluate ROM as assessed by the Cumulative Analogue Joint Involvement Scale for 
FOP (CAJIS). 
 To evaluate the subject and Investigator global assessment of movement at the original 
flare-up site. 
 To evaluate pain and selling at the original flare-up site using numeric rating scales 
(NRS) or the Faces Pain Scale-Revised (FPS-R) in subjects under 8 years of age. 
 To evaluate physical function using age-appropriate forms of the FOP-Physical Function 
Questionnaire (FOP-PFQ). 
 To evaluate physical and mental health using age-appropriate forms of the Patient 
Reported Outcomes Measurement Information System (PROMIS) Global Health Scale. 
 To evaluate the use of assistive devices and adaptations for daily living by FOP subjects. 
 To evaluate bone, cartilage, angiogenesis, and inflammation biomarkers; and explore 
correlations between changes from baseline in biomarkers and clinical efficacy. 
The secondary objectives for the Flare-up Component are:  
 To evaluate the effect of palovarotene on active ROM at the new, distinct flare-up site as 
assessed by goniometer. 


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 To evaluate the effect of palovarotene on ROM as assessed by CAJIS. 
 To evaluate the effect of palovarotene by the subject and Investigator global assessment 
of movement at the new, distinct flare-up site. 
 To evaluate the effect of palovarotene on physical function using age-appropriate forms 
of the FOP-PFQ. 
 To evaluate the effect of palovarotene on physical and mental health using age-
appropriate forms of the PROMIS Global Health Scale. 
 To evaluate the effect of palovarotene on the use of assistive devices and adaptations for 
daily living by FOP subjects. 
 To evaluate the effects of palovarotene on soft tissue swelling and cartilage formation at 
the new, distinct flare-up site as assessed by magnetic resonance imaging (MRI); or the 
effect of palovarotene on soft tissue swelling as assessed by ultrasound (US) in subjects 
unable to undergo MRI. 
 To evaluate bone, cartilage, angiogenesis, and inflammation biomarkers; and explore 
correlations between changes from baseline in biomarkers and clinical efficacy. 
2.2 
Study Population 
Approximately 40 subjects who completed Study PVO-1A-201 will be enrolled in Study 
PVO-1A-202 Part A. 
2.3 
Study Design 
Study PVO-1A-202 Part A is a Phase 2, multicenter, event-based, open-label extension of Study 
PVO-1A-201.  This open-label extension will give subjects who completed Study PVO-1A-201 
the opportunity to be followed for up to an additional 36 months, and receive open-label 
palovarotene should they experience up to two, new, distinct flare-ups. 
All enrolled subjects will participate in the Follow-up Component of the study.  The Follow-up 
Component will include visits at Study Screening and Study Months 6, 12, 18, 24, 30, and 36.  
Study Day 1 will be the date of informed consent.  Visit windows are +/2 weeks.  Assessments 
related to flare-ups during the Follow-up Component will be evaluated at the original flare-up 
site from Study PVO-1A-201.   
Subjects who experience an eligible flare-up will participate in the Flare-up Component of the 
study.   The Flare-up Component will include visits at Flare-up Screening and Flare-up Weeks 2, 
4, 6, 9, and 12.  Flare-up Day 1 will be the date of first dose of study drug for the flare-up.  Visit 
windows are +/- 3 days.  Assessments related to flare-ups during the Flare-up Component will be 
evaluated at new flare-up sites from Study PVO-1A-202 Part A.  Note that subjects may have 
more than one unique new flare-up and that each flare-up will be assessed and analyzed 
independently. 
2.4 
Study Treatment 
Subjects who experience an eligible flare-up will receive palovarotene 10 mg for 14 days 
followed by palovarotene 5 mg for 28 days or exposure equivalent doses based on subject 


STATISTICAL ANALYSIS PLAN, PROTOCOL PVO-1A-202 PART A 
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PROPRIETARY AND CONFIDENTIAL 
weight.  Weight-adjusted doses of palovarotene estimated to achieve exposures equivalent to 10 
mg and 5 mg are: 
Weight Range 
Category 
10-mg Equivalent 
5-mg Equivalent 
2.5-mg Equivalent * 
20 to <40 kg 
6 mg 
3 mg 
1.5 mg 
40 to <60 kg 
8 mg 
4 mg 
2 mg 
≥60 kg 
10 mg 
5 mg 
2.5 mg 
* In the event of dose de-escalation. 
In the event the subject requires dose de-escalation due to an intolerable side effect in Study 
PVO-1A-201, then the dose the subject will receive for a subsequent flare-up will be determined 
by the Investigator and the Medical Monitor.  Dose reduction to one half of the palovarotene 
dose may also occur should the subject experience an adverse event that may otherwise result in 
study drug discontinuation; if a subject is already receiving the lowest possible dose, then study 
drug will be discontinued. 
Subjects who do not experience an eligible flare-up will not be treated. 
2.5 
Randomization and Blinding 
This is an open-label study and does not involve randomization or blinding. 
3 
General 
Categorical data will be summarized with counts and percentages.  Percentages will be 
calculated based on the number of non-missing values and will be reported to one decimal place. 
Continuous data will be summarized with descriptive statistics including the number of 
non-missing values, mean, standard deviation, standard error, median, minimum, and maximum.  
Minimum and maximum will be reported to the same precision as the raw values, mean and 
median will be reported to one additional decimal place, and standard deviation and standard 
error will be reported to two additional decimal places.  Some discretion may be applied. 
All data will be listed.  When listings will be provided instead of summaries or require additional 
description, they are described in this document. 
3.1 
Adjustments for Covariates 
Baseline covariates may be added to statistical models as the data allow.  The sample size of this 
study may preclude the inclusion of covariate effects in some instances. 
3.2 
Handling of Dropouts or Missing Data 
As there is no effective treatment for these subjects, it is assumed they will be highly motivated 
to adhere to the protocol and treatment visits.  Thus, it is expected that there will be limited 
missing data, and most subjects will complete the study.  The primary analysis will be performed 
using observed data only.  Missing data will not be replaced.  


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3.3 
Interim Analyses 
No interim analysis is planned. 
3.4 
Multicenter Studies 
A review of by-center effects will be performed in the context of data listing review.  However, 
the sample size precludes formal assessment of by-center effects. 
3.5 
Multiple Comparison/Multiplicity 
As this is an extension of an initial proof-of-concept study, no correction for multiple testing is 
planned. 
3.6 
Examination of Subgroups 
The sample size in this study is not sufficient to allow for rigorous assessment of outcomes by 
subgroups, and the study is not powered for subgroup assessment.  However, exploratory 
assessments of the outcomes may be performed by a number of extrinsic or intrinsic factors, 
including age of the subject, location of the flare-up, number of flare-up treatments, or other 
variables as appropriate. 
3.7 
Study Day and Flare-up Study Day 
Study Day will be determined from the date of informed consent (Study Day 1); Study Day -1 
will be the day immediately prior to Study Day 1.   
Flare-up Study Day will be determined from the date of first dose of a treated flare-up (Flare-up 
Study Day 1); Flare-up Study Day -1 will be the day immediately prior to Flare-up Study Day 1.   
4 
Analysis Populations 
There will be five populations defined for the analysis. 
4.1 
Enrolled Population 
The Enrolled Population will include all subjects enrolled in Study PVO-1A-202 Part A.  
Analyses based on the Enrolled Population will generally be summarized by treatment 
(Untreated, Palovarotene 10 mg/5 mg) and in total.  The Enrolled Population will be the primary 
population for demographic and baseline summaries and for the analysis of adverse events.    
4.2 
Untreated Population 
The Untreated Population will include all subjects who did not take any palovarotene in 
Study PVO-1A-202 Part A.   
4.3 
Treated Population 
The Treated Population will include all subjects who took at least one dose of palovarotene in 
Study PVO-1A-202 Part A.  Analyses based on the Treated Population will generally be 
summarized in total.  Note that data collected for flare-ups may use each flare-up as the unit of 


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PROPRIETARY AND CONFIDENTIAL 
analysis rather than each subject.  The Treated Population will be the primary population for 
analysis of safety assessments performed at Flare-up Component visits.  
4.4 
Efficacy Population 
The Efficacy Population will include all subjects in the Treated Population who had an evaluable 
Week 6 or Week 12 image (CT scan or x-ray).  Analyses based on the Efficacy Population will 
generally be summarized in total.  Note that data collected for flare-ups may use each flare-up as 
the unit of analysis rather than each subject.  The Efficacy Population will be the primary 
population for analysis of efficacy assessments performed at Flare-up Component visits.   
4.5 
 Per Protocol Population 
The Per Protocol (PP) Population will include all subjects in the Efficacy Population with no 
major protocol deviations that may impact the efficacy assessment.  Exclusions from the PP 
Population will be identified prior to database lock.  Analyses based on the PP Population will 
generally be summarized in total.  Note that data collected for new unique flare-ups may use 
each flare-up as the unit of analysis rather than each subject.  The PP Population will be a 
secondary population for analysis of selected efficacy assessments performed at Flare-up 
Component visits. 
5 
Treatment Period and Non-Treatment Period 
The Treatment Period is defined as the period of days during the Flare-up Component(s) from 
Flare-up Study Day 1 through the date of completion of the Flare-up Component (ie, Flare-up 
Study Day 84).  The Treatment Period includes all days during Flare-up Components for subjects 
in the Treated Population.      
The Non-Treatment Period is defined as the period of days outside of the Treatment Period.  The 
Non-Treatment Period includes all days in the study for subjects in the Untreated Population and 
days before, after, or in between Flare-up Components for subjects in the Treated Population. 
6 
Subject Data 
6.1 
Subject Disposition and Analysis Populations 
The following will be summarized with counts and percentages of subjects in the Enrolled 
Population: 
 Subjects who were enrolled (Enrolled Population). 
 Subjects who did not take any palovarotene (Untreated Population). 
 Subjects who took at least one dose of palovarotene (Treated Population). 
 Subjects in the Treated Population who had an evaluable Week 6 or Week 12 image (CT 
scan or x-ray) (Efficacy Population). 
 Subjects in the Efficacy Population who did not have major protocol deviations that may 
impact the efficacy assessment (PP Population). 
 Subjects who discontinued from Part A early along with reasons for discontinuation.  
 Subjects who completed Part A. 


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6.2 
Eligibility Criteria 
Eligibility criteria (inclusion/exclusion) will be listed. 
6.3 
Protocol Deviations 
Major protocol deviations will be identified from the clinical data prior to freezing the database 
for Part A and may include, but are not limited to departures from the inclusion/exclusion 
criteria, non-compliance with investigational product, use of restricted concomitant medications, 
and non-compliance with study procedures.  Major protocol deviations will be summarized for 
the Enrolled Population. 
6.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics such as age, sex, race, ethnicity, height, and 
weight will be summarized for the Enrolled, Efficacy, and PP Populations. 
6.5 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
Version 17.0).  The incidence of medical history conditions will be summarized by MedDRA 
body system and preferred term for the Enrolled Population. 
6.6 
Flare-ups Starting During Part A 
The number of treated flare-ups will be summarized with counts and percentages of subjects in 
the Treated, Efficacy, and PP Populations. 
Treated flare-up data as reported by the subject and the Investigator including symptoms, 
probable causes, and location(s) will be summarized for the Treated, Efficacy, and PP 
Populations. 
Data for untreated flare-ups will be listed. 
6.7 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary (March 2014).  
Glucocorticoids taken for a flare-up are defined as courses of glucocorticoids that start within 9 
days after the start of the flare-up and are specified as taken for the current flare-up on the 
electronic case report form (eCRF).  Courses of glucocorticoids are defined as days of 
continuous treatment allowing for up to a 2-day interruption. 
The use of the following concomitant medications will be summarized by anatomic therapeutic 
class (ATC) term and preferred term for the Enrolled Population: 
 Prior medications that were on-going at Study Day 1 excluding glucocorticoids. 
(Medications with start date before Study Day 1 and end date on or after Study Day 1.)   
 New-onset medications during the Non-Treatment Period excluding glucocorticoids.  
(Medications with start date on or after Study Day 1 and not during the Treatment 
Period.) 


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 Glucocorticoids taken for flare-ups during the Non-Treatment Period.   
 New-onset glucocorticoids during the Non-Treatment Period.  (Courses of 
glucocorticoids with start date on or after Study Day 1 and not during the Treatment 
Period, and not taken for treated flare-up.)     
The use of the following concomitant medications will be summarized by anatomic therapeutic 
class (ATC) term and preferred term for the Treated Population: 
 Prior medications that were on-going at Flare-up Study Day 1 excluding glucocorticoids.  
(Medications with start date before Flare-up Study Day 1 and end date on or after 
Flare-up Study Day 1.) 
 New-onset medications during the Treatment Period excluding glucocorticoids.  
(Medications with start date on or after Flare-up Study Day 1 and on or before the date of 
completion of the Flare-up Component, ie, Day 84.) 
 Glucocorticoids taken for treated flare-ups.     
 New-onset glucocorticoids during the Treatment Period.  (Courses of glucocorticoids not 
taken for the treated flare-up with start date on or after Flare-up Study Day 1 and on or 
before the date of completion of the Flare-up Component.) 
For the purposes of analysis, incomplete medication start and stop dates will be imputed.  If a 
medication start date is incomplete, January will be imputed for missing month and the first day 
of the month will be imputed for missing day.  If a medication stop date is incomplete, December 
will be imputed for missing month and the last day of the month will be imputed for missing day.  
If the imputed medication stop date is after the date of study completion, the date of study 
completion will be used instead. 
A listing of courses of glucocorticoids will include additional derived data such as start and stop 
dates with associated Flare-up Day, start day of the glucocorticoid relative to the start of the 
flare-up, duration of use, and total amount taken. 
6.8 
Duration of Exposure 
Duration of exposure to study drug for each treated flare-up will be calculated from the date of 
first dose for the flare-up to the date of last dose for the flare-up.  Duration of exposure to study 
drug for each subject will be calculated as the number of days exposed to study drug, ie, the sum 
of the exposure for each flare-up.  
Days of exposure to study drug for flare-ups and subjects will be summarized for the Treated 
Population with descriptive statistics.  Weeks of exposure to study drug will be summarized with 
counts and percentages of flare-ups in the Treated Population according to the following 
categories: 
 ≤ 2 weeks 
 >2 – 4 weeks 
 >4 – 6 weeks 
Note that flare-ups with exposure over 42 days (due to windowing) will be included in the last 
category. 


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Dose reductions (no dose reductions, any dose reductions) will be summarized with counts and 
percentages of flare-ups and subjects in the Treated Population.   
The number of days after flare-up onset to the date of first dose of study drug for the flare-up 
will be summarized for the Treated Population with descriptive statistics.  
6.9 
Duration of Participation in Part A 
Duration of participation in Part A will be calculated from the date of informed consent to the 
date of completion of Part A/discontinuation.  Months of participation will be calculated as days 
of participation / 30.5 and summarized for the Enrolled Population with descriptive statistics.  
Months of participation will also be summarized with counts and percentages of subjects in the 
Enrolled Population according to the following categories: 
 ≤ 6 months 
 >6 – 12 months 
 >12 – 18 months 
 >18 – 24 months 
 >24 – 30 months 
 >30 – 36 months 
6.10 Compliance 
Compliance to study drug for each treated flare-up will be calculated based on the number of 
actual capsules taken and the expected number of capsules as specified in the protocol for 42 
days of dosing.  The number of actual capsules will be calculated as the number of capsules 
dispensed – the number of capsules returned – the number of capsules lost.  For example, a 
subject who took 10 capsules and was expected to take 42 capsules would be 10/42 = 23.8% 
compliant. 
Percent compliance will be summarized for the Treated Population with descriptive statistics.  
Categories of percent compliance (<80%, ≥80%) will be summarized for the Treated Population 
with counts and percentages of flare-ups. 
7 
Efficacy Data 
Efficacy assessments at Flare-up Component visits will generally be presented in total for the 
Efficacy Population.  The primary efficacy analysis and selected other efficacy analyses will also 
be presented for the PP Population.  Efficacy assessments at Follow-up Component visits will be 
listed. 
Imaging Reads 
Imaging data includes results from CT scan, x-ray, MRI, and US.  Results will be read and 
interpreted using two different review processes (Primary Read and Global Read) as described in 
the study protocol.      
The Primary Read review will be performed by two independent musculoskeletal radiologists 
during the study as images are made available.  If there is sufficient agreement between the 


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independent reviews, both will be used for analysis.  If there is insufficient agreement between 
the independent reviews, an adjudication review will be performed and used for analysis.  
Imaging procedures performed (yes, yes but not evaluable, no) will be summarized at scheduled 
visits with counts and percentages of subjects or flare-ups as appropriate.   
The Global Read review will be performed at the end of the study by a global review team with 
access to all imaging modalities concurrently, as well as, selected clinical data for an individual 
subject.  The main objective of the Global Read review is to reduce any potential variability 
created by the Primary Read process.  More specifically, the Global Read review will resolve 
some of the structured independence of the Primary Read review where cases were evaluated on 
a time point-by-time point basis for each flare-up location, and each imaging modality was 
interpreted in isolation.  The Global Read review will include assessments of the presence of HO 
including whether there is a new and/or enlarged lesion and the presence and severity of edema. 
The outcomes from the pre-planned Primary Read review will be used to determine the primary 
conclusions for this study.  However, outcomes from the Global Read review will be used to 
further explicate the palovarotene treatment effect, and in developing and designing future 
clinical trials for the FOP program. 
7.1 
Primary Efficacy 
CT scan (or x-ray for subjects unable to undergo CT scan) will be performed at: 
 Screening/Baseline, Week 6, and Week 12 (Flare-up Component). 
The primary efficacy analysis is the proportion of flare-ups with no new HO at Week 12 as 
assessed by CT scan (or by x-ray for subjects unable to undergo CT scan).  Note that “no new 
HO at Week 12” means no new HO at Week 12 compared to baseline. 
The presence of HO at baseline and the incidence of no new HO and new HO at post-baseline 
visits will be summarized with counts and percentages of flare-ups.   
Similar analyses will be performed for subgroups defined by baseline edema severity (no edema, 
any edema, mild edema, moderate edema, severe edema, and moderate or severe edema [higher-
intensity flare-ups]).  See Section 7.2.4 for a description of edema determination. 
7.2 
Secondary/Exploratory Efficacy  
7.2.1 Volume of HO and HO Grades 
Volume of HO and HO grades (defined below) will be determined from CT scan at visits as 
specified in Section 7.1 for primary efficacy.   
The volume of HO at baseline will be calculated as the sum of the volumes for each lesion.  The 
volume of new HO at post-baseline visits will be calculated as follows: 
1. If there is no new HO, impute new volume = 0.  (NVOL = 0) 
2. If there is new HO  


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a. Subtract the volume of baseline HO from the volume of post-baseline HO for 
each lesion.  (new volume at each lesion = NVOL1, NVOL2, … NVOLL where L 
is the number of lesions) 
b. If the volume of post-baseline HO < the volume of baseline HO for a given lesion 
i, impute new volume = 0.  (NVOLi = 0) 
c. Calculate the total volume of new HO.  (NVOL = NVOL1 + NVOL2 + … + 
NVOLL) 
If an adjudication review is performed, the volume from the adjudication review will be used for 
analysis.  Otherwise, the average of the volumes from the independent reviews will be used for 
analysis.   
Volume of HO at baseline and volume of new HO at post-baseline visits will be summarized 
with descriptive statistics.  Similar summaries will be provided for the subgroup of flare-ups with 
new HO at any post-baseline visit. 
HO lesions will be graded according to the following scale: 
 Grade 0 – Imputed when there is no new HO 
 Grade 1 – Fluid attenuation without evidence of calcification at CT 
 Grade 2 – Calcification of soft tissues without evidence of bone formation 
 Grade 3 – Immature bone formation 
 Grade 4 – Mature bone with cortical differentiation 
The HO grade at baseline will be calculated as the maximum HO grade across lesions.  The new 
HO grade at post-baseline visits will be calculated as follows: 
1. If there is no new HO, impute new HO grade = 0.   
2. If there is new HO  
a. If there was no baseline HO, calculate the maximum HO grade across lesions. 
b. If there was baseline HO, calculate the maximum HO grade across lesions where 
there was no baseline HO. 
HO grade at baseline and new HO grade at post-baseline visits will be summarized with counts 
and percentages of flare-ups. 
7.2.2 Area of HO and HO Scores 
Area of HO and HO scores will be determined from x-ray.  Subjects unable to undergo CT scan 
will have x-ray performed at: 
 Screening/Baseline, Week 6, and Week 12 (Flare-up Component). 
Area of HO at baseline will be calculated as the sum of the areas for each lesion.  The area of 
new HO at post-baseline visits will be calculated using both anterior/posterior (AP) and lateral 
views as follows: 
1. If there is no new HO, impute new area = 0.  (NAREA = 0) 
2. If there is new HO  


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a. Subtract the area of baseline HO from the area of post-baseline HO for each 
lesion.  (NAREA1, NAREA2, … NAREAL where L is the number of lesions) 
b. If the area of post-baseline HO < the area of baseline HO for a given lesion i, 
impute new area = 0.  (NAREAi = 0) 
c. Calculate the total area of new HO.  (NAREA = NAREA1 + NAREA2 + … + 
NAREAi) 
For each review, the maximum area from the AP or lateral view will be used for analysis. 
If an adjudication review is performed, the area from the adjudication review will be used for 
analysis.  Otherwise, the average of the areas from the independent reviews will be used for 
analysis.   
Area of HO at baseline and area of new HO at post-baseline visits will be listed.   
HO lesions will be scored according to the following scale: 
 0 – No HO 
 1 – Single or multiple spicules (punctate) or islands (non-contiguous) of HO 
 2 – Coalescing islands or reticular complexes of bone 
 3 – Single contiguous HO having longest dimension ≤1/2 the diameter of the reference 
normotopic bone in any projection 
 4 – Single contiguous HO having longest dimension >1/2 but ≤1 diameter of the 
reference normotopic bone in any projection 
 5 – Single contiguous HO having longest dimension >1 but ≤2 diameter of the reference 
normotopic bone in any projection  
 6 – Single contiguous HO having longest dimension >2 diameters of the reference 
normotopic bone in any projection 
The HO score at baseline will be calculated as the maximum HO score across lesions.  The new 
HO score at post-baseline visits will be calculated as follows: 
1. If there is no new HO, impute new HO score = 0.   
2. If there is new HO  
a. If there was no baseline HO, calculate the maximum HO score across lesions. 
b. If there was baseline HO, calculate the maximum HO score across lesions where 
there was no baseline HO. 
HO score at baseline and new HO score at post-baseline visits will be listed. 
7.2.3 New or Enlarged HO and Severity of New HO 
New HO lesions are those that did not exist at baseline.  Enlarged HO lesions are lesions that 
existed at baseline but increased in volume (or area by x-ray) post-baseline.  The incidence of 
new HO lesions only, enlarged HO lesions only, or both new HO and enlarged HO lesions will 
be summarized at each scheduled visit with counts and percentages of flare-ups. 
The severity of new HO (mild, moderate, severe) will be summarized at each scheduled visit 
with counts and percentages of flare-ups. 


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7.2.4 Presence of Soft Tissue Swelling (Edema) and/or Cartilage Formation, Severity of 
Edema, and Volume of Edema 
MRI (or US for subjects unable to undergo MRI) will be performed at: 
 Screening/Baseline, Week 6, and Week 12 (Flare-up Component). 
Note that US does not include an assessment of cartilage formation.  If an adjudication review is 
performed, the severity and volume of edema from the adjudication review will be used for 
analysis.  Otherwise, the maximum severity and the average volume of edema from the 
independent reviews will be used for analysis.  Note also that when edema is assessed as mild 
with US, moderate will be imputed for analysis.  
The presence of edema and the presence of cartilage formation will be summarized at each 
scheduled visit with counts and percentages of flare-ups.   
The severity of edema (no edema, any edema, mild edema, moderate edema, severe edema, 
moderate or severe edema [higher intensity flare-ups]) will be summarized at each scheduled 
visit with counts and percentages of flare-ups.   
The shift in severity of edema from baseline to each post-baseline visit will also be summarized 
with counts and percentages of flare-ups. 
Volume of edema at each scheduled visit will be summarized with descriptive statistics.       
7.2.5 Active Range of Motion  
Range of motion (ROM) at the primary and secondary joints will be assessed using a goniometer 
at: 
 Screening/Baseline, Week 6, and Week 12 (Flare-up Component). 
Arcs of motion as defined in Table 1 will be calculated based on raw ROM measurements.  If 
any of the contributing raw ROM measurements are missing, the arc of motion will not be 
calculated.  Percent of normal arc of motion will be calculated as 100 x arc of motion / normal 
adult arc of motion. 
 


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Table 1.  
Arcs of Motion 
Joint 
Arc of Motion 
Calculation Based on Raw ROM 
Measurements 
Normal Adult Arc of 
Motion (degrees) 
Hip 
Extension/Flexion 
Extension + Flexion 
140 
 
Abduction/Adduction 
Abduction + Adduction 
60 
 
Total Arc of Motion 
Extension + Flexion + Abduction + 
Adduction 
200 
Knee 
Total Arc of Motion 
Extension + Flexion 
135 
Shoulder 
Total Arc of Motion 
Flexion + Abduction-glenohumeral 
+ Abduction-shoulder complex 
490 
Elbow 
Extension/Flexion 
Extension + Flexion 
150 
 
Supination/Pronation 
Supination + Pronation 
160 
 
Total Arc of Motion 
Extension + Flexion + Supination + 
Pronation 
310 
Wrist 
Total Arc of Motion 
Extension + Flexion 
150 
Ankle 
Dorsiflexion/Plantarflexion 
Dorsiflexion + Plantarflexion 
70 
 
Subtalar Inversion/Subtalar 
Eversion 
Subtalar Inversion + Subtalar 
Eversion 
50 
 
Total Arc of Motion 
Dorsiflexion + Plantarflexion + 
Subtalar Inversion + Subtalar 
Eversion 
120 
Cervical Spine 
Extension/Flexion 
Extension + Flexion 
90 
 
 
Lateral  
45 
 
 
Rotation 
60 
 
Total Arc of Motion 
Extension + Flexion + Lateral + 
Rotation 
195 
Jaw 
Total Arc of Motion 
Opening 
35 mm 
Lumbar Spine 
 
Flexion 
6 cm 
 
 
Extension 
1 cm 
 
Total Arc of Motion 
Flexion + Extension 
7 cm 
Source:  Norken and White (2011)1 
 
Percent of normal arc of motion values and changes from baseline will be summarized at each 
scheduled visit with descriptive statistics.  Summaries will be provided separately for: 
 Percent of normal total arc of motion at the primary joint (subjects have one total arc of 
motion at the primary joint) 
 Percent of normal arc of motion at the primary joint by joint and arc of motion (subjects 
may have more than one arc of motion at the primary joint) 
 Percent of normal arc of motion at the secondary joints by joint and arc of motion 
(subjects may have more than one arc of motion at one or more secondary joints) 


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Similar summaries for percent of normal total arc of motion will be provided for subgroups 
defined by presence of new HO at any post-baseline visit (new HO, no new HO).  
7.2.6 Cumulative Analogue Joint Involvement Scale 
Range of motion at the primary and secondary joints will also be assessed using the Cumulative 
Analogue Joint Involvement Scale (CAJIS) at: 
 Screening/Baseline, Week 6, and Week 12 (Flare-up Component). 
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). 
The CAJIS Mobility subscore 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). 
The CAJIS Total score, CAJIS Upper Extremity subscore, and CAJIS Mobility subscore and 
changes from baseline will be listed.   
7.2.7 Global Assessment of Movement  
Flare-up movement compared to baseline will be assessed by the subject (or parent proxy) and 
Investigator at: 
 Week 6 and Week 12 (Flare-up Component). 
Assessment results will be listed.   
7.2.8 FOP-Physical Function Questionnaire (FOP-PFQ) 
Age-appropriate forms of the FOP-PFQ will be administered to subjects (or parent proxy) at: 
 Screening/Baseline, Week 2, Week 4, Week 6, Week 9, and Week 12 (Flare-up 
Component). 
The adult form will be administered to subjects 15 years and older.  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 questions are 
described in detail in Appendices 7A, 7B, and 7C of the protocol.   


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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. 
The Upper Extremities subscore will be calculated as: 
 The sum of the scores from 15 questions (questions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 
25, and 26) and ranges from 15x1 = 15 to 15x5 = 75 for the adult form. 
 The sum of the scores from 18 questions (questions 1, 2, 6, 7, 8, 9, 10, 11, 16, 17, 18, 19, 
21, 22, 23, 24, 25, and 26) and ranges from 18x1 = 18 to 18x5 = 90 for the pediatric 
form. 
The Mobility subscore will be calculated as: 
 The sum of the scores from 13 questions (questions 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 
24, 27, and 28) and ranges from 13x1 = 13 to 13x5 = 65 for the adult form. 
 The sum of the scores from 8 questions (questions 3, 4, 5, 12, 13, 14, 15, and 20) and 
ranges from 8x1 = 8 to 8x5 = 40 for the pediatric form. 
The Total score, Upper Extremities subscore, and Mobility subscore are defined based on 
information from PROMIS and Hays et al (2013)2 for the adult form and a medical review of the 
questions for the pediatric form. 
If a subject is missing some (but not more than 20%) of the contributing question scores, the 
Total score, Upper Extremities subscore, or Mobility subscore 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.  The 
determination for sufficient non-missing scores will be made independently for the Total score, 
Upper Extremities subscore, and Mobility subscore. 
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 2 illustrates some 
sample derivations of the percentage of worst score. 


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Table 2.  
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% 
 
Percentage of worst scores and changes from baseline will be summarized at each scheduled visit 
with descriptive statistics.  Similar summaries will be provided for the percentage of worst 
Mobility Subscore for the subgroup of subjects with flare-ups in lower extremities and for the 
percentage of worst Upper Extremity Subscore for the subgroup of subjects with flare-ups in the 
upper extremities.   
Note that flare-ups in the lower extremities include the following flare-up locations reported by 
the Investigator: abdomen, ankle or foot, distal lower extremities, hip, knee, lower back, and 
lumbar spine.  Flare-ups in the upper extremities include the following flare-up locations 
reported by the Investigator: chest, cervical spine, head, jaw, distal upper extremities, elbow, 
shoulder, wrist or hand, thoracic spine, and upper back. 
7.2.9 PROMIS Global Health 
An age-appropriate form of the PROMIS Global Health short form will be administered to 
subjects (or parent proxy) at: 
 Screening/Baseline, Week 2, Week 4, Week 6, Week 9, and Week 12 (Flare-up 
Component). 
The adult form will be administered to subjects 15 years and older.  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 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.  The questions are described in detail in 
Appendices 8A, 8B, and 8C of the protocol.   
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 3. 


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Table 3.  
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 detail in Appendix 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. 
T-scores and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Data from adult and pediatric forms will be summarized separately. 
7.2.10 Flare-up Pain and Swelling 
Flare-up pain and swelling will be assessed at: 
 Screening/Baseline, Week 2, Week 4, Week 6, Week 9, and Week 12 (Flare-up 
Component). 
Adults and pediatric subjects 8 years and older will rate the pain associated with their flare-ups 
using a scale from 0 (no pain) to 10 (worst pain ever experienced).  Pediatric subjects less than 
9 years old will rate pain using the Faces Pain Scale – Revised (FPS-R), which ranges from 0 (no 
pain) to 10 (very much pain) in 2-point increments.  Swelling associated with flare-ups will be 
rated on a scale from 0 (no swelling) to 10 (worst swelling ever experienced). 
Ratings for pain and swelling and changes from baseline will be summarized at each scheduled 
visit with descriptive statistics. 


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7.2.11 Assistive Devices and Adaptations for Daily Living 
Subjects will be given a list of FOP assistive devices and adaptations grouped into 12 categories 
and asked to select those they use for daily living.  The assessment will occur at: 
 Screening/Baseline, Week 6, and Week 12 (Flare-up Component). 
The use of assistive devices and adaptations will be summarized overall and by category at each 
scheduled visit with counts and percentages of flare-ups.  The number of devices and adaptations 
used will be summarized overall and by category at each scheduled visit with descriptive 
statistics. 
The use of new-onset assistive devices and adaptations will be summarized overall and by 
category with counts and percentages of flare-ups.  New-onset assistive devices and adaptations 
are defined as assistive devices and adaptations used at a post-baseline visit that were not used at 
baseline.   
7.2.12 Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers 
Blood and urine samples for cartilage, bone, angiogenesis, and inflammation biomarkers will be 
collected at: 
 Screening/Baseline, Week 2, Week 4, Week 6, and Week 12 (Flare-up Component). 
Bone and cartilage biomarkers include osteocalcin, bone specific alkaline phosphatase (B-ALP), 
procollagen type I C-terminal propeptide (PICP), procollagen 1 N-terminal propeptide (P1NP), 
CD retinoic acid-sensitive protein (CD-RAP), and C-terminal telopeptide (CTX).  The 
angiogenesis biomarker is the ratio of fibroblast growth factor and urine creatinine.  
Inflammation biomarkers include erythrocyte sedimentation rate (ESR), C reactive protein 
(CRP), interleukin 6 (IL-6), interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF), creatine 
kinase (CK), and lactate dehydrogenase (LDH). 
Biomarkers values and changes from baseline will be summarized at each scheduled visit with 
descriptive statistics.  Note that results obtained locally rather than from the central laboratory 
will not be used to calculate change from baseline and will be excluded from these summaries.  
Results captured as “<” or “>” will be rounded up or down accordingly for analysis (eg, “<0.61” 
will be rounded to 0.60).  
Abnormal values at baseline and new-onset abnormal values post-baseline will be summarized 
with counts and percentages of flare-ups.  New-onset abnormal values are defined as values from 
biomarkers that were normal at baseline and abnormal post-baseline or were abnormal at 
baseline and abnormal in the opposite direction post-baseline (eg, abnormal low at baseline and 
abnormal high post-baseline).  Note that results obtained locally will be included in these 
summaries.  
The following figures will be generated for the Flare-up Component (note that the unit of 
analysis is each flare-up): 
 Mean biomarker values over time (one figure per biomarker, each figure with one line). 


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 Mean biomarker values over time by incidence of new HO (one figure per biomarker, 
each figure with one distinctive line per subgroup [new HO, no new HO]).   
 Mean biomarker values over time by baseline edema status (one figure per biomarker, 
each figure with one distinctive line per subgroup [baseline edema present, baseline 
edema not present]). 
 Biomarker values over time by flare-up (one figure per biomarker, each figure with one 
distinctive line per flare-up).  Flare-ups will be identified in the legend with subject ID, 
flare-up identifier (eg, Flare A, Flare B), gender, and age. 
 Mean percent of normal high biomarker values over time (one figure per biomarker, each 
figure with one line).  Percent of normal high = 100 x value / upper limit of normal range. 
 Mean percent of normal high biomarker values over time by incidence of new HO (one 
figure per biomarker, each figure with one distinctive line per subgroup [new HO, no new 
HO]).   
 Mean percent of normal high biomarker values over time by baseline edema status (one 
figure per biomarker, each figure with one distinctive line per subgroup [baseline edema 
present, baseline edema not present]). 
 Percent of normal biomarker values over time by flare-up (one figure per biomarker, each 
figure with one distinctive line per flare-up).  Flare-ups will be identified in the legend 
with subject ID, flare-up identifier, gender, and age. 
7.2.13 Duration of Active Symptomatic Flare-up 
Subjects will keep a daily diary during the Flare-up Component where the question “Is your 
flare-up ongoing today?” is answered.  Subjects with at least 80% of diary data (at least 67 days 
with non-missing data) will be used for analysis.   
The number of symptomatic days will be calculated as the number of days where the diary 
question is answered “Yes”.  The number of symptomatic days will be summarized with 
descriptive statistics. 
The status of the flare-up will be determined at Week 6 and Week 12.  If there are no 
symptomatic days recorded in the diary, the flare-up will be considered “Resolved prior to the 
first dose of study drug”.  If the last symptomatic day recorded in the diary is on or before the 
specified visit and is followed by at least one asymptomatic day (ie, diary question is answered 
“No”), the flare-up will be considered “Resolved”.  If the last symptomatic day recorded is on 
the last diary entry, the flare-up will be considered “Not resolved”.  The status of the flare-up 
will be summarized at Week 6 and Week 12 with counts and percentages of subjects or flare-ups 
as appropriate. 
The days to flare-up resolution will be calculated as follows: 
 If the flare-up was considered “Resolved prior to the first dose of study drug”, days to 
flare-up resolution = 0. 
 If the flare-up was considered “Resolved”, days to flare-up resolution = date of flare-up 
resolution – date of first dose + 1, where the date of flare-up resolution is the last 
symptomatic day. 


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 If the flare-up was considered “Not resolved”, days to flare-up resolution = date of last 
diary entry – date of first dose + 1. 
The days to flare-up resolution will be summarized with descriptive statistics. 
8 
Safety Data 
Adverse events will be presented for the Enrolled Population as described in Section 8.1.  Safety 
assessments at Flare-up Component visits will generally be presented in total for the Treated 
Population.  Safety assessments at Follow-up Component visits will be listed.           
8.1 
Adverse Events 
Adverse events (AEs) will be recorded from the time informed consent is signed through study 
completion.  All AEs will be coded to body system and preferred term using the Medical 
Dictionary for Regulatory Affairs (MedDRA) Version 17.0.  At least possibly related AEs are 
defined as AEs assessed by the Investigator as possibly, probably, or definitely related to study 
drug.  Adverse events that require Common Terminology Criteria for Adverse Events (CTCAE) 
grading as indicated on the eCRF are considered to be retinoid-associated AEs.   
Adverse events with start date on or after Flare-up Study Day 1 and on or before the date of 
completion for the Flare-up Component will be attributed to the Treatment Period.  Adverse 
events with start date on or after Study Day 1 that are not attributed to the Treatment Period will 
be attributed to the Non-Treatment Period.   
For the Untreated Population, AEs will be summarized in total (note, these are all 
Non-Treatment Period AEs).  For the Treated Population, AEs will be summarized by period 
(Non-Treatment Period AEs and Treatment Period AEs) and in total.  For the Enrolled 
Population, AEs will be summarized for the Non-Treatment Period and in total.   
The incidence of the following AEs will be summarized with counts and percentages of subjects 
(overview and also by MedDRA body system and preferred term): 
 Any AEs 
 Any AEs by maximum severity 
 Any AEs at least possibly related to study drug 
 Any AEs at least possibly related to study drug by maximum severity 
 Any retinoid-associated AEs 
 Any retinoid-associated AEs by maximum CTCAE grading 
 Any serious adverse events (SAEs)  
 Any AEs leading to dose modification or interruption of study drug  
 Any AEs leading to discontinuation of study drug 
 Any AEs leading to discontinuation of study 
Data listings will be provided for (1) all AEs, (2) SAEs, (3) AEs leading to dose modification or 
interruption of study drug, (4) AEs leading to discontinuation of study drug, and (5) AEs leading 
to discontinuation of study.  Study Day and/or Flare-up Study Day for AE start and stop dates 
will be included on AE listings as appropriate. 


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8.2 
Safety Laboratory Assessment 
Samples for safety laboratory assessments (biochemistry, lipids, hematology, coagulation, and 
urinalysis) will be collected at: 
 Screening/Baseline, Week 2, Week 4, Week 6, and Week 12 (Flare-up Component). 
Values and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Mean values (+/- standard error) will be plotted over time during the Flare-up 
Component for triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, 
amylase, and lipase.  Note that results obtained locally rather than from the central laboratory 
will not be used to calculate change from baseline and will be excluded from these summaries.  
Potentially clinically significant (PCS) values at baseline and new-onset PCS values 
post-baseline will be summarized with counts and percentages of subjects or flare-ups as 
appropriate.  New-onset PCS values are defined as values that were not PCS at baseline and were 
PCS post-baseline.  Note that results obtained locally will be included in these summaries.  PCS 
values are defined in Table 4. 
Table 4.  
Potentially Clinically Significant Safety Laboratory Values 
  
PCS Low 
PCS High 
Biochemistry 
 
 
Aspartate aminotransferase  
N/A 
3 x ULN 
Alanine aminotransferase 
N/A 
3 x ULN 
Amylase 
N/A 
3 x ULN 
Lipase, pancreatic 
N/A 
3 x ULN 
Bilirubin  
N/A 
>2 mg/dL 
Thyroxine  
<4.0 mcg/dL 
>13.0 mcg/dL 
Lipids 
 
 
Cholesterol 
N/A 
>300 mg/dL 
Triglycerides 
N/A 
>400 mg/dL 
Hematology 
 
 
Leukocytes 
<2.8 x 109/L 
>16.0 x 109/L 
Hemoglobin (females) 
<9.5 g/dL 
>17.5 g/dL 
Hemoglobin (males) 
<11.5 g/dL 
>19.0 g/dL 
Hematocrit (females) 
<32% 
>54% 
Hematocrit (males) 
<37% 
>60% 
Platelets 
<75 x 109/L 
>700 x 109/L 
 
A listing will be provided for all subjects with PCS lipase values that will include all lipase 
results during the study along with associated palovarotene and glucocorticoid dosing data (dose 
and start and stop dates). 


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8.3 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be collected at: 
 Screening/Baseline, Week 2, Week 4, Week 6, and Week 12 (Flare-up Component). 
Values and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Mean values (+/- standard error) will be plotted over time during the Flare-up 
Component for blood pressure and heart rate. 
Potentially clinically significant (PCS) values at baseline and new-onset PCS values 
post-baseline will be summarized with counts and percentages of subjects or flare-ups as 
appropriate.  New-onset PCS values are defined as values that were not PCS at baseline and were 
PCS post-baseline.  PCS values are defined in Table 5. 
Table 5.  
Potentially Clinically Significant Vital Sign Values 
  
PCS Low 
PCS High 
Systolic blood pressure 
<86 mmHg or a decrease of ≥25 
mmHg from baseline 
>180 mmHg or an increase of ≥25 
mmHg from baseline 
Diastolic blood pressure 
<48 mmHg or a decrease of ≥20 
mmHg from baseline 
>110 mmHg or an increase of ≥20 
mmHg from baseline 
Heart rate 
<45 bpm or a decrease of ≥20 bpm 
from baseline 
(1) >105 bpm AND an increase of 
≥20 bpm from baseline 
(2) >125 bpm 
mmHg=millimeters of mercury, bpm=beats per minute. 
 
8.4 
Body Weight 
Body weight will be collected at: 
 Screening/Baseline, Week 2, Week 4, Week 6, and Week 12 (Flare-up Component). 
Values and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Mean values (+/- standard error) will be plotted over time during the Flare-up 
Component. 
8.5 
Knee and Hand/Wrist Radiograph 
Subjects under the age of 18 years at the time of enrollment into Study PVO-1A-202 with open 
epiphyseal growth plates will undergo knee and hand/wrist radiographs (AP view) at: 
 Screening/Baseline and Week 12 (Flare-up Component). 
Knee and hand/wrist radiographs will be performed remotely (eg, at a local medical facility) for 
subjects who are unable or unwilling to attend site visits.  Once a subject has achieved 100% 
skeletal maturity (as confirmed by radiography), knee and hand/wrist radiographs will no longer 
be required.  The incidence of abnormalities may be summarized with counts and percentages of 
subjects.   


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8.6 
Linear Growth Assessment 
A linear growth assessment will be performed for subjects under the age of 18 years at the time 
of enrollment into Study PVO-1A-202 with open epiphyseal growth plates at: 
 Screening/Baseline and Week 12 (Flare-up Component). 
Height will be measured at Study Month 12 (Follow-up Component) and Screening/Baseline 
(Flare-up Component). 
Based on work by Chumlea (1994)3, knee height can be used to predict total height (stature) for 
children who are mobility-impaired.  Separate equations were established for White and for 
Black children by gender, as follows: 
 White boys: predicted stature = 40.54 + (2.22 x knee height) 
 Black boys: predicted stature = 39.60 + (2.18 x knee height) 
 White girls: predicted stature = 43.21 + (2.15 x knee height) 
 Black girls: predicted stature = 46.59 + (2.02 x knee height) 
When race is not reported as White or Black, the calculation for the White boy/girl will be used. 
Values and changes from baseline will be summarized for height, knee to heel length, and 
predicted stature at each scheduled visit with descriptive statistics.  Values for height and knee to 
heel length may be plotted over time with the actual palovarotene dose taken at each visit 
identified.     
8.7 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at: 
 Screening/Baseline and Week 6 (Flare-up Component). 
Values and changes from baseline will be summarized for continuous ECG parameters at each 
scheduled visit with descriptive statistics.   
Abnormal ECG categories will be assigned based on raw findings as shown in Table 6. 


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Table 6.  
Abnormal Electrocardiogram Categories 
 Abnormal ECG Category 
Raw Findings 
Rhythm  
* Atrial premature complexes 
* Ventricular premature complexes 
* Sinus arrhythmia 
* Sinus tachycardia 
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 
Miscellaneous 
* Long QT interval 
* Short PR interval 
 
Overall interpretation and abnormal ECG categories will be summarized at each scheduled visit 
with counts and percentages of flare-ups.  New-onset ECG abnormalities are defined as 
abnormalities that did not exist at baseline.  New-onset ECG abnormalities will be summarized 
counts and percentages of flare-ups. 
Incidence of QTc >450 msec, QTc >500 msec, or change from baseline in QTc >60 msec will be 
summarized with counts and percentages of flare-ups. 
Potentially clinically significant (PCS) values at baseline and new-onset PCS values 
post-baseline will be summarized with counts and percentages of flare-ups.  New-onset PCS 
values are defined as values that were not PCS at baseline and were PCS post-baseline.  PCS 
values are defined in Table 7. 


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Table 7.  
Potentially Clinical Significant Electrocardiogram Values 
  
PCS Low 
PCS High 
PR interval 
N/A 
>200 msec or an increase of ≥20 msec 
QRS interval 
N/A 
>100 msec or an increase of ≥10 msec 
QT interval, QTcF, QTcB 
N/A 
>500 msec or an increase of ≥60 msec 
msec = millisecond, QTcF = rate-corrected QT interval using Fridericia’s formula (QT interval divided 
by the cube root of the RR interval), QTcB = rate-corrected QT interval using Bazett’s formula (QT 
interval divided by the square root of the RR interval) 
 
8.8 
Physical Examination 
A comprehensive physical examination will be performed at: 
 Screening/Baseline, Week 6, and Week 12 (Flare-up Component). 
Physical examination results will be summarized at each scheduled visit by body system with 
counts and percentages of flare-ups. 
8.9 
Columbia-Suicide Severity Rating Scale  
Suicidal ideation and behavior will be assessed using the Columbia-Suicide Severity Rating 
Scale (C-SSRS) at: 
 Screening/Baseline, Week 2, Week 4, Week 6, Week 9, and Week 12 (Flare-up 
Component). 
Data listings will be provided for (1) all C-SSRS results; and (2) for subjects reporting any type 4 
or type 5 suicidal ideations. 
 
 
 
 
 
 
 
 


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9 
References 
1. Norken CC, White DJ. Measurement of Joint Motion: A Guide to Goniometry. 4th ed. 
Philadelphia, PA: F.A. Davis Company; 2011. 
2. Hays RD, Spritzer KL, Amtmann D, et al. Upper-extremity and mobility subdomains 
from the Patient-Reported Outcomes Measurement Information System (PROMIS) adult 
physical functioning item bank. Arch Phys Med Rehabil. 2013;94(11):2291-2296. 
doi:10.1016/j.apmr.2013.05.014. 
3. Chumlea WC, Guo SS, Steinbaugh ML.  Prediction of stature from knee height for black 
and white adults and children with application to mobility-impaired or handicapped 
persons.  J Am Diet Assoc. 1994;94(12):1385-1388, 1391. 
 


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Appendices 
Appendix 1.  PROMIS T-Score Conversions 
The following conversion tables 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 (more healthy) 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 
14 
26.1 
3.6 
 
14 
22.7 
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 
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 
 
 
 


Statistical Analysis Plan 
 
A Phase 2, Open-Label Extension, Efficacy and Safety Study of a 
RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous 
Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP) 
 
Study Number:  PVO-1A-202 Part B 
 
Original Protocol: 04 June 2014 
Amendment 1: 30 September 2014 
Amendment 2: 22 June 2015 
Amendment 3: 10 March 2016 
  
  
Statistical Analysis Plan Version: 1.0 
Statistical Analysis Plan Date: 23 October 2018 
 
 
Clementia Pharmaceuticals Inc. 
4150 Saint Catherine Street West, Suite 550 
Montreal, Quebec, H3Z 2Y5 
Canada 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Clementia Pharmaceuticals Inc. is strictly prohibited except to the extent required under applicable laws 
or regulations.  Persons to whom the information is disclosed must be informed that the information is confidential  
 
 




STATISTICAL ANALYSIS PLAN, PROTOCOL PVO-1A-202 PART B 
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Table of Contents 
Table of Contents .............................................................................................................................3 
List of Tables ...................................................................................................................................5 
List of Abbreviations .......................................................................................................................6 
1 Introduction ................................................................................................................................7 
2 Overview ....................................................................................................................................7 
2.1 Study Objectives ..................................................................................................................7 
2.1.1 Primary Objective ..........................................................................................................7 
2.1.2 Secondary Objectives.....................................................................................................7 
2.2 Study Population ..................................................................................................................8 
2.3 Study Design ........................................................................................................................9 
2.4 Study Treatment .................................................................................................................10 
2.5 Randomization and Blinding .............................................................................................11 
3 General .....................................................................................................................................11 
3.1 Adjustments for Covariates................................................................................................11 
3.2 Handling of Dropouts or Missing Data ..............................................................................11 
3.3 Interim Analyses ................................................................................................................11 
3.4 Multicenter Studies ............................................................................................................11 
3.5 Multiple Comparison/Multiplicity .....................................................................................11 
3.6 Examination of Subgroups .................................................................................................11 
3.7 Part B Study Day, Non-Flare-up Day, and Flare-up Day ..................................................12 
4 Analysis Populations ................................................................................................................12 
4.1 Enrolled Population ...........................................................................................................12 
4.2 Treated Population .............................................................................................................12 
4.3 Flare-up Population ............................................................................................................12 
4.4 Flare-up Per Protocol Population .......................................................................................12 
4.5 Pharmacokinetic Population ..............................................................................................12 
4.6 WBCT Population ..............................................................................................................13 
4.7 WBCT Per-Protocol Population ........................................................................................13 
4.8 Non-Flare-up Treated Population ......................................................................................13 
5 Subject Data .............................................................................................................................13 
5.1 Subject Disposition and Analysis Populations ..................................................................13 


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5.2 Eligibility Criteria ..............................................................................................................14 
5.3 Protocol Deviations ............................................................................................................14 
5.4 Demographic and Other Baseline Characteristics .............................................................14 
5.5 Medical History .................................................................................................................14 
5.6 Treated Flare-ups Starting During Part B ..........................................................................14 
5.7 Concomitant Medications ..................................................................................................15 
5.8 Exposure ............................................................................................................................16 
5.9 Compliance ........................................................................................................................17 
6 Efficacy Data ...........................................................................................................................17 
6.1 Primary Efficacy Endpoint ................................................................................................18 
6.2 Secondary Efficacy Endpoints for Flare-up Based Treatment ..........................................18 
6.2.1 Volume of HO and HO Grades ....................................................................................19 
6.2.2 Area of HO and HO Scores .........................................................................................20 
6.2.3 HO Lesion Scoring ......................................................................................................20 
6.2.4 New or Enlarged HO and Severity of New HO ...........................................................21 
6.2.5 Presence of Soft Tissue Swelling (Edema) and/or Cartilage Formation, Severity of 
Edema, and Volume of Edema ...............................................................................................21 
6.2.6 Active Range of Motion...............................................................................................22 
6.2.7 Cumulative Analogue Joint Involvement Scale (CAJIS) ............................................24 
6.2.8 Global Assessment of Movement ................................................................................24 
6.2.9 FOP-Physical Function Questionnaire (FOP-PFQ) .....................................................24 
6.2.10 PROMIS Global Health ...............................................................................................26 
6.2.11 Flare-up Pain and Swelling ..........................................................................................27 
6.2.12 Assistive Devices and Adaptations for Daily Living ...................................................28 
6.2.13 Bone, Cartilage, Angiogenesis, and Inflammation Biomarkers ..................................28 
6.2.14 Duration of Active Symptomatic Flare-up ..................................................................29 
6.3 Secondary Efficacy Endpoints for Non-Flare-up Based Treatment ..................................30 
6.3.1 Whole Body Burden of HO .........................................................................................30 
6.3.2 Volume of HO..............................................................................................................30 
7 Safety Data ...............................................................................................................................30 
7.1 Adverse Events ..................................................................................................................31 


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7.1.1 Number of Flare-ups Per Subject-Month .....................................................................32 
7.2 Safety Laboratory Assessments .........................................................................................32 
7.3 Vital Signs ..........................................................................................................................33 
7.4 Body Weight ......................................................................................................................34 
7.5 Knee and Hand/Wrist Radiograph .....................................................................................34 
7.6 Linear Growth Assessment ................................................................................................35 
7.7 Electrocardiogram ..............................................................................................................35 
7.8 Physical Examination.........................................................................................................36 
7.9 Columbia-Suicide Severity Rating Scale ...........................................................................36 
8 Pharmacokinetics Data.............................................................................................................36 
9 Changes from Protocol ............................................................................................................38 
10 References ................................................................................................................................38 
Appendices .....................................................................................................................................39 
Appendix 1.  PROMIS T-Score Conversions ................................................................................39 
 
List of Tables 
Table 1.  
Arcs of Motion............................................................................................................ 23 
Table 2.  
Sample Derivations for the Percentage of Worst Score for the FOP-PFQ ................. 25 
Table 3.  
Rescaled PROMIS Global Health Scale Scores ......................................................... 27 
Table 4.  
Potentially Clinically Significant Safety Laboratory Values ..................................... 33 
Table 5.  
Potentially Clinically Significant Vital Sign Values .................................................. 34 
Table 6.  
Abnormal Electrocardiogram Categories ................................................................... 35 
Table 7.  
Potentially Clinical Significant Electrocardiogram Values ........................................ 36 
 
 
 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ATC 
anatomic therapeutic class 
AP 
anterior/posterior 
CAJIS 
Cumulative Analogue Joint Involvement Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
Full Analysis Set 
FOP 
Fibrodysplasia Ossificans Progressiva 
FOP-PFQ 
FOP-Physical Function Questionnaire 
FPS-R 
Faces Pain Scale-Revised 
GEE 
generalized estimating equation 
HO 
heterotopic ossification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NHS 
Natural History Study 
NRS 
numeric rating scales 
PCS 
potentially clinically significant 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
RARγ 
retinoic acid receptor gamma 
ROM 
range of motion 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
ULN 
upper limit of normal 
US 
Ultrasound 
WBCT 
whole body CT  
 
 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes the analyses to be performed for Study PVO-1A-
202 Part B based on Amendment 3 of the protocol dated 10 March 2016 and the France-specific 
Amendment 1 of the protocol for Study PVO-1A-204, dated 07 September 2016.  Data collected 
for Study PVO-1A-202 Part B and Study PVO-1A-204 will be combined for the analyses.  For 
the purposes of this SAP, “Study PVO-1A-202 Part B” (or simply “Part B”) represents data from 
both studies. 
The analyses performed for Study PVO-1A-202 Parts A and C are described in separate SAPs.   
2 
Overview 
2.1 
Study Objectives 
2.1.1 Primary Objective 
The primary objective is: 
 To evaluate the safety and efficacy of different palovarotene dosing regimens in subjects 
with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the 
formation of new heterotopic ossification (HO) as assessed by low-dose computed 
tomography (CT) scan (or plain radiographs for subjects unable to undergo CT scan). 
2.1.2 Secondary Objectives 
 To evaluate the effect of palovarotene to prevent HO as assessed by low-dose, whole 
body computed tomography (WBCT) scan, excluding head. 
 To evaluate the effect of palovarotene on active range of motion (ROM) at the flare-up 
site as assessed by goniometer.  
 To evaluate the effect of palovarotene on ROM as assessed by the Cumulative Analogue 
Joint Involvement Scale (CAJIS) for FOP.  
 To evaluate the effect of palovarotene by the subject and Investigator global assessment 
of movement at the flare-up site.  
 To evaluate the effect of palovarotene on physical function using age-appropriate forms 
of the FOP Physical Function Questionnaire (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 effect of palovarotene on pain and swelling associated with the flare-up 
using numeric rating scales (NRS) or the Facial Pain Scale-Revised (FPS-R) in subjects 
under 8 years of age.  
 To evaluate the effect of palovarotene on the use of assistive devices and adaptations for 
daily living by FOP subjects.  
 To evaluate the effects of palovarotene on soft tissue swelling and cartilage formation at 
the flare-up site as assessed by magnetic resonance imaging (MRI); or the effect of 


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palovarotene on soft tissue swelling as assessed by ultrasound (US) in subjects unable to 
undergo MRI.  
 To evaluate bone, cartilage, angiogenesis, and inflammation biomarkers and explore 
correlations between changes from baseline in biomarkers and clinical efficacy.  
 To evaluate the pharmacokinetics of palovarotene during the first treated flare-up.  
 To evaluate the ability of different dosing regimens of palovarotene to prevent new flare-
ups.  
 To evaluate the long-term safety and efficacy of prior palovarotene treatment at the 
original flare-up site in Study PVO-1A-201; efficacy will be based on the amount of new 
HO formed at the original flare-up site as assessed by low-dose CT scan (or plain 
radiographs in subjects unable to undergo CT scan) in the Pediatric Cohort or low-dose 
whole body CT scan, excluding head, in the Adult Cohort.  
2.2 
Study Population 
A total of approximately 60 subjects will be enrolled in Part B including approximately 40 
subjects who completed Study PVO-1A-201 and up to 20 new Adult Cohort subjects.  The Adult 
Cohort will include subjects with at least 90% skeletal maturity, regardless of age; the Pediatric 
Cohort will include subjects with less than 90% skeletal maturity, regardless of age.  Any 
Pediatric Cohort subject who achieves ≥90% skeletal maturity during Part B may be considered 
for enrollment into the Adult Cohort at the discretion of the Investigator. 
Flare based analyses will include the treatment groups: PVO 20/10 mg, Prior Non-Flare-up/PVO 
20/10 mg, and Combined PVO 20/10 mg (=PVO 20/10 mg + Prior Non-Flare-up/PVO 20/10 mg 
groups).  PVO 20/10 mg is defined as flare-ups that did not have prior non-flare-up treatment.  
Prior Non-Flare-up/PVO 20/10 mg is defined as flare-ups that were treated with Non-Flare-up 5 
mg treatment prior to the start of the flare-up treatment.  It is important to mention that the flare-
up analyses is based on flare-ups, thus subjects may be included in both treatment groups, 
depending on when non-flare-up dosing began. 
WBCT analyses are based on the PVO Non-Flare-up/PVO 20/10 mg treatment group and will 
include the following subsets: Treated Flare-ups, Under/Untreated Flare-ups, No Flare-ups, and 
Combined Treated/No Flare-ups. 
Only subjects with Non-Flare-up treatment are imaged using WBCT, thus only the PVO Non-
Flare-Up/PVO 20/10 mg treatment group is present.  This treatment group is subset into 3 
different treatment groups, depending on whether or not the subjects had treated, untreated or no 
flares during the duration between the baseline and Month 12 WBCT scans.  Treated Flare-ups 
are defined as subjects who received non-flare-up/flare-up regimen for all flare-ups.  
Under/Untreated Flare-ups are defined as subjects who did not receive palovarotene dosing for 
all flare-ups.  No flare-ups are defined as subjects who received the non-flare-up regimen and did 
not report any flare-ups. 
Safety treatment groups include the PVO 20/10 mg and Non-Flare-up 5 mg groups.  
 


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2.3 
Study Design 
PVO-1A-202 Part B is a Phase 2, multicenter, event-based, open-label extension of 
Study PVO-1A-201.  This open-label extension will give subjects who completed 
Study PVO-1A-201 (including any subject who participated in Part A of Study PVO-1A-202) 
the opportunity to be followed for up to 2 years.   
Subjects in the Adult Cohort will follow all procedures and undergo all assessments as specified 
in the Schedule of Assessments in Table 1 of the protocol.  Site visits will occur at Part B 
Screening and at Study Months 12 and 24.  The visit window for the visits at Study Months 12 
and 24 is +/- 2 months where Study Day 1 is the date of screening in Part B.  Remote visits 
(assessments performed at home or at a local medical facility) and telephone contact with the 
study site will occur every 3 months unless the Investigator deems that a site visit is necessary. 
The visit window for remote visits is +/- 2 weeks.  Urine pregnancy tests will be performed each 
month for female subjects of childbearing potential.   
Subjects in the Adult and Pediatric Cohorts receiving flare-up based treatment will follow all 
procedures and undergo all assessments as specified in the Schedule of Assessments in Table 2 
of the protocol.  These subjects will have site visits at Flare-Up Screening/Baseline (as soon as 
possible after the start of the flare-up) and at Flare-Up Day 84/end-of-treatment (EOT); and 
remote visits, where possible, at Flare-Up Days 14, 28, 42, 56, and 70.  Should treatment be 
extended beyond Flare-up Day 84, 10 mg palovarotene (or the dose-equivalent) will be 
administered, in 4-week increments, until the flare-up resolves, with remote visits performed 
every 2 weeks while on treatment.  The visit window is +/- 3 days where Flare-Up Day 1 is the 
date of first dose of flare-up based palovarotene except for Flare-up Day 84/EOT where the visit 
window is -3 days.  Note that for analysis, visits will be displayed as Flare-Up Day 1, Flare-Up 
Week 2, Flare-Up Week 4, Flare-Up Week 6, Flare-Up Week 8, Flare-Up Week 10, Flare-Up 
Week 12, Flare-Up Week ## (for extended treatment), and EOT.  
Pharmacokinetic blood samples will be collected within the first 7 days of starting flare-up based 
treatment and at Flare-up Day 84 at 0, 3, 6, 10, and 24 hours post-dose for the first treated 
flare-up only. 
To assess an adequate number of flare-ups with the new dosing regimens, it is anticipated that 
each subject will participate in Part B of the study for approximately 18-24 months.  Once a 
flare-up has resolved, the Adult Cohort subjects will resume non-flare-up based treatment of 
5 mg once daily.  Initiation of flare-up based treatment for a new flare-up can occur at any time 
after resolution of the prior flare-up. 
Data regarding the original flare-up for those subjects from Study PVO-1A-201 will be collected 
at the Part B Screening visit (when the subject signs the informed consent) for the Adult Cohort 
according to the Schedule of Assessments in Table 1 of the Protocol; or at the Study Month 12 
visit (starting from initial enrollment into Study PVO-1A-202) for the Pediatric Cohort according 
to the Schedule of Assessments in Table 3 of the Protocol. 
Assessments for the Study Month 12 visit can be performed in conjunction with any of the site 
visits associated with flare-up based treatment (Flare-up Screening or Flare-up Day 84) as long 


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as those visits are within 5 months before or after the scheduled Study Month 12 visit.  Subjects 
on Non-Flare-up dosing regimen will also be contacted by telephone at Study Months 6, 18, and 
24 to assess concomitant medications and adverse events (AEs).  The visit window is +/- 2 
weeks where Day 1 is the date of informed consent for Part A. 
2.4 
Study Treatment 
Subjects in the Adult Cohort were scheduled to be treated with 5 mg palovarotene daily for up to 
24 months (non-flare-up based treatment); however, some adult subjects chose not to receive 
non-flare-up based treatment. 
Flare-up based treatment will begin as soon as possible after a subject reports onset of a flare-up 
and the flare-up has been confirmed by the Investigator.  In the event of an eligible flare-up, 
subjects in the Adult Cohort will receive open-label palovarotene treatment as follows:  
 20 mg for 28 days. The first dose will be taken upon flare-up confirmation by the 
Investigator.  
 10 mg for 56 days, for a total flare-up treatment duration of 84 days; treatment may be 
extended if the flare-up is ongoing and continue until the flare-up resolves.  Dosing will 
be extended in 4-week intervals and be based on clinical signs and symptoms as assessed 
by the Investigator.  
Subjects not receiving non-flare-up based dosing will only be treated during eligible flare-ups 
and will receive weight-adjusted doses of 20 and 10 mg palovarotene as follows:  
Weight Range  
Category 
20-mg 
Equivalent 
15-mg 
Equivalent 
10-mg  
Equivalent 
7.5-mg  
Equivalent* 
5-mg  
Equivalent* 
20 to <40 kg 
12.5 mg 
10 mg 
6 mg 
4 mg 
3 mg 
40 to <60 kg 
15 mg 
12.5 mg 
7.5 mg 
5 mg 
4 mg 
≥60 kg 
20 mg 
15 mg 
10 mg 
7.5 mg 
5 mg 
* In the event of dose de-escalation. 
If the subject experiences intolerable side effects during flare-up based dosing, the dose may be 
reduced to the next lower dose; if the subject is already receiving the lowest possible dose, then 
study drug will be discontinued.  Treatment may be extended after the 84-day treatment period 
(flare-up based dosing) if the flare-up is ongoing and continue until the flare-up resolves.  Dosing 
will be extended in 4-week intervals based on clinical signs and symptoms as assessed by the 
Investigator, with remote visits performed every 2 weeks while on treatment.  In the event the 
subject requires 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.  
After the Flare-up Day 84/EOT visit has been conducted and the flare-up is considered resolved, 
subjects in the Adult Cohort will resume the non-flare-up based treatment. 
Subjects not receiving non-flare-up based dosing who do not experience an eligible flare-up will 
not be treated. 


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2.5 
Randomization and Blinding 
This is an open-label study and does not involve randomization or blinding. 
3 
General 
Categorical data will be summarized with counts and percentages.  Percentages will be 
calculated based on the number of non-missing values and will be reported to one decimal place. 
Continuous data will be summarized with descriptive statistics including the number of 
non-missing values, mean, standard deviation, standard error, median, minimum, and maximum.  
Minimum and maximum will be reported to the same precision as the raw values, mean and 
median will be reported to one additional decimal place, and standard deviation and standard 
error will be reported to two additional decimal places.   
All data will be listed.  When listings are provided instead of summaries or require additional 
description, they are described in this document. 
3.1 
Adjustments for Covariates 
No statistical modeling will be performed so adjustment for covariates is not planned.  
3.2 
Handling of Dropouts or Missing Data 
As there is no effective treatment for subjects with FOP, it is assumed they will be highly 
motivated to adhere to the protocol and treatment visits.  Thus, it is expected that there will be 
minimal missing data, and most subjects will complete the study.  The efficacy analysis will be 
performed using observed data only.  Missing efficacy data will not be imputed.  
3.3 
Interim Analyses 
No interim analysis is planned. 
3.4 
Multicenter Studies 
A review of by-center effects will be performed in the context of data listing review.  However, 
the sample size precludes formal assessment of by-center effects. 
3.5 
Multiple Comparison/Multiplicity 
As this is an extension of an initial proof-of-concept study, no adjustment for multiple testing is 
planned. 
3.6 
Examination of Subgroups 
The sample size in this study is not sufficient to allow rigorous assessment of outcomes by 
subgroups, and the study is not powered for subgroup assessment.  However, exploratory 
assessments of the outcomes may be performed with a limited number of extrinsic or intrinsic 
factors, including age of the subject, location of the flare-up, amount of new HO, number of 
flare-up treatments, or other variables as appropriate. 


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3.7 
Part B Study Day, Non-Flare-up Day, and Flare-up Day 
For all subjects, Study Day will be determined from the date of informed consent (Part B Study 
Day 1); Part B Study Day -1 will be the day immediately prior to Part B Study Day 1.  
For subjects receiving non-flare-up based treatment, Non-Flare-up Day will be determined from 
the date of first dose of non-flare-up treatment (Part B Non-Flare-up Day 1). 
For subjects receiving flare-up treatment, Flare-up Day will be determined from the date of first 
dose of flare-up treatment (Flare-up Day 1). 
4 
Analysis Populations 
There will be seven Part B populations defined for the analysis. 
4.1 
Enrolled Population 
The Enrolled Population will include all subjects enrolled in Part B.  The Enrolled Population 
will be the primary population for demographic and baseline summaries and for analysis of 
adverse events.      
4.2 
Treated Population 
The Treated Population will include all subjects who took at least one dose of palovarotene in 
Part B (either flare-up treatment or non-flare-up treatment).  The analysis will be stratified as 
follows: PVO 20/10 mg only (including weight-adjusted doses), PVO 20/10 mg (including 
weight-adjusted doses) with prior non-flare-up treatment, and non-flare-up treatment only.  
4.3 
Flare-up Population 
The Flare-up Population will include all subjects in the Treated Population who took at least one 
dose of flare-up based treatment in Part B.  The analysis will be stratified based on subjects who 
took PVO 20/10 mg only (including weight-adjusted doses) and subjects took PVO 20/10 mg 
(including weight-adjusted doses) with prior non-flare-up treatment.   
4.4 
Flare-up Per Protocol Population 
The Flare-up Per Protocol (PP) Population will include all subjects in the Flare-up Population 
with no major protocol deviations that may impact the efficacy assessment and who were at least 
80% compliant with flare-up dosing.  Exclusions from the Flare-up PP Population will be 
identified prior to database lock.  The analysis will be stratified as before for the Flare-up 
Population. 
4.5 
Pharmacokinetic Population 
The Pharmacokinetic (PK) Population will include all subjects in the Flare-up Population who 
have sufficient blood samples collected for valid estimation of PK parameters.  The analysis will 
be stratified as before for the Flare-up Population. 


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4.6 
 WBCT Population 
The WBCT Population will include subjects in the Flare-up Population who had prior non-flare-
up treatment and have Baseline and Month 12 WBCT scans. 
4.7 
WBCT Per-Protocol Population 
The WBCT Per-Protocol Population will include all subjects in the WBCT Population with no 
major protocol deviations that may impact the efficacy assessment and who were at least 80% 
compliant with non-flare-up dosing.  Exclusions from the WBCT PP Population will be 
identified prior to database lock. 
4.8 
Non-Flare-up Treated Population 
The Non-Flare-up Treated Population will include all subjects in the Treated Population who 
took at least one dose of non-flare-up based treatment in Part B.  The Non-Flare-up Treated 
Population will be used to assess safety data for non-flare-up based treatment assessments. 
5 
Subject Data 
In general, subject data will be summarized for the Enrolled Population by cohort and in total. 
5.1 
Subject Disposition and Analysis Populations 
The following will be summarized with counts and percentages using the number of subjects in 
the Enrolled Population as the denominator: 
 Subjects who were enrolled (Enrolled Population). 
 Subjects in the Enrolled Population who took at least one dose of palovarotene (Treated 
Population). 
 Subjects in the Treated Population who took at least one dose of flare-up based 
palovarotene (Flare-up Population). 
 Subjects in the Flare-up Population who did not have major protocol deviations that may 
impact the efficacy assessment and were at least 80% compliant with flare-up dosing 
(Flare-up PP Population). 
 Subjects in the Flare-up Population who had sufficient blood samples collected for valid 
estimation of PK parameters (PK Population). 
 Subjects in the Flare-up Population who took at least one dose of non-flare-up based 
palovarotene and also have Baseline and Month 12 WBCT scans (WBCT Population). 
 Subjects in the WBCT Population who did not have major protocol deviations that may 
impact the efficacy assessment and were at least 80% compliant with non-flare-up dosing 
(WBCT PP Population). 
 Subjects who discontinued from Part B early along with reasons for discontinuation.  
 Subjects who completed Part B. 
 Duration of participation in Part B.  This will be calculated from the date of informed 
consent to the date of completion of Part B/discontinuation.   


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o Months of participation calculated as days of participation / 30.5.  Months of 
participation will also be summarized with counts and percentages of subjects in 
the Enrolled Population according to the following categories: 
 ≤ 6 months 
 >6 – 12 months 
 >12 – 18 months 
 >18 – 24 months 
Summaries will be presented for the following groups: subjects receiving non-flare-up 
based treatment only, subjects receiving flare-up based treatment only, and subjects 
receiving both non-flare-up based and flare-up based treatment. 
5.2 
Eligibility Criteria 
Eligibility criteria (inclusion/exclusion) will be listed with any specific criteria that were not met 
shown in the by-subject listing for the Enrolled Population. 
5.3 
Protocol Deviations 
Major protocol deviations will be identified prior to locking the database for Part B and may 
include, but are not limited to departures from the inclusion/exclusion criteria, non-compliance 
with investigational product, use of restricted concomitant medications, and non-compliance 
with study procedures.  Major protocol deviations will be summarized for the Enrolled 
Population. 
5.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics such as age, sex, race, ethnicity, height, and 
weight will be summarized for all analysis populations. 
5.5 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
Version 17.0).  The incidence of medical history conditions will be summarized by MedDRA 
body system and preferred term for the Enrolled Population. 
5.6 
Treated Flare-ups Starting During Part B 
The number of treated flare-ups will be summarized with counts and percentages of subjects in 
the Flare-up Population and Flare-up PP Population.  Similar summaries will be provided for the 
number of flare-ups with dosing extended beyond 12 weeks, the number of flare-ups for which 
an interruption of study drug occurred during flare-up dosing, and the number of flare-ups for 
which study drug was discontinued during flare-up dosing. 
Treated flare-up data as reported by the subject and the Investigator including symptoms, 
probable causes, and location(s) will be summarized for the Flare-up and Flare-up PP 
Populations. 


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The number of days after flare-up onset to the date of first dose of study drug for the flare-up 
will be summarized for the Flare-up Population with descriptive statistics. 
Data for untreated flare-ups will be listed. 
5.7 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary (March 2014).  
Glucocorticoids taken for a flare-up are defined as courses of glucocorticoids that start within 
9 days after the start of the flare-up and are specified as taken for the current flare-up on the 
electronic case report form (eCRF).  Courses of glucocorticoids are defined as days of 
continuous treatment allowing for up to a 2-day interruption. 
The use of the following concomitant medications will be summarized by anatomic therapeutic 
class (ATC) term and preferred term for the Enrolled Population: 
 Prior medications that were on-going at Study Day 1 excluding glucocorticoids. 
(Medications with start date before Study Day 1 and end date on or after Study Day 1.)   
 New-onset medications outside flare-up based treatment periods excluding 
glucocorticoids.  (Medications with start date on or after Study Day 1 and not during 
Flare-up Day 1 through Flare-up Day 84/EOT.) 
 Glucocorticoids outside flare-up based treatment periods that were on-going at Study 
Day 1.  (Courses of glucocorticoids with start date before Study Day 1 and end date on or 
after Study Day 1.) 
 New-onset Glucocorticoids outside flare-up based treatment periods.  (Courses of 
glucocorticoids with start date on or after Study Day 1, not during Flare-up Day 1 
through Flare-up Day 84/EOT, and are specified as not being taken for a flare-up.)  
The use of the following concomitant medications will be summarized by ATC term and 
preferred term for the Flare-up Population: 
 Prior medications that were on-going at Flare-up Day 1 excluding glucocorticoids.  
(Medications with start date before Flare-up Day 1 and end date on or after Flare-up 
Day 1.) 
 New-onset medications during flare-up based treatment periods excluding 
glucocorticoids.  (Medications with start date during Flare-up Day 1 through Flare-up 
Day 84/EOT.) 
 Glucocorticoids taken for treated flare-ups defined as courses of glucocorticoids that start 
within 9 days after the start of the flare-up and are specified as taken for the current flare-
up on the eCRF.     
 New-onset glucocorticoids during flare-up based treatment periods defined as courses of 
glucocorticoids that start more than 9 days after the start of the flare-up or are specified as 
not being taken for the current flare-up on the eCRF. 
For the purposes of analysis, incomplete medication start and stop dates will be imputed.  If a 
medication start date is incomplete, January will be imputed for missing month and/or the first 
day of the month will be imputed for missing day.  If a medication stop date is incomplete, 


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December will be imputed for missing month and the last day of the month will be imputed for 
missing day.  If the imputed medication stop date is after the date of study completion, the date 
of study completion will be used instead. 
A listing of courses of glucocorticoids will include additional derived data such as start and stop 
dates, based on the first dose date of flare-up treatment, with associated Flare-up Day, start day 
of the glucocorticoid relative to the start of the flare-up onset date, duration of use, and total 
amount taken. 
5.8 
Exposure 
Exposure to flare-up based treatment for each treated flare-up will be calculated from the date of 
first dose for the flare-up to the date of last dose for the flare-up.  Days of exposure to flare-up 
based treatment will be summarized for the Flare-up Population with descriptive statistics.  
Similarly, exposure to high flare-up treatment (the 20-mg dose), low flare-up treatment (the 
10-mg dose), and non-flare-up treatment (5 mg) will be summarized.  Separate summaries will 
include and exclude weight-adjusted doses.     
Weeks of exposure to flare-up based treatment will be summarized with counts and percentages 
of flare-ups in the Flare-up Population according to the following categories: 
 ≤2 weeks 
 >2 – 4 weeks 
 >4 – 6 weeks 
 >6 – 8 weeks 
 >8 – 10 weeks 
 >10 – 12 weeks 
 >12 weeks 
Months of exposure to non-flare-up based treatment will be summarized with counts and 
percentages in the Non-Flare-up Treated Population according to the following categories: 
 >0 – 3 months 
 >3 – 6 months 
 >6 – 9 months 
 >9 – 12 months 
 >12 months 
Total exposure to study drug for each subject will be calculated as the number of days exposed to 
study drug.  For subjects who received only flare-up based treatment, total exposure is the sum of 
the exposure for each flare-up.  Note that this calculation excludes days between flare-ups.  For 
subjects who received non-flare-up based treatment, total exposure is calculated from the date of 
first dose of study drug to the date of last dose of study drug, adjusting for any days of study 
drug interruption.  Days of exposure will be summarized with counts and percentages of subjects 
in the Treated Population. 


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Dose reductions (no dose reductions, any dose reductions) will be summarized with counts and 
percentages of flare-ups and subjects in the Treated Population.  Similarly, dose reduction 
categories (ie, 20 to 15 mg, 20 to 10 mg, etc.) will be summarized with counts and percentages. 
The number of subjects who experienced an interruption of study drug during non-flare-up 
dosing and the number of subjects who discontinued study drug during non-flare-up dosing will 
be summarized with counts and percentages. 
5.9 
Compliance 
Overall compliance to study drug will be calculated for each subject based on actual study drug 
taken (mg) and the expected study drug taken (mg) over the course of Part B.   
Actual study drug taken will be calculated as the sum of study drug taken from each bottle where 
study drug taken from each bottle is the number of capsules taken multiplied by capsule strength.   
Expected study drug taken will be calculated based on the protocol-defined treatment regimen.  
Subjects experiencing eligible flare-ups are expected to take 20 mg for 28 days followed by 
10 mg for 56 days (or longer if treatment is extended).  If the number of days of treatment is 
extended, weight-adjusted doses, and dose reductions should be taken into account in this 
calculation.  Subjects in the Adult Cohort who are taking non-flare-up treatment are expected to 
take 5 mg each day they are not taking flare-up based treatment.  
For example, if a subject in the Adult Cohort took 90 5-mg capsules from bottle 1, 28 20-mg 
capsules from bottle 2, and 50 10-mg capsules from bottle 3, then the actual study drug taken is 
equal to 90 x 5 + 28 x 20 + 50 x 10 = 1510 mg.  The subject started non-flare-up based treatment 
on Study Day 1, started flare-up based treatment on Study Day 11, and completed Part B on 
Study Day 174.  Treatment was not extended for this flare-up, and doses were not 
weight-adjusted or reduced.  Therefore, the subject was expected to take 20 mg for 28 days 
followed by 10 mg for 56 days for the flare-up and 5 mg for 90 days (174 total days in Part B – 
84 days of flare-up based treatment).  Expected study drug taken = 90 x 5 + 28 x 20 + 56 x 10 = 
1570 mg.  Compliance would be calculated as: 1510 mg / 1570 mg = 96.2%. 
Percent compliance will be summarized for the Treated Population with descriptive statistics.  
Categories of percent compliance (<80%, ≥80%) will be summarized for the Treated Population 
with counts and percentages of subjects. 
6 
Efficacy Data 
Efficacy data for flare-up based treatment assessments will generally be presented by the 
following treatment groups for the Flare-up Population: PVO 20/10 mg, Prior Non-Flare-
up/PVO 20/10 mg, and Combined PVO 20/10 mg.  The primary efficacy analysis and other 
selected efficacy analyses will also be performed using the Flare-up PP Population.   
Imaging Reads 
Imaging data includes results from CT scan, x-ray, MRI, US, and WBCT scan.  Results will be 
read and interpreted using the Primary Read process only.      


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The Primary Read review will be performed by two independent musculoskeletal radiologists 
during the study as images are made available.  If there is sufficient agreement between the 
independent reviews, both will be used for analysis.  If there is insufficient agreement between 
the independent reviews, an adjudication review will be performed and used for analysis.  The 
definition of what constitutes agreement between the independent reviews is described in the 
PVO-1A202 FOP Independent Review Charter, version 10, dated 16Feb2017.  Imaging 
procedures performed (categorized as “Yes”, “Yes but not evaluable”, or “No”) will be 
summarized at scheduled visits with counts and percentages of subjects or flare-ups as 
appropriate.   
6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of flare-ups with no new HO at Week 12 as 
assessed by CT scan (or by x-ray for subjects unable to undergo CT scan).   Note that “no new 
HO at Week 12” means no new HO at Week 12 compared to baseline where baseline is Flare-up 
Day 1 and Week 12 is Week 12 for subjects who completed treatment at Week 12.    
Similar analyses will be performed for subjects who had extended treatment.  This data will be 
referenced as the EOT time point.   
The primary efficacy endpoint will be presented for the Flare-up Population and the Flare-up PP 
Population for the following treatment groups: PVO 20/10 mg, Prior Non-Flare-up/PVO 20/10 
mg, and Combined PVO 20/10 mg.   
The presence of “HO at baseline” and the incidence of “No new HO”, “New HO at Week 12”, 
and “New HO at EOT” will be summarized with counts and percentages of flare-ups.  The 
asymptotic 95% confidence intervals for the proportions will be presented. 
Similar analyses will be performed for subgroups defined by baseline edema (missing, no edema, 
and any edema) and baseline edema severity (no edema, any edema, mild edema, moderate 
edema, severe edema, and moderate or severe edema [higher-intensity flare-ups]).  See Section 
6.2.5 for a description of edema determination. 
6.2 
Secondary Efficacy Endpoints for Flare-up Based Treatment 
The secondary efficacy endpoints for Flare-up based treatment will be presented by treatment 
group (PVO 20/10 mg, Prior Non-Flare-up/PVO 20/10 mg, and Combined PVO 20/10 mg) for 
the Flare-up Population and the Flare-up PP Population.   
Secondary efficacy endpoints for flare-up based treatment include: 
1. Change from baseline in amount of bone formation (volume) as assessed by low-dose CT 
scan at Flare-up Week 12 and EOT.   
2. Presence of soft tissue swelling and/or cartilage by MRI at Flare-up Week 12 and EOT; 
or presence of soft tissue swelling by US at Flare-up Week 12 and EOT in subjects 
unable to undergo MRI.  
3. Change from baseline in active ROM measured by goniometer at the flare-up site at 
Flare-up Week 12 and EOT.  


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4. Change from baseline in ROM as assessed by CAJIS at Flare-up Week 12 and EOT.  
5. Subject and Investigator global assessment of movement at the flare-up site at Flare-Up 
Week 12 and EOT.  
6. Change from baseline in physical function using age-appropriate forms of the FOP-PFQ 
at Flare-up Weeks 4, 8, 12, and EOT.  
7. Change from baseline in physical and mental health using age-appropriate forms of the 
PROMIS Global Health Scale at Flare-up Weeks 4, 8, 12, and EOT.  
8. Change from baseline in the use of assistive devices and adaptations for daily living by 
FOP subjects at Flare-up Week 12 and EOT.  
9. Change from baseline in cartilage, bone, angiogenesis, and inflammation biomarkers at 
Flare-up Weeks 4, 8, 12, and EOT.  
10. Duration of active, symptomatic flare-up (start date and end date), as assessed by the 
subject and the Investigator.  
11. WBCT Volume at Baseline, Month 12, and Change from Baseline to Month 12.  Similar 
analyses will be performed for subjects with a new HO at Month 12 and for subjects with 
no new HO at Month 12.   
Baseline for flare-up based assessments is Flare-up Day 1. 
6.2.1 Volume of HO and HO Grades 
The volume of HO and HO grades (defined below) will be determined from CT imaging.   
The volume of HO at baseline will be calculated as the sum of the volumes for each lesion.  The 
volume of new HO at post-baseline visits will be calculated as follows: 
1. If there is no new HO, assign new volume = 0.  (NVOL = 0) 
2. If there is new HO  
a. Subtract the volume of baseline HO from the volume of post-baseline HO for 
each lesion (new volume at each lesion = NVOL1, NVOL2, … NVOLL where L is 
the number of lesions). 
b. If the volume of post-baseline HO < the volume of baseline HO for a given lesion 
i, impute new volume = 0 (NVOLi = 0). 
c. Calculate the total volume of new HO (NVOL = NVOL1 + NVOL2 + … + 
NVOLL). 
If an adjudication review is performed, the volume from the adjudication review will be used for 
analysis.  Otherwise, the average of the volumes from the independent reviews will be used for 
analysis.   
Volume of HO at baseline and volume of new HO at post-baseline visits will be summarized 
with descriptive statistics.  Similar summaries will be provided for those subjects in the Flare-up 
Population who had flare-ups with new HO at any post-baseline visit. 
HO lesions will be graded according to the following scale: 
 Grade 0 – Imputed when there is no new HO 
 Grade 1 – Fluid attenuation without evidence of calcification at CT 


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 Grade 2 – Calcification of soft tissues without evidence of bone formation 
 Grade 3 – Immature bone formation 
 Grade 4 – Mature bone with cortical differentiation 
The HO grade at baseline will be calculated as the maximum HO grade across lesions.  The new 
HO grade at post-baseline visits will be calculated as follows: 
1. If there is no new HO, assign new HO grade = 0.   
2. If there is new HO  
a. If there was no baseline HO, calculate the maximum HO grade across lesions. 
b. If there was baseline HO, calculate the maximum HO grade across lesions where 
there was no baseline HO. 
HO grade at baseline and new HO grade at post-baseline visits will be summarized with counts 
and percentages of flare-ups. 
6.2.2 Area of HO and HO Scores 
The area of HO and HO scores will be determined from x-ray for subjects unable to undergo CT 
scan. 
Area of HO at baseline will be calculated as the sum of the areas for each lesion.  The area of 
new HO at post-baseline visits will be calculated using both anterior/posterior (AP) and lateral 
views as follows: 
1. If there is no new HO, assign new area = 0 (NAREA = 0). 
2. If there is new HO  
a. Subtract the area of baseline HO from the area of post-baseline HO for each 
lesion (NAREA1, NAREA2, … NAREAL where L is the number of lesions). 
b. If the area of post-baseline HO < the area of baseline HO for a given lesion i, 
impute new area = 0 (NAREAi = 0). 
c. Calculate the total area of new HO (NAREA = NAREA1 + NAREA2 + … + 
NAREAi). 
For each review, the maximum area from the AP or lateral view will be used for analysis. 
If an adjudication review is performed, the area from the adjudication review will be used for 
analysis.  Otherwise, the average of the areas from the independent reviews will be used for 
analysis.   
Area of HO at baseline and area of new HO at post-baseline visits will be listed.   
Area of HO and volume of HO (CT scan) will not be pooled.  They will be presented in separate 
listings. 
6.2.3 HO Lesion Scoring 
HO scores will be determined from x-ray for subjects unable to undergo CT scan.  
HO lesions will be scored according to the following scale: 
 0 – No HO 


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 1 – Single or multiple spicules (punctate) or islands (non-contiguous) of HO 
 2 – Coalescing islands or reticular complexes of bone 
 3 – Single contiguous HO having longest dimension ≤1/2 the diameter of the reference 
normotopic bone in any projection 
 4 – Single contiguous HO having longest dimension >1/2 but ≤1 diameter of the 
reference normotopic bone in any projection 
 5 – Single contiguous HO having longest dimension >1 but ≤2 diameter of the reference 
normotopic bone in any projection  
 6 – Single contiguous HO having longest dimension >2 diameters of the reference 
normotopic bone in any projection 
The HO score at baseline will be calculated as the maximum HO score across lesions.  The new 
HO score at post-baseline visits will be calculated as follows: 
1. If there is no new HO, impute new HO score = 0.   
2. If there is new HO  
a. If there was no baseline HO, calculate the maximum HO score across lesions. 
b. If there was baseline HO, calculate the maximum HO score across lesions where 
there was no baseline HO. 
HO score at baseline and new HO score at post-baseline visits will be listed. 
HO lesion scores will not be pooled with HO lesion grades (CT scan) above.  They will be 
described separately. 
6.2.4 New or Enlarged HO and Severity of New HO 
New HO lesions are those that did not exist at baseline.  Enlarged HO lesions are lesions that 
existed at baseline but increased in volume by CT (or area by x-ray) post-baseline.  The 
incidence of new HO lesions only, enlarged HO lesions only, or both new HO and enlarged HO 
lesions will be summarized at each scheduled visit with counts and percentages of flare-ups. 
The severity of new HO (mild, moderate, severe) will be summarized at each scheduled visit 
with counts and percentages of flare-ups. 
6.2.5 Presence of Soft Tissue Swelling (Edema) and/or Cartilage Formation, Severity of 
Edema, and Volume of Edema 
Presence of edema and cartilage formation will be determined from MRI (or US for subjects 
unable to undergo MRI).  Note that US does not include an assessment of cartilage formation.   
If an adjudication review is performed, the severity and volume of edema from the adjudication 
review will be used for analysis.  Otherwise, the maximum severity and the average volume of 
edema from the independent reviews will be used for analysis.  Note also that when edema is 
assessed as mild with US, moderate will be imputed for analysis.  
The presence of edema and the presence of cartilage formation will be summarized at each 
scheduled visit with counts and percentages of flare-ups.   


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The severity of edema (no edema, any edema, mild edema, moderate edema, severe edema, 
moderate or severe edema [higher intensity flare-ups]) will be summarized at each scheduled 
visit with counts and percentages of flare-ups.   
The shift in severity of edema from baseline to each post-baseline visit will also be summarized 
with counts and percentages of flare-ups. 
Volume of edema at each scheduled visit will be summarized with descriptive statistics.       
6.2.6 Active Range of Motion  
Range of motion at the primary and secondary joints will be assessed using a goniometer.  The 
primary joint will be indicated on the eCRF and all other joints will be considered secondary. 
Arcs of motion as defined in Table 1 will be calculated based on raw ROM measurements.  If 
any of the contributing raw ROM measurements are missing, the arc of motion will not be 
calculated.  Percent of normal arc of motion will be calculated as 100 x arc of motion / normal 
adult arc of motion. 


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Table 1.  
Arcs of Motion 
Joint 
Arc of Motion 
Calculation Based on Raw ROM 
Measurements 
Normal Adult Arc of 
Motion (degrees) 
Hip 
Extension/Flexion 
Extension + Flexion 
140 
 
Abduction/Adduction 
Abduction + Adduction 
60 
 
Total Arc of Motion 
Extension + Flexion + Abduction + 
Adduction 
200 
Knee 
Total Arc of Motion 
Extension + Flexion 
135 
Shoulder 
Total Arc of Motion 
Flexion + Abduction-glenohumeral 
+ Abduction-shoulder complex 
490 
Elbow 
Extension/Flexion 
Extension + Flexion 
150 
 
Supination/Pronation 
Supination + Pronation 
160 
 
Total Arc of Motion 
Extension + Flexion + Supination + 
Pronation 
310 
Wrist 
Total Arc of Motion 
Extension + Flexion 
150 
Ankle 
Dorsiflexion/Plantarflexion 
Dorsiflexion + Plantarflexion 
70 
 
Subtalar Inversion/Subtalar 
Eversion 
Subtalar Inversion + Subtalar 
Eversion 
50 
 
Total Arc of Motion 
Dorsiflexion + Plantarflexion + 
Subtalar Inversion + Subtalar 
Eversion 
120 
Cervical Spine 
Extension/Flexion 
Extension + Flexion 
90 
 
 
Lateral  
45 
 
 
Rotation 
60 
 
Total Arc of Motion 
Extension + Flexion + Lateral + 
Rotation 
195 
Jaw 
Total Arc of Motion 
Opening 
35 mm 
Lumbar Spine 
 
Flexion 
6 cm 
 
 
Extension 
1 cm 
 
Total Arc of Motion 
Flexion + Extension 
7 cm 
Source:  Norken and White (2011)1 
 
Percent of normal arc of motion values and changes from baseline will be summarized at each 
scheduled visit with descriptive statistics.  Summaries will be provided separately for: 
 Percent of normal total arc of motion at the primary joint (subjects have one total arc of 
motion at the primary joint) 
 Percent of normal arc of motion at the primary joint by joint and arc of motion (subjects 
may have more than one arc of motion at the primary joint) 
 Percent of normal arc of motion at the secondary joints by joint and arc of motion 
(subjects may have more than one arc of motion at one or more secondary joints) 


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Similar summaries for percent of normal total arc of motion will be provided for subgroups 
defined by presence of new HO at any post-baseline visit (new HO, no new HO).  
6.2.7 Cumulative Analogue Joint Involvement Scale (CAJIS) 
Range of motion across the whole body will also 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). 
The CAJIS Mobility subscore 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). 
The CAJIS Total score, CAJIS Upper Extremities subscore, and CAJIS Mobility subscore and 
changes from baseline will be summarized at each scheduled visit with descriptive statistics.  
Similar summaries will be provided for subgroups defined by presence of new HO at any 
post-baseline visit (new HO, no new HO).   
6.2.8 Global Assessment of Movement  
Flare-up movement compared to baseline will be assessed by the subject (or parent proxy) and 
Investigator.  Assessment results will be summarized at each scheduled visit with counts and 
percentages of flare-ups.  Similar summaries will be provided for subgroups defined by presence 
of new HO at any post-baseline visit (new HO, no new HO).   
6.2.9 FOP-Physical Function Questionnaire (FOP-PFQ) 
Age-appropriate forms of the FOP-PFQ will be administered to subjects (or parent proxy).  The 
adult form will be administered to subjects 15 years and older.  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 questions are 
described in detail in Appendices 7A, 7B, and 7C of the protocol.   
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. 


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 The sum of the scores from each question and ranges from 26x1 = 26 to 26x5 = 130 for 
the pediatric form. 
The Upper Extremities subscore will be calculated as: 
 The sum of the scores from 15 questions (questions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 
25, and 26) and ranges from 15x1 = 15 to 15x5 = 75 for the adult form. 
 The sum of the scores from 18 questions (questions 1, 2, 6, 7, 8, 9, 10, 11, 16, 17, 18, 19, 
21, 22, 23, 24, 25, and 26) and ranges from 18x1 = 18 to 18x5 = 90 for the pediatric 
form. 
The Mobility subscore will be calculated as: 
 The sum of the scores from 13 questions (questions 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 
24, 27, and 28) and ranges from 13x1 = 13 to 13x5 = 65 for the adult form. 
 The sum of the scores from 8 questions (questions 3, 4, 5, 12, 13, 14, 15, and 20) and 
ranges from 8x1 = 8 to 8x5 = 40 for the pediatric form. 
The Total score, Upper Extremities subscore, and Mobility subscore are defined based on 
information from PROMIS and Hays et al (2013)2 for the adult form and a medical review of the 
questions for the pediatric form. 
If a subject is missing some (but not more than 20%) of the contributing question scores, the 
Total score, Upper Extremities subscore, or Mobility subscore 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.  The 
determination for sufficient non-missing scores will be made independently for the Total score, 
Upper Extremities subscore, and Mobility subscore. 
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 2 illustrates some 
sample derivations of the percentage of worst score. 
Table 2.  
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% 
 


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Percentage of worst scores and changes from baseline will be summarized at each scheduled visit 
with descriptive statistics.  Similar summaries will be provided for the percentage of worst 
Mobility Subscore for the subgroup of subjects with flare-ups in lower extremities and for the 
percentage of worst Upper Extremity Subscore for the subgroup of subjects with flare-ups in the 
upper extremities.   
Note that flare-ups in the lower extremities include the following flare-up locations reported by 
the Investigator: abdomen, ankle or foot, distal lower extremities, hip, knee, lower back, and 
lumbar spine.  Flare-ups in the upper extremities include the following flare-up locations 
reported by the Investigator: chest, cervical spine, head, jaw, distal upper extremities, elbow, 
shoulder, wrist or hand, thoracic spine, and upper back. 
Similar summaries will be provided for subgroups defined by presence of new HO at any 
post-baseline visit (new HO, no new HO). 
6.2.10 PROMIS Global Health 
An age-appropriate form of the PROMIS Global Health short form will be administered to 
subjects (or parent proxy).  The adult form will be administered to subjects 15 years and older.  
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 
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.  The questions are described in detail in 
Appendices 8A, 8B, and 8C of the protocol.   
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 3. 


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Table 3.  
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 detail in Appendix 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. 
T-scores and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Data from adult and pediatric forms will be summarized separately.  Similar 
summaries will be provided for subgroups defined by presence of new HO at any post-baseline 
visit (new HO, no new HO). 
6.2.11 Flare-up Pain and Swelling 
Adults and pediatric subjects 8 years and older will rate the pain associated with their flare-ups 
using a numeric rating scale (NRS) from 0 (no pain) to 10 (worst pain ever experienced).  
Pediatric subjects less than 9 years old will rate pain using the Faces Pain Scale – Revised (FPS-
R), which ranges from 0 (no pain) to 10 (very much pain) in 2-point increments.  Swelling 
associated with flare-ups will be rated on a scale from 0 (no swelling) to 10 (worst swelling ever 
experienced). 
Ratings for pain and swelling and changes from baseline will be summarized at each scheduled 
visit with descriptive statistics. 


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6.2.12 Assistive Devices and Adaptations for Daily Living 
Subjects will be given a list of FOP assistive devices and adaptations grouped into 12 categories 
and asked to select those they use for daily living.   
The use of assistive devices and adaptations will be summarized overall and by category at each 
scheduled visit with counts and percentages of flare-ups.  The number of devices and adaptations 
used will be summarized overall and by category at each scheduled visit with descriptive 
statistics. 
The use of new-onset assistive devices and adaptations will be summarized overall and by 
category with counts and percentages of flare-ups.  New-onset assistive devices and adaptations 
are defined as assistive devices and adaptations used at a post-baseline visit that were not used at 
baseline.   
6.2.13 Bone, Cartilage, Angiogenesis, and Inflammation Biomarkers 
Blood and urine samples will be collected for cartilage, bone, angiogenesis, and inflammation.  
Bone and cartilage biomarkers include osteocalcin, bone specific alkaline phosphatase (B-ALP), 
procollagen type I C-terminal propeptide (PICP), procollagen 1 N-terminal propeptide (P1NP), 
CD retinoic acid-sensitive protein (CD-RAP), and C-terminal telopeptide (CTX).  The 
angiogenesis biomarker is the ratio of fibroblast growth factor and urine creatinine.  
Inflammation biomarkers include erythrocyte sedimentation rate (ESR), C reactive protein 
(CRP), interleukin 6 (IL-6), interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF), creatine 
kinase (CK), and lactate dehydrogenase (LDH). 
Biomarkers values and changes from baseline will be summarized at each scheduled visit with 
descriptive statistics.  Note that results obtained locally rather than from the central laboratory 
will not be used to calculate change from baseline and will be excluded from these summaries.  
Results captured as “<” or “>” will be rounded up or down accordingly for analysis (eg, “<0.61” 
will be rounded to 0.60).  
Abnormal values at baseline and new-onset abnormal values post-baseline will be summarized 
with counts and percentages of flare-ups.  New-onset abnormal values are defined as values from 
biomarkers that were normal at baseline and abnormal post-baseline or were abnormal at 
baseline and abnormal in the opposite direction post-baseline (eg, abnormal low at baseline and 
abnormal high post-baseline).  Note that results obtained locally will be included in these 
summaries.  
The following figures will be generated (note that the unit of analysis is each flare-up): 
 Mean biomarker values over time (one figure per biomarker, each figure with one line). 
 Mean biomarker values over time by incidence of new HO (one figure per biomarker, 
each figure with one distinctive line per subgroup [new HO, no new HO]).   
 Mean biomarker values over time by baseline edema status (one figure per biomarker, 
each figure with one distinctive line per subgroup [baseline edema present, baseline 
edema not present]). 


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 Biomarker values over time by flare-up (one figure per biomarker, each figure with one 
distinctive line per flare-up).  Flare-ups will be identified in the legend with subject ID, 
flare-up identifier (eg, Flare A, Flare B), gender, and age. 
 Mean percent of normal high biomarker values over time (one figure per biomarker, each 
figure with one line).  Percent of normal high = 100 x value / upper limit of normal range. 
 Mean percent of normal high biomarker values over time by incidence of new HO (one 
figure per biomarker, each figure with one distinctive line per subgroup [new HO, no new 
HO]).   
 Mean percent of normal high biomarker values over time by baseline edema status (one 
figure per biomarker, each figure with one distinctive line per subgroup [baseline edema 
present, baseline edema not present]). 
 Percent of normal biomarker values over time by flare-up (one figure per biomarker, each 
figure with one distinctive line per flare-up).  Flare-ups will be identified in the legend 
with subject ID, flare-up identifier, gender, and age. 
6.2.14 Duration of Active Symptomatic Flare-up 
Subjects will keep a daily diary during the Flare-up Component where the question “Is your 
flare-up ongoing today?” is answered.  Subjects with at least 80% of diary data (at least 67 days 
with non-missing data) will be used for analysis.   
The number of symptomatic days will be calculated as the number of days where the diary 
question is answered “Yes”.  The number of symptomatic days will be summarized with 
descriptive statistics. 
The status of the flare-up will be determined at Week 12 and EOT.  If there are no symptomatic 
days recorded in the diary, the flare-up will be considered “Resolved prior to the first dose of 
study drug”.  If the last symptomatic day recorded in the diary is on or before the specified visit 
and is followed by at least one asymptomatic day (ie, diary question is answered “No”), the flare-
up will be considered “Resolved”.  If the last symptomatic day recorded is on the last diary entry, 
the flare-up will be considered “Not resolved”.  The status of the flare-up will be summarized at 
Week 12 and EOT with counts and percentages of flare-ups. 
The days to flare-up resolution will be calculated as follows: 
 If the flare-up was considered “Resolved prior to the first dose of study drug”, days to 
flare-up resolution = 0. 
 If the flare-up was considered “Resolved”, days to flare-up resolution = date of flare-up 
resolution – date of first dose + 1, where the date of flare-up resolution is the last 
symptomatic day. 
 If the flare-up was considered “Not resolved”, days to flare-up resolution = date of last 
diary entry – date of first dose + 1. 
The days to flare-up resolution will be summarized with descriptive statistics.  


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6.3 
Secondary Efficacy Endpoints for Non-Flare-up Based Treatment 
Efficacy data for non-flare-up based treatment assessments will generally be presented in total 
for the WBCT Population.   
Secondary efficacy endpoints for non-flare-up based treatment include: 
1. Change from baseline in whole body burden of HO as assessed by low-dose WBCT scan, 
excluding head, at Study Months 12 and 24.  
2. Change from baseline in ROM as assessed by CAJIS at Study Months 12 and 24.  
3. Change from baseline in physical function using age-appropriate forms of the FOP-PFQ 
at Study Months 12 and 24. 
4. Change from baseline in physical and mental health using age-appropriate forms of the 
PROMIS Global Health Scale at Study Months 12 and 24. 
5. Change from baseline in the use of assistive devices and adaptations for daily living by 
FOP subjects at Study Months 12 and 24. 
6. Change from baseline in biomarkers at Study Months 12 and 24. 
Baseline is Part B Screening.  
6.3.1 Whole Body Burden of HO 
Whole body burden (volume) of HO will be determined from the WBCT scan.  HO will be 
assessed at 15 locations including head and neck, left and right elbow, left and right hip, left and 
right knee, left and right shoulder, left and right distal lower extremities, left and right distal 
upper extremities, lower spine/abdomen, and upper spine/chest.    
Whole body burden of HO will be calculated as the sum of the volumes for each location.  If 
there is no HO, 0 will be assigned for analysis. 
Volume of HO and change from baseline (total and by region) will be summarized for subjects 
with any new HO at Month 12 and no new HO at Month 12, with descriptive statistics by the 
following subsets: Treated Flare-ups, Under/Untreated Flare-ups, and No Flare-ups. 
6.3.2 Volume of HO 
The change from baseline in the amount of new HO formed at the original flare-up site will be 
summarized and provided in a listing. 
7 
Safety Data 
Adverse events will generally be presented by treatment group (PVO 20/10 mg only (including 
weight-adjusted doses); PVO 20/10 mg (including weight-adjusted doses) with prior non-flare-
up treatment; and non-flare-up treatment only) and in total for the Enrolled and Treated 
Populations.  The treatment groups will be based on when the AE occurred and will 
corresponding to the following groups: No treatment (prior to any treatment or between flares if 
not on non-flare-up dosing), Non-flare-up treatment, and Flare-up treatment PVO 20/10 mg 
(including weight-adjusted doses).        


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Safety data for flare-up based treatment assessments will generally be presented by cohort and in 
total for the Flare-up Population.  Baseline is Flare-up Day 1 (the date of first dose of flare-up 
treatment).    
Safety data for non-flare-up based treatment assessments will generally be presented in total for 
the Non-Flare-up Treated Population (the date of first dose of non-flare-up treatment; Non-flare-
up Day 1).  Baseline is Part B Screening/Baseline.  
7.1 
Adverse Events 
Adverse events will be recorded from the time informed consent (Part B Study Day 1) is signed 
through study completion.  All AEs will be coded to body system and preferred term using 
MedDRA Version 17.0.  At least possibly related AEs are defined as AEs assessed by the 
Investigator as possibly, probably, or definitely related to study drug.  Adverse events that 
require Common Terminology Criteria for Adverse Events (CTCAE) grading (Version 4.03, 14 
June 2010) as indicated on the eCRF are considered to be retinoid-associated AEs.   
Adverse events with start date on or after Flare-up Day 1 and on or before the date of completion 
for the Flare-up treatment will be attributed to the Flare-up Treatment Period.  Adverse events 
with start date on or after Non-Flare-up Day 1 for which the patient is not undergoing flare-up 
treatment will be attributed to the Non-Flare Treatment Period.  Adverse events with start date on 
or after Study Day 1 that are not attributed to the flare-up or non-flare-up treatments will be 
attributed to the Non-Treatment Period. 
For the both the Enrolled Population and the Treated Population, AEs will be summarized by 
period (Non-Treatment Period, Non-Flare Treatment Period, Flare-up Treatment Period) and in 
total. 
The incidence of the following AEs will be summarized with counts and percentages of subjects 
(overall and by MedDRA body system and preferred term): 
 Any AEs 
 Any AEs by maximum severity 
 Any AEs at least possibly related to study drug 
 Any AEs at least possibly related to study drug by maximum severity 
 Any retinoid-associated AEs  
 Any retinoid-associated AEs at least possibly related to study drug 
 Any retinoid-associated AEs by maximum CTCAE grading  
 Any retinoid-associated AEs by maximum severity 
 Any retinoid-associated AEs by seriousness 
 Any serious adverse events (SAEs)  
 Any severe/life threatening retinoid-associated AE by maximum CTCAE grading 
 Any AEs leading to dose modification or interruption of study drug  
 Any AEs leading to discontinuation of study drug 
 Any AEs leading to discontinuation of study 


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Data listings will be provided for (1) all AEs, (2) SAEs, (3) AEs leading to dose modification or 
interruption of study drug, (4) AEs leading to discontinuation of study drug, and (5) AEs leading 
to discontinuation of study.  Part B Study Day and/or Flare-up Day for AE start and stop dates 
will be included on AE listings as appropriate. 
7.1.1 Number of Flare-ups Per Subject-Month   
Flare-ups are counted using the number of subject/Investigator-reported flare-ups and AEs with 
the ‘condition aggravated” preferred term that are medically reviewed and classified as unique 
flare-ups (not treated with palovarotene and not recorded as a subject/Investigator- reported 
flare-up).  Rates will be calculated by dividing the total number of flare-ups by the total subject 
months of follow-up.   
7.2 
Safety Laboratory Assessments 
Values and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Both the change from Screening/Baseline (patient based) and the change from 
Flare-up Day 1 (flare-up based) will be presented.  Mean values (+/- standard error) will be 
plotted over time for all laboratory parameters and biomarkers.  If multiple records occur within 
a post-baseline visit, the first non-missing value will be used.  Note that results obtained locally 
rather than from the central laboratory will not be used to calculate change from baseline and 
will be excluded from these summaries.  
Potentially clinically significant values at baseline and new-onset potentially clinically 
significant (PCS) values post-baseline will be summarized with counts and percentages of 
subjects or flare-ups as appropriate.  Separate analyses will be performed for the non-flare-up 
treatment visits and the flare-up treatment visits.  New-onset PCS values are defined as values 
that were not PCS at baseline and were PCS post-baseline.  Note that results obtained locally will 
be included in these summaries.  PCS values are defined in Table 4. 


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Table 4.  
Potentially Clinically Significant Safety Laboratory Values 
  
PCS Low 
PCS High 
Biochemistry 
 
 
Aspartate aminotransferase  
N/A 
3 x ULN 
Alanine aminotransferase 
N/A 
3 x ULN 
Amylase 
N/A 
3 x ULN 
Lipase, pancreatic 
N/A 
3 x ULN 
Bilirubin  
N/A 
>2 mg/dL 
Thyroxine  
<4.0 mcg/dL 
>13.0 mcg/dL 
Lipids 
 
 
Cholesterol 
N/A 
>300 mg/dL 
Triglycerides 
N/A 
>400 mg/dL 
Hematology 
 
 
Leukocytes 
<2.8 x 109/L 
>16.0 x 109/L 
Hemoglobin (females) 
<9.5 g/dL 
>17.5 g/dL 
Hemoglobin (males) 
<11.5 g/dL 
>19.0 g/dL 
Hematocrit (females) 
<32% 
>54% 
Hematocrit (males) 
<37% 
>60% 
Platelets 
<75 x 109/L 
>700 x 109/L 
 
A listing will be provided for all subjects with PCS lipase values that will include all lipase 
results during the study along with associated palovarotene and glucocorticoid dosing data (dose 
and start and stop dates).  A by-subject listing of all laboratory parameters will be generated. 
7.3 
Vital Signs 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature. 
Values and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Both the change from Screening/Baseline (patient base) and the change from Flare-up 
Day 1 (flare-up based) will be presented.  Mean values (+/- standard error) will be plotted over 
time for blood pressure and heart rate.  If multiple records occur within a post-baseline visit, the 
first non-missing value will be used. 
Potentially clinically significant values at baseline and new-onset PCS values post-baseline will 
be summarized with counts and percentages of subjects or flare-ups as appropriate.  Separate 
analyses will be performed for the non-flare-up treatment visits and the flare-up treatment visits.  
New-onset PCS values are defined as values that were not PCS at baseline and were PCS post-
baseline.  PCS values are defined in Table 5. 


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Table 5.  
Potentially Clinically Significant Vital Sign Values 
  
PCS Low 
PCS High 
Systolic blood pressure 
<86 mmHg or a decrease of ≥25 
mmHg from baseline 
>180 mmHg or an increase of ≥25 
mmHg from baseline 
Diastolic blood pressure 
<48 mmHg or a decrease of ≥20 
mmHg from baseline 
>110 mmHg or an increase of ≥20 
mmHg from baseline 
Heart rate 
<45 bpm or a decrease of ≥20 bpm 
from baseline 
(1) >105 bpm AND an increase of 
≥20 bpm from baseline 
(2) >125 bpm 
mmHg = millimeters of mercury, bpm = beats per minute. 
 
7.4 
Body Weight 
Values and changes from baseline will be summarized at each scheduled visit with descriptive 
statistics.  Mean values (+/- standard error) will be plotted over time. 
7.5 
Knee and Hand/Wrist Radiograph 
Subjects under the age of 18 years at the time of enrollment into Study PVO-1A-202 with open 
epiphyseal growth plates will undergo knee and hand/wrist radiographs (AP view) for 
assessment of epiphyseal growth plate. 
Knee and hand/wrist radiographs will be performed remotely (eg, at a local medical facility) for 
subjects who are unable or unwilling to attend site visits.  Once a subject has achieved 100% 
skeletal maturity (as confirmed by radiography), knee and hand/wrist radiographs will no longer 
be required.  Summary statistics of bone age and chronological age (values and changes from 
baseline) will be calculated at each scheduled visit.  Changes in bone age will be plotted over 
time.   
Summary tables of growth plate abnormalities identified in radiographs will include the 
following: 
 Number and percent of subject with epiphyseal growth plates open (by hand/wrist and/or 
knee). 
 Number and proportion of subjects with any abnormality at each visit, for each specific 
abnormality (e.g. growth recovery lines, Sclerosis, Under mineralization, etc.). 
 Number and proportion of subjects with any change from the prior timepoint for 
hand/wrist and knee by each abnormality for each visit. 
 Number and proportion of subjects with any change from the prior timepoint for 
hand/wrist and knee by each abnormality across all post-screening visits.  For summaries 
across all timepoints, the worst case for a given subject will be used in the analysis. 
 Number and proportion of subjects with any change from the prior timepoint for 
hand/wrist and knee across all abnormalities and post-screening visits.  For summaries 
across all abnormalities and timepoints, the worst case for a given subject will be used in 
the analysis.   


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7.6 
Linear Growth Assessment 
A linear growth assessment will be performed for subjects under the age of 18 years at the time 
of enrollment into Study PVO-1A-202 with open epiphyseal growth plates using stadiometry and 
knee height assessments. 
7.7 
Electrocardiogram 
Values and changes from baseline will be summarized for continuous ECG parameters at each 
scheduled visit with descriptive statistics.  Both the change from Screening/Baseline (patient 
based) and the change from Flare-up Day 1 (flare-up based) will be presented.  If multiple 
records occur within a post baseline visit, the first non-missing value will be used.   
Abnormal ECG categories will be assigned based on raw findings as shown in Table 6. 
Table 6.  
Abnormal Electrocardiogram Categories 
 Abnormal ECG Category 
Raw Findings 
Rhythm  
* Atrial premature complexes 
* Ventricular premature complexes 
* Sinus arrhythmia 
* Sinus tachycardia 
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 
Miscellaneous 
* Long QT interval 
* Short PR interval 
 
Overall interpretation and abnormal ECG categories will be summarized at each scheduled visit 
with counts and percentages of flare-ups.  New-onset ECG abnormalities are defined as 


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abnormalities that did not exist at baseline.  New-onset ECG abnormalities will be summarized 
counts and percentages of subjects or flare-ups as appropriate. 
Incidence of QTc >450 msec, QTc >500 msec, or change from baseline in QTc >60 msec will be 
summarized with counts and percentages of subjects or flare-ups as appropriate. 
Potentially clinically significant values at baseline and new-onset PCS values post-baseline will 
be summarized with counts and percentages of subjects or flare-ups as appropriate.  New-onset 
PCS values are defined as values that were not PCS at baseline and were PCS post-baseline.  
PCS values are defined in Table 7. 
Table 7.  
Potentially Clinical Significant Electrocardiogram Values 
  
PCS Low 
PCS High 
PR interval 
N/A 
>200 msec or an increase from baseline of ≥20 
msec 
QRS interval 
N/A 
>100 msec or an increase from baseline of ≥10 
msec 
QT interval, QTcF, QTcB 
N/A 
>500 msec or an increase from baseline of ≥60 
msec 
msec = millisecond, QTcF = rate-corrected QT interval using Fridericia’s formula (QT interval divided 
by the cube root of the RR interval), QTcB = rate-corrected QT interval using Bazett’s formula (QT 
interval divided by the square root of the RR interval) 
 
7.8 
Physical Examination 
Physical examination results will be summarized at each scheduled visit by body system with 
counts and percentages of subjects or flare-ups as appropriate. 
7.9 
Columbia-Suicide Severity Rating Scale  
Suicidal ideation and behavior will be assessed using the Columbia-Suicide Severity Rating 
Scale (C-SSRS). 
Data listings will be provided for (1) all C-SSRS results; and (2) for subjects reporting any type 4 
or type 5 suicidal ideations. 
8 
Pharmacokinetics Data 
Pharmacokinetics will be assessed within 7 days of flare-up based treatment initiation and at the 
end of treatment for the first treated flare-up.  Blood samples will be taken at 0, 3, 6, 10, and 24 
hours post-dose. 
Plasma palovarotene concentrations will be summarized with descriptive statistics (number of 
non-missing values, arithmetic mean, standard deviation, standard error, coefficient of variation, 
geometric mean, median, minimum, and maximum).  All plasma concentrations below the limit 
of quantification (LOQ) will be set to zero for the purpose of calculating descriptive statistics.  If 


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at any time point, 1/3 or more of subjects have <LOQ values, descriptive statistics will not be 
calculated at that time point.  PK concentrations will be imputed using the following: 
 If 0-hour concentration missing, then 24-hour concentration used to replace the missing 
concentration. 
 If 24-hour concentration missing, then 0-hour concentration used to replace the missing 
concentration. 
 Invalid 24-hour concentrations were replaced with the 0-hour concentrations.  Twenty-
four-hour concentrations were determined to be invalid if concentration is greater than 
the 10-hour value (i.e. assumed to have been obtained after next day dose instead of 
before next day dose). 
 
If any other blood sample collections are missing, PK parameters will not be assessed.  Actual 
sampling times will be used for the PK analysis, if available.  Nominal sampling times will be 
used for descriptive statistics. 
Individual concentration-time profiles for palovarotene will be presented (linear and semi-
logarithmic scales).  Arithmetic means (+/- standard deviation) concentration-time profiles will 
also be presented (linear and semi-logarithmic scales). 
An exploration of the effects of body weight on PK will be performed as the data allow.   
The PK analysis of palovarotene will be conducted using model-independent methods as 
implemented in WinNonlinTM.  The PK variables analyzed will include AUC0-24(ss), Cmax(ss), 
Cmin(ss), Tmax(ss), CL/F, λz, and t1/2z at steady-state.  The PK variables are defined as follows: 
AUC0-24(ss) 
Area under the concentration versus time curve over the 24-hour dosing 
interval; calculated using linear trapezoid rule. 
Cmax(ss) 
Maximum or peak measured plasma concentration at steady-state. 
Cmin(ss) 
Minimum or trough measured plasma concentration at steady-state. 
Tmax(ss) 
Time of maximum or peak measured plasma concentration at steady-state, 
obtained by inspection. 
CL/F 
Clearance defined as:  Dose/AUC0-24(ss). 
λz 
Terminal rate constant 
t1/2z 
Apparent terminal elimination half-life; calculated as ln(2)/ λz.  The number 
of data points included in the regression will be determined by visual 
inspection, but a minimum of three data points in the terminal phase, 
excluding Cmax, will be required to estimate λz. 


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9 
Changes from Protocol 
 For the purposes of clarity and consistency of nomenclature, the Flare-up Rate Population 
described in the protocol was renamed as the Non-Flare Treated Population. 
The initial secondary objective listed in Section 2.1.2 was not included in Amendment 3 of the 
protocol for Study PVO-1A-202 Part B or Amendment 1 of the protocol for Study PVO-1A-204. 
The protocol describes the primary comparison of outcomes to be from data collected from the 
NHS and Phase 2 study.  These comparisons will be performed in a future analysis and the 
analysis described here will instead focus on comparisons solely from Study PVO-1A-202 Part B 
between treatment groups of PVO 20/10 mg and Prior Non-Flare-up/PVO 20/10 mg, for flare 
based analyses; and treatment groups of treated, untreated, or no-flares, for WBCT based 
analyses. 
10 References 
1. Norken CC, White DJ. Measurement of Joint Motion: A Guide to Goniometry. 4th ed. 
Philadelphia, PA: F.A. Davis Company; 2011. 
2. Hays RD, Spritzer KL, Amtmann D, et al. Upper-extremity and mobility subdomains 
from the Patient-Reported Outcomes Measurement Information System (PROMIS) adult 
physical functioning item bank. Arch Phys Med Rehabil. 2013;94(11):2291-2296. 
doi:10.1016/j.apmr.2013.05.014. 
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. Chumlea WC, Guo SS, Steinbaugh ML.  Prediction of stature from knee height for black 
and white adults and children with application to mobility-impaired or handicapped 
persons.  J Am Diet Assoc. 1994;94(12):1385-1388, 1391. 
 


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Appendices 
Appendix 1.  PROMIS T-Score Conversions 
The following conversion tables 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 (more healthy) 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 
14 
26.1 
3.6 
 
14 
22.7 
3.8 


STATISTICAL ANALYSIS PLAN, PROTOCOL PVO-1A-202 PART B 
PALOVAROTENE 
 
 
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 OCTOBER 2018 
PROPRIETARY AND CONFIDENTIAL 
Pediatric Self-Completed Total 
 
Pediatric Proxy-Completed Total 
Raw Score 
T-Score 
Standard Error 
 
Raw Score 
T-Score 
Standard Error 
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 
 
 
 


Statistical Analysis Plan 
A Phase 2, Open-Label Extension, Efficacy and Safety Study of a 
-Specific Agonist (Palovarotene) in the Treatment of Preosseous 
Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP) 
 
Study Number:  PVO-1A-202 Part C 
 
Original Protocol: 04 June 2014 
Amendment 1: 30 September 2014
Amendment 2: 22 June 2015 
Amendment 3: 10 March 2016 
Amendment 4: 
Amendment 5: 
Amendment 6: 
Amendment 7: 
Amendment 8: 
01 September 2017
06 June 2018 
08 March 2019 
01 November 2019 
30 November 2020 
 
Statistical Analysis Plan Version: 1.1 
Statistical Analysis Plan Date: 16 December 2022 
Clementia Pharmaceuticals Inc. 
1000 de la Gauchetiere, suite 1200 
Montreal, QC H3B 4W5 Canada  
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Clementia Pharmaceuticals Inc. is strictly prohibited except to the extent required under applicable laws 
or regulations. Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.  




STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
Table of Contents
List of Tables ................................................................................................................................................ 6 
List of Abbreviations .................................................................................................................................... 7 
1 
Introduction ............................................................................................................................................ 8 
1.1 
Context for Version 1.1.................................................................................................................... 8 
1.2 
Context for Version 0.3 (Final) ........................................................................................................ 8 
2 
Overview ................................................................................................................................................ 9 
2.1 
Study Objectives .............................................................................................................................. 9 
2.1.1 Primary Objective...................................................................................................................... 9 
2.1.2 Secondary Objectives ................................................................................................................ 9 
2.2 
Study Design .................................................................................................................................... 9 
2.3 
Study Treatment ............................................................................................................................. 11 
2.4 
Study Populations .......................................................................................................................... 12 
2.5 
Randomization and Blinding ......................................................................................................... 13 
3 
General Statistical Consideration ......................................................................................................... 13 
3.1 
Definition of Baseline .................................................................................................................... 13 
3.1.1 Baseline for Non-Flare-up Based Treatment ........................................................................... 13 
3.1.2 Baseline for Flare-up Based Treatment ................................................................................... 14 
3.1.3 Baseline for Subjects Never Receive PVO Treatment in Part C ............................................. 14 
3.1.4 Baseline for Subjects who Restarted Palovarotene After Dosing interruption in Part C ........ 14 
3.2 
Part C Study Day, Flare-up Cycle Days and Non-Flare-up Days .................................................. 14 
3.2.1 Part C Study Day 1 .................................................................................................................. 14 
3.2.2 Flare-up Cycle and Flare-Up Cycle Day 1 .............................................................................. 14 
3.2.3 Duration of Flare-up Treatment............................................................................................... 14 
3.2.4 Duration of Non-Flare-up Treatment ...................................................................................... 14 
3.3 
Definition of New-Onset Potentially Clinically Significant (PCS) Value ..................................... 15 
3.4 
Adjustments for Covariates ............................................................................................................ 15
3.5 
Handling of Dropouts or Missing Data .......................................................................................... 15
3.6 
Unscheduled Assessments for Clinical Laboratory Test, Vital Sign and ECG ............................. 15 
3.7 
Handling of Partial Dates for Medications .................................................................................... 16 
3.8 
Handling of Partial Dates for Adverse Events ............................................................................... 16 
3.9 
Interim Analyses ............................................................................................................................ 16 
3.10 Multicenter Studies ........................................................................................................................ 16 
3.11 Multiple Comparison/Multiplicity ................................................................................................. 17 
3.12 Examination of Subgroups ............................................................................................................. 17 
4 
Analysis Populations ............................................................................................................................ 17 
4.1 
Enrolled Population ....................................................................................................................... 17 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
4.2
Treated Population......................................................................................................................... 17
4.3 
Flare-up Treated Population .......................................................................................................... 17 
4.4 
Flare-up Per Protocol Population ................................................................................................... 17 
4.5 
Non-Flare-up Treated Population .................................................................................................. 17 
4.6 
Restart Full Analysis Set ................................................................................................................ 18 
4.7 
Part D Analysis Set ........................................................................................................................ 18 
4.8 
Pharmacokinetic Population .......................................................................................................... 18 
5 
Subject Data ......................................................................................................................................... 18 
5.1 
Subject Disposition ........................................................................................................................ 18 
5.2 
Eligibility Criteria .......................................................................................................................... 18 
5.3 
Protocol Deviations ........................................................................................................................ 19 
5.4 
Demographic and Other Baseline Characteristics ......................................................................... 19 
5.5 
Medical History ............................................................................................................................. 19 
5.6 
Prior and Concomitant Medications .............................................................................................. 19 
5.7 
Treated Flare-ups Starting During Part C ...................................................................................... 20 
5.8 
Annualized Flare-up Rate .............................................................................................................. 21 
5.9 
Exposure in Part C ......................................................................................................................... 21 
5.9.1 Exposure to Flare-up Based Treatment ................................................................................... 21 
5.9.2 Exposure to Non Flare-up Based Treatment ........................................................................... 22 
5.9.3 Total Exposure to Study Drug for Each Subject ..................................................................... 22 
5.9.4 Duration of Subject Participation in Part C ............................................................................. 23 
5.9.5 Duration of Subject Participation in Part D ............................................................................. 23 
5.10 Compliance .................................................................................................................................... 23 
6 
Efficacy Data ........................................................................................................................................ 23 
6.1 
Primary Efficacy Endpoint ............................................................................................................ 23 
6.2 
Secondary Efficacy Endpoints ....................................................................................................... 24
6.2.1 New HO ................................................................................................................................... 24 
6.2.2 Cumulative Analogue Joint Involvement Scale (CAJIS) ........................................................ 24 
6.2.3 FOP-Physical Function Questionnaire (FOP-PFQ) ................................................................. 25 
6.2.4 PROMIS Global Health ........................................................................................................... 26 
7 
Safety Data ........................................................................................................................................... 27 
7.1 
Adverse Events .............................................................................................................................. 28 
Adverse Event Variables ................................................................................................................ 29 
Deaths ............................................................................................................................................ 30 
7.2 
Safety Laboratory Assessments ..................................................................................................... 30 
7.3 
Vital Signs ...................................................................................................................................... 32


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
7.4
Body Weight.................................................................................................................................. 32
7.5 
Linear Growth Assessment ............................................................................................................ 32 
7.6 
Electrocardiogram .......................................................................................................................... 33 
7.7 
Physical Examination..................................................................................................................... 34 
7.8 
Columbia-Suicide Severity Rating Scale ....................................................................................... 35 
7.9 
Bone Safety Data ........................................................................................................................... 35 
7.9.1 Knee and Hand/Wrist Radiographs ......................................................................................... 36 
7.9.2 WBCT Bilateral Hand/Wrist and Knee Growth Plate Morphology Assessment .................... 37 
7.9.3 WBCTs Measurements of Femur and Tibia Lengths .............................................................. 38 
7.9.4 Evaluation of Bilateral Hips by WBCT Safety Read .............................................................. 39 
7.9.4.1 
Assessments for Spinal Health ..................................................................................... 39 
8 
Pharmacokinetics Data ......................................................................................................................... 39 
9 
Changes from Protocol introduced in SAP Version 0.3 (13 July 2020) ............................................... 41 
10 Changes from Protocol introduced in SAP Version 1.1 (16 December 2022) ..................................... 41 
11 Changes from SAP Version 0.3 (13 July 2020) introduced in SAP Version 1.1 (16 Dec. 2022) ........ 42 
12 References ............................................................................................................................................ 44 
13 APPENDIX .......................................................................................................................................... 45 
 
 
 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
List of Tables
Table 1: Weight-Adjusted Palovarotene Doses and Dose De-Escalation Doses ........................................ 12 
Table 2: Sample Derivations for the Percentage of Worst Score for the FOP-PFQ ................................... 26 
Table 3: Rescaled PROMIS Global Health Scale Scores ........................................................................... 27 
Table 4: Potentially Clinically Significant Safety Laboratory Values ........................................................ 31 
Table 5: Potentially Clinically Significant Vital Sign Values .................................................................... 32 
Table 6: Abnormal Electrocardiogram Categories ..................................................................................... 33 
Table 7: Potentially Clinically Significant Electrocardiogram Values ....................................................... 34 
Table 8: PK Parameters .............................................................................................................................. 40 
Table 9: PROMIS T-Score Conversions for Adult Global Physical and Mental Health ............................ 45 
Table 10: PROMIS T-Score Conversions for Pediatric Global Health ...................................................... 46 
Table 11: Flare-up Location Mapping ........................................................................................................ 47 
 
 
 
 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
List of Abbreviations
Abbreviation
Definition
AE
adverse event
ATC
anatomic therapeutic class
AP
anterior/posterior
CAJIS
Cumulative Analogue Joint Involvement Scale
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report 
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events 
ECG
electrocardiogram
eCRF
electronic case report form
FOCBP 
Female subjects of childbearing potential 
FOP 
Fibrodysplasia Ossificans Progressiva
FOP-PFQ
FOP-Physical Function Questionnaire 
GEE
generalized estimating equation
HO 
heterotopic ossification 
LPLV 
last patient last visit 
MedDRA 
Medical Dictionary for Regulatory Activities
NDA 
New Drug Application
NHS
Natural History Study
PCS
potentially clinically significant
PROMIS 
Patient-Reported Outcomes Measurement Information System 
 
retinoic acid receptor gamma
ROM
range of motion
SAE
serious adverse event
SAP 
statistical analysis plan 
ULN 
upper limit of normal
US
United States
WBCT 
whole body computed tomography
wLME 
weighted linear mixed effect model


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
1 
Introduction 
1.1 
Context for Version 1.1 
This statistical analysis plan amendment is introduced in preparation for the writing of the final CSR, 
which will include summaries of data collected after the start of the prolonged palovarotene dosing 
interruption that started in late 2019/early 2020 described below and up to LPLV in late 2022. This 
includes data from subjects who restarted palovarotene after the interruption and subjects who did not 
restart. The final CSR is not intended to include a rerun of tables and content already included in the 
interim CSRs from 2021 and 2022. 
1.2 
Context for Version 0.3 (Final) 
This Statistical Analysis Plan (SAP) describes the analyses to be performed for Study PVO-1A-202 Part C 
based on Amendment 4 of the protocol dated 01 September 2017, and all subsequent amendments; along 
with the France-specific Amendment 2 of the protocol for Study PVO-1A-204 dated 02 November 2017, 
and all subsequent amendments. Data collected for Study PVO-1A-202 Part C and Study PVO-1A-204 will 
be combined for the analyses. For the purposes of this SAP, “Study PVO-1A-202 Part C” (or simply “Part 
C”) represents data from both studies. 
The analyses performed for Study PVO-1A-202 Parts A and B are described in separate SAPs. PK analysis 
is described in this SAP. However, the PK analysis will be performed separately.  
The focus of this document is the analyses to be included in an interim CSR for the palovarotene NDA, 
which will not include summaries of all efficacy endpoints. This SAP may be amended to include additional 
details of analyses to be performed for the final CSR based on the locked Part C data. 
As WBCT and X-Ray bone safety data are collected sequentially from Study PVO-1A-201 through PVO-
1A-202C, the combination of bone safety analysis will be provided in the integrated safety analysis. 
However, listing of bone safety for Part C will be provided in this SAP.   
This amendment is introduced after the second interim analysis in Study PVO-1A-301 (“Study 301”) but 
before the planned third interim analysis (anticipated to be held in mid-May 2020). The futility boundary 
for Study 301 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 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
has not yet resumed for these subjects. Dosing on all other subjects in Study 301 and Study 202 Part C 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 logistical considerations.
2 
Overview 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective is: 
 
To evaluate the safety and efficacy of different palovarotene dosing regimens in subjects with FOP. 
Efficacy will be based on the ability of palovarotene to prevent heterotopic ossification (HO) as 
assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. 
2.1.2 
Secondary Objectives 
 
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 (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 D: To implement safety measures 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. 
2.2 
Study Design 
PVO-1A-202 Part C is a Phase 2, multicenter, open-label extension of Study PVO-1A-202 Part B. This 
continuation of the open-label extension study will give subjects who participated in Part B the opportunity 
to be followed for up to an additional 36 months. There will be no new subjects in Part C. 
Part D 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 in Part D. Subjects will follow assessments outlined in Table 
4 of the protocol as long as they are not 100% skeletally mature.  Part C plus Part D total duration will not 
exceed 48 months. 
Added assessments for spinal health will be carried out on low dose WBCT scans collected in the study. 
 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
Non Flare-up Based Treatment
Subjects will follow all procedures and undergo all assessments as specified in the Schedule of 
Assessments in Table 1 and Table 2 of the protocol. Subjects who cannot receive non-flare-up based 
treatment will only undergo annual assessments (clinical laboratory tests will not be performed). In the 
event of a flare-up or traumatic event, these subjects will receive flare-up based treatment and undergo all 
flare-up based assessments, including clinical laboratory tests and radiographs if they have not reached 
100% skeletal maturity. 
 
Subjects from Part B Continuing Non-Flare-Up Based Treatment into Part C 
Subjects who began non-flare-up based treatment during Part B will continue this visit schedule into Part 
C and will receive non-flare-up based treatment for up to an additional 48 months. Therefore, these subjects 
may undergo non-flare-up based treatment for up to 72 months over the entire study. These subjects will 
follow all procedures and undergo all assessments as specified in the Schedule of Assessments in Table 1 
of the protocol, including low dose WBCT scan (excluding head) at all annual site visits (Months 12, 24, 
36, 48,  60 and 72). Non-flare-up Day 1 is the first day that non-flare-up based treatment was initiated 
during Part B, and total duration of treatment will continue into Part C. 
Remote visits (e.g., at home or at a local medical facility; and via telephone contact from clinical site 
personnel) will occur every 3 months unless the Investigator deems that a site visit is necessary; urine 
pregnancy tests will be performed each month for female subjects of childbearing potential (FOCBP). 
 
Subjects from Part B Starting Non-Flare-Up Based Treatment During Part C 
Subjects who will start non-flare-up based treatment during Part C will receive non-flare-up based treatment 
for up to 48 months. These subjects will follow all procedures and undergo all assessments as specified in 
the Schedule of Assessments in Table 2 of the protocol, including low-dose WBCT scan (excluding head) 
at Screening and at all annual site visits (Part C Screening and Months 12, 24, 36 and 48.). Non-flare-up 
Day 1 is the first day that non-flare-up based treatment is initiated during Part C for these subjects. 
Remote visits (e.g., at home or at a local medical facility; and via telephone contact from clinical site 
personnel) will occur every 3 months unless the Investigator deems that a site visit is necessary; urine 
pregnancy tests will be performed each month for female subjects of childbearing potential (FOCBP). 
Blood samples for PK assessment of non-flare-up dosing will be collected at the first 3-month safety 
assessment at pre-dose and 3, 6, 10, and 24 hours post-dose; if samples cannot be or were not obtained at 
the 3-month safety assessment, or if a subject is on flare-up based treatment, then the PK blood sample for 
non-flare-up based treatment can be obtained during any subsequent 3-month safety visit. 
Flare-up Based Treatment 
Subjects receiving flare-up based treatment will follow all procedures and undergo all assessments as 
specified in the Schedule of Assessments in Table 3 of the protocol. Assessments will occur at Flare-up 
Cycle Safety Day 1 at 4 weeks, and every 8 weeks thereafter until treatment of the last flare-up or traumatic 
event in the flare-up cycle is completed. If after 12 weeks all flare-ups have not resolved then additional 
treatment and assessments will be performed every 4 weeks until all flare-ups have resolved. 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 non-flare-up based treatment with 5 mg palovarotene once daily 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
(weight-adjusted doses for skeletally immature subjects). Additional knee and hand/wrist radiograph 
assessments will also be performed every 3 months (±2 weeks) in skeletally immature 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.   
Off Treatment Part D:  
No study drug will be administered in Part D.  For skeletally immature subjects in Part D, added Year 1 
(Y1) and Year 2 (Y2), post last dose of study treatment assessments that include linear height, knee height, 
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 D will end.  The total duration of participation in Part C and Part D combined is a maximum of 4 years 
(±1 month). 
Pharmacokinetics 
The pharmacokinetics (PK) of palovarotene dosing will be assessed at the first 3-month safety assessment 
during non-flare-up based treatment; if samples cannot be or were not obtained during the first 3-month 
safety assessment, or if subjects are on flare-up based treatment, then PK blood samples for non-flare-up 
treatment can be obtained during any subsequent 3-month safety visit. 
Pharmacokinetics (PK) 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, 
PK blood samples can be obtained during any subsequent flare-up dosing cycle. Pharmacokinetic blood 
samples will be collected at pre-dose and 3, 6, 10, and 24 hours post-dose. Subjects who underwent PK 
assessment under PVO-1A-202 Protocol Amendment 3 (Part B) will not have PK assessed again; however, 
these subjects will require a non-flare-up treatment PK assessed at a 3-month safety visit. 
2.3 
Study Treatment 
As of 04 December 2019, 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. 
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 receive open-label palovarotene treatment as follows: 
 
20 mg for 4 weeks (28 days) once daily. The first dose will be taken upon flare-up confirmation by 
the Investigator. To be followed by: 
 
10 mg for 8 weeks (56 days) once daily, for a total flare-up treatment duration of 12 weeks (84 
days); 10 mg treatment may be extended if the flare-up is ongoing and continue until the flare-up 
resolves. Dosing will be extended in 4-week intervals and be based on clinical signs and symptoms 
as assessed by the Investigator. 
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. 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
All dosing, regardless of non-flare-up or flare-up based, will be weight-adjusted in subjects under the age 
of 18 years with less than 90% skeletal maturity on hand/wrist radiography at Screening. (Note: all weight-
but radiographic assessment of the growth plate will continue until these subjects achieve 100% skeletal 
maturity at both knee and hand/wrist locations.)  
Table 1: Weight-Adjusted Palovarotene Doses and Dose De-Escalation Doses 
If the subject experiences intolerable side effects, the dose may be reduced to the next lower dose; if the 
subject is already receiving the lowest possible dose as shown in the Table 1, then study drug will be 
discontinued. Treatment may be extended after the 84-day treatment period (flare-up based dosing) if the 
flare-up is ongoing and continue until the flare-up resolves. Dosing will be extended in 4-week intervals 
based on clinical signs and symptoms as assessed by the Investigator, with remote visits performed every 
4 weeks while on treatment. In the event the subject requires 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.  
Should a subject experience an intercurrent flare-up (defined as a new flare-up or marked worsening of the 
original flare-up), or if the Investigator confirms the presence of a 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 confirmation by the Investigator (ie, 4 weeks of 20 mg palovarotene 
followed by 8 weeks of 10 mg palovarotene [or weight-based equivalent]). A Flare-up Cycle will include 
the first flare-up or traumatic event and any subsequent intercurrent flare-ups or traumatic event 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, at 4 weeks, and every 8 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 the 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.  
2.4 
Study Populations 
A total of approximately 60 subjects will be enrolled in Part C including up to 40 subjects enrolled from 
Study PVO-1A-201 and up to 20 new adult subjects enrolled during Part B. All subjects will have 
participated in Part B and no new subjects will be enrolled in Part C and D.  
 
 
Weight 
Range  
Category
20-mg
Equivalent 
15-mg
Equivalent 
10-mg  
Equivalent 
7.5-mg 
Equivalent* 
5-mg 
Equivalent* 
2.5-mg 
Equivalent* 
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
 
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 equivalent, respectively.  


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Flare-up Based Treatment Group: 
Flare-up based analyses will be based on flare-up cycles in Part C and will include the treatment group 
combined PVO 20/10 mg.  
Combined PVO 20/10 mg is defined as flare-up cycles that flare-ups were treated with PVO 20/10 mg (or 
weight-based equivalent) during Part C, regardless of whether non-flare-up PVO 5 mg (or weight-based 
equivalent) treatment had been administered prior to the flare-up dosing.  
Non-Flare-up Based Treatment Group:  
Non-flare-up based analyses is based on subjects and will include the treatment group with PVO 5 mg (or 
weight-based equivalent).  
PVO 5 mg group is defined as subjects who received at least one dose of non-flare-up regimen (regardless 
of whether they received the flare-up regimen) during Part C.  
Untreated (Never Received PVO Treatment) Group:  
Untreated is defined as subjects who were not on the non-flare-up regimen and did not receive flare-up 
based treatment in Part C. 
2.5 
Randomization and Blinding 
This is an open-label study and does not involve randomization or blinding. 
3 
General Statistical Consideration 
Categorical data will be summarized with counts and percentages. Percentages will be calculated based on 
the number of non-missing values and will be reported to one decimal place. 
Continuous data will be summarized with descriptive statistics including the number of non-missing values, 
mean, standard deviation, standard error, median, minimum, and maximum. Minimum and maximum will 
be reported to the same precision as the raw values, mean and median will be reported to one additional 
decimal place, and standard deviation and standard error will be reported to two additional decimal places. 
Non-flare-up based summaries will be performed based on visits in Table 1 and Table 2 in the protocol.  
Flare-up based summaries will be performed based on flare-ups at flare-up visits: Flare-up Day 1, Flare-up 
Week 4 (28 days), Flare-up Week 12 (Day 84) etc.   
To distinguish flare-up based analysis from subject based analysis, m will be used for number of flare-ups 
and n will be used for number of subjects.  
In summary of change from baseline analysis for Enrolled Population, baseline from non-flare-up based 
treatment will be used for subjects in group PVO 20/10 mg only.    
3.1 
Definition of Baseline 
Unless otherwise stated, baseline will be defined as Section 3.1.1 to 3.1.3. 
3.1.1 
Baseline for Non-Flare-up Based Treatment 
 
For subjects from Part B continuing non-flare-up based treatment into Part C (i.e., subjects who 
ever received at least one dose of non-flare-up based treatment in both Part B and Part C), baseline 


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will be based on assessment prior to first non-flare-up treatment in Part B. For subjects who 
continued from Part B into Part C a Part C baseline is defined as the first assessment in Part C.  
 
For subjects who did not receive any non-flare-up based treatment in Part B but start non-flare-up 
based treatment during Part C, baseline will be based on assessment prior to first non-flare-up 
treatment in Part C.  
3.1.2 
Baseline for Flare-up Based Treatment 
For subject receiving flare-up based treatment in Part C, baseline values will be the last available value 
prior to or on the date of first dose of flare-up treatment with the cycle.    
3.1.3 
Baseline for Subjects Never Receive PVO Treatment in Part C 
For subjects who never received any PVO Treatment in Part C, baseline is defined as the most recent non-
missing measurement on Part C Study Day 1.  
If baseline is missing in Part C, then baseline will be based on assessment prior to first non-flare-up 
treatment in Part B.  
3.1.4 
Baseline for Subjects who Restarted Palovarotene After Dosing interruption in Part C 
For subjects who paused dosing either because of the partial clinical hold for subjects <14 years on 
December 4, 2019 or because of interruption after Study PVO-1A-301 crossed futility on January 24th 2020 
and subsequently re-started palovarotene their re-start baseline is defined as the first assessments after re-
start.  
3.2
Part C Study Day, Flare-up Cycle Days and Non-Flare-up Days 
3.2.1 
Part C Study Day 1 
For all subjects, Part C Study Day 1 is defined as the date of informed consent in Part C. Part C Study Day 
-1 will be the day immediately prior to Part C Study Day 1.  
3.2.2 
Flare-up Cycle and Flare-Up Cycle Day 1 
 
A Flare-up Cycle will include the first flare-up and any subsequent intercurrent flare-ups during 
the same dosing period.  
 
Flare-Up Cycle Day 1 is defined as the first day that study drug is administered for the first flare-
up during that cycle.  
3.2.3 
 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 meds were not taken/interrupted during the flare-up cycle + 1). 
3.2.4 
Duration of Non-Flare-up Treatment  
Based on study design, subjects are assumed to be on non-flare-up based treatment from the date they 
received 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 


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date – duration of flare-up treatment (days) - days where non-flare-up meds were not taken/interrupted + 
1). Duration of flare-up treatment (days) is defined in 3.2.3. 
3.3 
Definition of New-Onset Potentially Clinically Significant (PCS) Value 
New-onset potentially clinically significant (PCS) values are defined as values that were not PCS at baseline 
and were PCS at post-baseline. 
3.4 
Adjustments for Covariates 
As requested by US FDA during review of the US NDA, Ipsen is conducting multiple analyses comparing 
annualized new HO between Study 202 Part C and NHS, including 
 
GEE for new HO from all scans in Study 202 Part C, such that baseline is more than 30 days after 
the end of the previous flare-up, versus NHS. (Subjects without 2 WBCTs in Study 202 Part C 
where the first is at least 30 days after the end of the previous flare-up are not included.) 
 
GEE for new HO from all scans post-restart in Study 202 Part C, such that baseline is more than 
30 days after the end of the previous flare-up, versus NHS. (Subjects without 2 WBCTs post-restart 
in Study 202 Part C where the first is at least 30 days after the end of the previous flare-up are not 
included.) 
These models are run with 3 covariates in addition to treatment – baseline age, sex, total HO – and with 5 
covariates in addition to treatment – baseline age, sex, total HO, CAJIS, time since last flare up.  
In addition to these regression-based techniques, FDA has requested that propensity-score-based methods, 
including matched pairs analyses and weighted analyses also be performed to compare annualized new HO 
in Study 202 versus NHS. Propensity scores are being generated using the set of 5 covariates listed above. 
Additional analyses are also being performed, including those that pool Study 202 Part B and Part C as well 
as several in which Study 202 and Study 301 data are pooled. 
3.5 
Handling of Dropouts or Missing Data 
As there is no effective treatment for subjects with FOP, it is assumed they will be highly motivated to 
adhere to the protocol and treatment visits. Thus, it is expected that there will be minimal missing data, and 
most subjects will complete the study. The efficacy analysis will be performed using observed data only. 
Missing efficacy data will not be imputed.  
3.6 
Unscheduled Assessments for Clinical Laboratory Test, Vital Sign and ECG 
 
For unscheduled visits, continuous data from laboratories results, vital signs and ECG will not be 
used for statistical summary (such as mean with standard deviation). However, the unscheduled 
results will also not be used for assessment of potentially clinically significance (PCS) or 
abnormality.  
 
If multiple records occur within a post-baseline visit, the first non-missing value will be used.  
 
Lab results beyond the detectable limits will be reported as detectable limits for calculating 
descriptive statistics.  
 
Results for lab obtained locally rather than from the central laboratory will also be used for 
summaries.  
 
All the laboratory test results, vital sign and ECG will be included in the data listings as reported. 


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3.7
Handling of Partial Dates for Medications 
When determining prior or concomitant medications, partial start dates of prior and concomitant 
medications will be assumed to be the earliest possible date consistent with the partial date.  
For the purposes of analysis, incomplete medication start and stop dates will be imputed.  
 
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 medication 
would be considered as both prior and concomitant. 
 
If a medication start date is incomplete, January will be imputed for missing month and/or the first 
day of the month will be imputed for missing day.  
 
If a medication stop date is incomplete, December will be imputed for missing month and the last 
day of the month will be imputed for missing day.  
 
If the imputed medication stop date is after the date of study completion, the date of study 
completion will be used instead. 
3.8 
Handling of Partial Dates for Adverse Events 
 
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 non-flare-up dosing period. 
 
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 non-flare-up 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. 
 
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 cycle, the start date is imputed as the start date of the flare-up cycle 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 non-flare-
up 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.  
 
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. 
3.9 
Interim Analyses 
No formal interim analyses were planned for Part C. 
This document describes analyses to be included in the final CSR.  
3.10 Multicenter Studies 
A review of by-center effects will be performed in the context of data listing review. However, the sample 
size precludes formal assessment of by-center effects. 


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3.11
Multiple Comparison/Multiplicity
As this is an extension of an initial proof-of-concept study, no adjustment for multiple testing is planned. 
3.12 Examination of Subgroups 
The sample size in this study is not sufficient to allow rigorous assessment of outcomes by subgroups, and 
the study is not powered for subgroup assessment. However, exploratory assessments of the outcomes may 
be performed with a limited number of extrinsic or intrinsic factors, including age of the subject, location 
of the flare-up, amount of new HO, number of flare-up treatments, patients with extended flare-up dosing, 
or other variables as appropriate. 
4 
Analysis Populations 
4.1 
Enrolled Population 
The Enrolled Population will include all subjects enrolled in Part C.  
Unless stated, analysis for Enrolled Population will be presented by groups: PVO 20/10 mg Only, nonflare-
up PVO 5 mg, PVO total, and Never Received PVO Treatment. The PVO 20/10 mg Only group only 
includes subjects who didn’t take PVO 5 mg.  
4.2 
Treated Population 
The Treated Population will include all subjects in the Enrolled Population who took at least one dose of 
palovarotene in Part C (either flare-up treatment or non-flare-up treatment).  
The analysis for Treated Population will be presented by group combined PVO 20/10 mg in Part C, 
non-flare-up treatment PVO 5 mg and PVO Total.  
The Treated Population will be the primary population for safety assessments.  
4.3 
Flare-up Treated Population 
The Flare-up Treated Population will include all subjects in the Treated Population who took at least one 
dose of flare-up based treatment in Part C.  
The analysis for Flare-up Treated Population will be presented by group:  combined PVO 20/10 mg. 
4.4 
Flare-up Per Protocol Population 
The Flare-up Per Protocol Population was to include all subjects in the Flare-up Treated Population with 
no major protocol deviations that may impact the efficacy assessment and who were at least 80% compliant 
with flare-up dosing.  
Due to the small sample size, particularly when the additional restriction that baseline WBCT must be taken 
more than 30 days after the end of the previous flare-up (as was the case for Study 301 and NHS), formal 
per-protocol analyses are not planned to be performed. 
4.5 
Non-Flare-up Treated Population 
The Non-Flare-up Treated Population includes all subjects in the Treated Population who took at least one 
dose of non-flare-up based treatment in Part C.  
The analysis will be presented for subjects who took PVO non-flare-up based dosing with 5 mg (including 
weight-adjusted doses). 


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4.6
Restart Full Analysis Set
Restart Full Analysis Set (RFAS) includes all enrolled subjects in the Principal Enrolled Population (EP) 
who restarted palovarotene therapy after January 2020 and have at least two HO volume measurements in 
Part C trial on or after restart, with the first such WBCT imaged at least 30 days after the end of the previous 
flare-up. 
4.7 
Part D Analysis Set 
Part D Population includes all skeletally immature subjects who stopped taking study medication 
for any reason before completion and had at least one follow-up visit following last dose. All 
analyses involving this population will be descriptive. 
4.8
Pharmacokinetic Population 
The Pharmacokinetic (PK) Population will include all subjects in the Treated Population who have at least 
one post-dose measurable concentration. The analysis will be presented for subjects who took non-flare-up 
based dosing of PVO 5 mg (including weight-adjusted) and/or flare-up based dosing of PVO 20/10 mg 
(including weight-adjusted doses). 
5 
Subject Data 
5.1 
Subject Disposition  
Subjects disposition will be summarized for Enrolled Population: 
 
Number of subjects in each analysis population 
 
Number of subjects who discontinued treatment from Part C early and reasons for discontinuation 
 
Number of subjects who prematurely withdrew from Part C and reason for study discontinuation 
 
Number of subjects who completed Part C. 
 
Duration (months) of participation in Part C. This will be calculated as (date of completion of Part 
C/discontinuation - date of informed consent for Part C)/30.5.  
 
Number of subjects by following categories: 
 
 
 
>6 – 12 months 
 
>12 – 18 months 
 
>18 – 24 months 
 
>24 months 
Note: The total duration of participation in Part C and Part D, is a maximum of 4 years.
Subjects disposition will be summarized for Enrolled Population in Part D by listings.
 
 
5.2 
Eligibility Criteria 
Eligibility criteria (inclusion/exclusion) will be listed with any specific criteria that were not met shown in 
the by-subject listing for the Enrolled Population. 


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5.3
Protocol Deviations
Major protocol deviations will be identified prior to locking the database for Part C and may include, but 
are not limited to, departures from the inclusion/exclusion criteria, non-compliance with investigational 
product, use of restricted concomitant medications, and non-compliance with study procedures. Major 
protocol deviations will be summarized for the Enrolled Population. 
For the NDA interim report, protocol deviations were not  summarized, due to the study being ongoing at 
that time. 
5.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics such as age, age group (6-15, 15+; 6-18, 18+), sex, race, 
ethnicity, height (cm), and weight (kg) will be summarized for all analysis populations. 
5.5 
Medical History 
Medical history will not be collected as there are no new subjects in Part C. Subjects medical history was 
collected and summarized previously in Part A and Part B. 
5.6 
Prior and Concomitant Medications 
 Prior and concomitant medications will be coded using the WHO Drug Dictionary (March 2014).  
 
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 Part C. Concomitant medications first received after first dose of study 
drug in Part C 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, or as a concomitant 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.  
The prior and new onset medications will be summarized based on the Enrolled Populations as follows: 
 
Prior medications discontinued prior to the first dose of study drug  
 
Prior medications ongoing at the first dose of study drug 
 
New onset medications during study 
 
Concomitant medications 
Systemic glucocorticoids will be summarized including:  
Glucocorticoids taken for palovarotene treated flare-ups for Flare-up Treated population
 
Glucocorticoids taken for condition aggravated adverse event for Enrolled Population 
 
Glucocorticoids taken for all other adverse event for Enrolled Population 
The medications will be summarized according to the WHODrug Global March 2014 by Anatomic 
Therapeutic Class (ATC) and preferred term.. The ATC Class 3 name will be presented if available, and if 
not available the ATC class 2 name will be presented.  


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Systemic glucocorticoids used for flare-ups is defined as initiated 9 days prior to start of palovarotene for 
a flare-up cycle or within 9 days of flare-up cycle initiation which is categorized as a steroid used for treated 
flare-up or taken initially for a flare-up treated with palovarotene during a flare-up cycle. 
For the purposes of analysis, incomplete medication start and stop dates will be imputed (See Section 3.7).  
5.7 
Treated Flare-ups Starting During Part C 
Treated flare-ups for flare-up based treatment during Part C will be summarized for Flare-up Treated 
Population and Flare-up Per Protocol Population including following variables: 
 
Total number of flare-up cycles 
 
Number of flare-up cycles with dosing extended beyond 12 weeks 
 
Number of flare-up cycles for which an interruption of study drug occurred during flare-up dosing 
overall and by high or low flare-up based doing. Where an interruption includes  14 days without 
dosing. 
 
Number of flare-up cycles with dosing reductions overall and by high or low flare-up based doing 
 
Number of flare-up cycles for which study drug was discontinued during flare-up dosing overall 
and by high or low flare-up based doing 
 
Total number of treated flare-ups across all flare-up cycles 
 
Number of flare-ups treated per cycle 
 
Number of flare-ups treated per cycle categorized 
 
1 flare-up 
 
2 flare-ups 
 
3 flare-ups 
 
4 flare-ups 
 
>5 flare-ups 
 
Number of intercurrent flare-ups treated per cycle 
 
Number of palovarotene treated trauma  flare-ups 
 A dose interruption is defined as dosing interrupted for at least 14 days without dosing. 
Number of subjects with treated flare-ups will also be summarized for Flare-up Treated Population 
including following variables: 
 
Number of subjects with treated flare-up cycles 
 
Number of subjects with treated flare-up cycles by categories 
 
1 flare-up cycle 
 
2 flare-up cycles 
 
3 flare-up cycles 
 
4 flare-up cycles 
 
-up cycles 
 
Number of subjects with flare-up cycle with dosing extended beyond 12 weeks 
 
Number of subjects for which an interruption of study drug occurred during flare-up cycle dosing 
overall and by high or low flare-up based doing 
 
Number of subjects for which study drug was discontinued during flare-up cycle dosing overall 
and by high or low flare-up based doing 


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Number of subjects with dose reduction during flare-up cycle dosing overall and by high or low 
flare-up based doing 
Treated flare-up data as reported by the subject and by Investigator including symptoms, probable causes, 
and location(s) will be summarized for the Flare-up Treated Population. 
Flare-up location mapping is described in Table 11. 
5.8 
Annualized Flare-up Rate  
Flare-ups are counted using the number of subject/Investigator-reported flare-ups (including intercurrent 
flare-ups). Rates will be calculated as the total number of flare-ups divided by duration of follow-up (year).  
The duration of follow-up (years) is defined as (last date on study – Part C Study Day 1 + 1)/365.25. Flare-
up rate will be calculated separately for pre-interruption, during interruption, and after re-start of 
palovarotene dosing. 
5.9 
Exposure in Part C 
Extent of study drug exposure will be summarized for flare-up based treatment and non-flare-up based 
treatment.  
5.9.1 
Exposure to Flare-up Based Treatment  
The summary of exposure by subject across all flare-up cycles will be included:  
 
Duration of flare-up treatment by subject across all flare-up cycles, defined as sum of days of 
exposure across all flare-up cycles (see Section 3.2.3 for calculation) 
 
Duration of flare-up treatment by subject according to the following categories: 
 
3 months 
 
>3 – <=6 months 
 
>6 – <=9 months 
 
>9 – <=12 months 
 
>12 – <=15 months 
 
>15 – <=18 months 
 
>18 – <=21 months 
 
>21 – <=24 months 
 
>24 months 
 
Duration of high flare-up treatment by subject (20-mg dose)  
 
Duration of low flare-up treatment by subject (10-mg dose)  
The summary of exposure by flare-up cycle will be included:  
 
Duration of flare-up treatment by flare-up cycle  
 
Duration of flare-up treatment by flare-up cycle, according to the following categories: 
 
2 weeks 
 
>2 – 4 weeks 
 
>4 – 6 weeks 
 
>6 – 8 weeks 
 
>8 – 10 weeks 


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>10 – 12 weeks 
 
>12 – 16 weeks 
 
>16 – 20 weeks 
 
>20 weeks 
 
Duration of high flare-up treatment by flare-up cycle (20-mg dose)  
 
Duration of low flare-up treatment by flare-up cycle (10-mg dose)  
If a subject has dose reduction, the exposure is counted by planned treatment. 
The following summaries will also be presented for Flare-up Treated Population: 
 
Number of days after flare-up onset to first dose of study drug for flare-up cycles, calculated as 
sum of (date of first dose of flare-up cycle – date of flare-up onset + 1) across all flare-up cycles 
5.9.2 
Exposure to Non Flare-up Based Treatment  
The following summary will be included: 
 
Number of subjects with non-flare-up based treatment 
 
Duration of non-flare-up based treatment (months), defined as days subjects received non-flare-up 
treatment/30.5 (see Section 3.2.4 for calculation) 
 
Number of subjects by following exposure categories in months: 
 
>0 – 6 months 
 
>6 – 12 months 
 
>12 – 18 months 
 
>18 – 24 months 
 
>24 months 
 
Number of subjects with at least one non-flare-up dose reduction 
 
Number of dose reductions by type (e.g. 5 to 2.5 mg) 
 
Number of subjects with study drug interruption, where a dose interruption is defined as dosing 
interrupted for at least 14 days without dosing 
 
Number of subjects with study drug discontinuation 
5.9.3 
Total Exposure to Study Drug for Each Subject  
Total exposure to study drug for each subject for Treated Population will be calculated as  duration of non-
flare-up treatment and flare-up treatment (see Section 3.2.3 and 3.2.4 for calculation).  
Total actual dose (mg) will be summarized by Enrolled Population.  
 
Total dose is calculated as the cumulative dose (mg) across all dosing regimens (non-flare-up and 
flare-up) for each subject.  
 
Total non-flare-up dose is calculated as the cumulative dose across all the non-flare-up treatment 
periods.  
 
Total flare-up dose is calculated as the cumulative dose taken across all flare-up cycles.  
 
All total dose calculations account for weight-adjusted doses, dose reductions  


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5.9.4
Duration of Subject Participation in Part C
Duration (months) of participation in Part C is calculated as (the earlier date of completion of Part C or 
discontinuation - the date of informed consent + 1)/30.5. For subjects ongoing, it is calculated as (data 
cutoff date – date of informed consent + 1)/30.5. 
Number and percentage of subjects will be summarized for following duration categories for Enrolled 
Population: 
 
<= 6 months 
 
>6 to 12 months 
 
>12 to 18 months 
 
>18 to 24 months 
 
>24 months 
5.9.5 
Duration of Subject Participation in Part D  
 
up to 24 months 
5.10 Compliance 
Compliance is defined as (duration of treatment/expected duration of treatment). Calculation of duration of 
treatment is described in Section 3.2.3 and 3.2.4. 
The expected duration of treatment is calculated as following: 
 
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 Treated Population with descriptive statistics. Compliance in 
category 
also be summarized for counts and percentages of subjects. 
6 
Efficacy Data 
Unless otherwise stated, efficacy data will be summarized using Enrolled Population presented by groups: 
PVO 20/10 mg Only, PVO 5 mg, PVO Total and Never Received PVO Treatment. The PVO 201/10 mg 
Only group only includes subjects who did not take PVO 5 mg.    
Imaging Reads 
Imaging data includes results from low-dose WBCT scans (excluding head) and radiographs.  
WBCT HO status and total HO volume or new HO volume will be summarized by visit. Those analysis 
will be included in the interim CSR. All other analysis will be presented in the final CSR.  
6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the annualized change in new HO volume as assessed by low-dose WBCT 
scan (excluding head) during Part C.  


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The change in new HO total volume will be compared to baseline where the baseline value was performed 
prior to the initiation of non-flare-up based dosing (in Part B or Part C).  
The WBCT HO total volume will be calculated as the sum of the volumes for each location of the WBCT 
assessment. If there is no HO, 0 will be assigned for analysis. 
The annualized change in new HO volume will not be summarized in the interim CSR for the palovarotene 
NDA, due to the ongoing nature of the reads.  This analysis will be included in the final CSR. However, all 
WBCT data (total and by region) HO volume, HO status, New HO volume by visit will be listed. 
Annualized HO will be summarized before the pause in palovarotene dosing, i.e. 4 December 2019 for 
patients younger than 14 years old or 24 January 2020 due to the crossing of the futility boundary in Study 
PVO-1A-301; and after restarting palovarotene. 
Inferential analyses are described in Section 3.4 Adjustment for Covariates. 
6.2 
Secondary Efficacy Endpoints  
Secondary efficacy endpoints for include: 
1. Percent of subjects with new HO at Months 12, 24, 36, and overall.  
2. Change from baseline in ROM as assessed by CAJIS at Months 6, 12, 18, 24, 30, and 36.  
3. Change from baseline in physical function using age-appropriate forms of the FOP-PFQ at Months 
6, 12, 18, 24, 30, and 36. 
4. Change from baseline in physical and mental 
function for subjects <15 years old using age-appropriate forms of the PROMIS Global Health 
Scale at Months 6, 12, 18, 24, 30, and 36. 
Secondary endpoints will also be summarized before the pause in palovarotene dosing and after restarting 
palovarotene. 
6.2.1 
New HO 
The presence of new HO at each scheduled visit will be determined by low-dose WBCT scan, excluding 
head. Note that “New HO” means new HO compared to baseline. Baseline will be based on assessment 
from WBCT prior to the start of Non-flare-up dosing in Part B or Part C. 
The presence of “HO at baseline” and the incidence of “No new HO”, and “New HO” will be summarized 
with counts and percentages overall and by regions.  
6.2.2 
Cumulative Analogue Joint Involvement Scale (CAJIS) 
Range of motion across the whole body will also 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). 


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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). 
The CAJIS Mobility subscore 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). 
The CAJIS Total score, CAJIS Upper Extremities subscore, and CAJIS Mobility subscore and changes 
from baseline (defined in Section 3.1) will be summarized at each scheduled visit with descriptive statistics.   
6.2.3 
FOP-Physical Function Questionnaire (FOP-PFQ) 
Age-appropriate forms of the FOP-PFQ will be administered to subjects (or parent proxy). The adult form 
will be administered to subjects 15 years and older. 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 questions are described in detail in 
Appendices 2A, 2B, and 2C of the protocol.  
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. 
The Upper Extremities subscore will be calculated as: 
 
The sum of the scores from 15 questions (questions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 25, and 
26) and ranges from 15x1 = 15 to 15x5 = 75 for the adult form. 
 
The sum of the scores from 18 questions (questions 1, 2, 6, 7, 8, 9, 10, 11, 16, 17, 18, 19, 21, 22, 
23, 24, 25, and 26) and ranges from 18x1 = 18 to 18x5 = 90 for the pediatric form. 
The Mobility subscore will be calculated as: 
 
The sum of the scores from 13 questions (questions 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 
and 28) and ranges from 13x1 = 13 to 13x5 = 65 for the adult form. 
 
The sum of the scores from 8 questions (questions 3, 4, 5, 12, 13, 14, 15, and 20) and ranges from 
8x1 = 8 to 8x5 = 40 for the pediatric form. 
The Total score, Upper Extremities subscore, and Mobility subscore are defined based on information from 
PROMIS and Hays et al (2013)1 for the adult form and a medical review of the questions for the pediatric 
form. 
If a subject is missing some (but not more than 20%) of the contributing question scores, the Total score, 
Upper Extremities subscore, or Mobility subscore 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. The determination for sufficient non-missing 
scores will be made independently for the Total score, Upper Extremities subscore, and Mobility subscore. 


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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 2 illustrates some sample derivations of the percentage of 
worst score. 
Table 2: 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% 
Percentage of worst scores and changes from baseline (defined in Section 3.1) of will be summarized at 
each scheduled visit with descriptive statistics. 
6.2.4 
PROMIS Global Health 
An age-appropriate form of the PROMIS Global Health short form will be administered to subjects (or 
parent proxy). The adult form will be administered to subjects 15 years and older. 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 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. The questions are described in detail in Appendices 8A, 8B, 
and 8C of the protocol.  
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 3. 


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Table 3: Rescaled PROMIS Global Health Scale Scores
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. The proxy-completed PROMIS form will be 
used for analyses unless only the self-completed form is available. 
Global Physical Health scores and Global Mental Health scores will also be converted to T-scores as 
described in detail in Appendix 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.  
PROMIS Global Heath T-score and changes from baseline (defined in Section 3.1) will be summarized at 
each scheduled visit with descriptive statistics. Data from adult (both physical health and mental health) 
and pediatric forms will be summarized separately.  
7 
Safety Data 
Safety data summaries in the final CSR will be based on the safety data presentations in recent documents, 
including the Safety Update included in the NDA and the Day 90 Safety Update; the primary difference 
will be that those summaries included data from all palovarotene studies, while the Study 202 presentations 
will only include data collected in Study 202.  
While the majority of content listed below corresponds to the data presentation in the interim CSR, it is also 
relevant for pooled summaries that will be the basis for the final CSR safety discussion. 
Adverse events will generally be presented by treatment period (See Section 7.1 for classification of 
treatment periods) and in total for the Enrolled Population.  
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.  
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 


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Safety data for flare-up based treatment assessments will generally be presented by group combined PVO 
20/10 mg for the Flare-up Treated Population.  
For vitals, labs, ECGs, physical examination, linear growth assessment and CSSR, summary for non-flare-
up based treatment assessments (at regular scheduled visits) will be presented by groups:  PVO 20/10 mg 
only, PVO 5 mg, PVO Total and Never Received PVO Treatment using Enrolled Population. The PVO 
201/10 mg only group only includes subjects who did not take PVO 5 mg. 
Assessments obtained in Part D 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. 
 
Pregnancy and Teratogenicity Assessment 
Pregnancy and pregnancy outcomes will be monitored throughout the study 
Pregnancy test results for females of child-bearing potential were provided as subject listings. 
A listing of pregnancy and pregnancy outcomes will summarize subject results 
7.1
Adverse Events 
Adverse events will be recorded from the time informed consent (Part C Study Day 1) is signed through 
study completion. All AEs will be coded to system organ class and preferred term using will be coded using 
a current version of MedDRA Study Drug Related Adverse Events: 
At least possibly related AEs are defined as AEs assessed by the Investigator as possibly, probably, or 
definitely related to study drug.  
Adverse events that require Common Terminology Criteria for Adverse Events (CTCAE) grading (Version 
4.03, 14 June 2010) as indicated on the eCRF are considered to be retinoid-associated AEs.  
Adverse Events Analysis Periods:  
All AEs collected during Part C from the time informed consent is signed are considered as treatment 
emergent adverse events (TEAEs).  
TEAEs will be summarized by period (Non-Treatment Period, Non-Flare-up Treatment Period, and 
Flare-up Treatment Period, Total Treatment Period) and in total. 
a) Flare-up treatment period 
Adverse events with start date on or after Flare-up Cycle Day 1 and on or before the date of completion for 
the Flare-up treatment will be attributed to the Flare-up treatment period.  
b) Non-Flare-up Treatment Period 
Adverse events with start date on or after first Non-Flare-up dose date in Part C for which the subjects are 
not undergoing flare-up treatment will be attributed to the Non-Flare-up Treatment Period. 


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Non-Flare-up Treatment Period is period that subjects taking non-flare-up dose including non-flare-up dose 
interruption periods. All flare-up cycles are excluded.  
c) Non-Treatment Period 
Adverse events with start date on or after Study Day 1 that are not attributed to the flare-up or non-flare-up 
treatments will be attributed to the Non-Treatment Period. 
Non-Treatment Period are period that subjects are receiving neither non-flare-up and nor flare-up treatment. 
In Part C, it is the period starting from Part C Study 1 to the day before first study drug dosing date 
(regardless of whether non-flare-up or flare-up based treatment), and the period from date of study drug 
discontinuation to end of study or study discontinuation date. 
Adverse Events Summary:  
The incidence of the following TEAEs will be summarized with counts and percentages of subjects (overall 
and by MedDRA system organ class and preferred term): 
Adverse Event Variables 
Adverse Event Observation Periods
 TEAEs are AEs with (first dose date of study drug during 202 C
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 in Part C + 7 days for All 
AEs (non-serious and serious AEs).   
 
Any AEs 
 
Any post treatment AEs 
 
Any TEAEs 
 
Any TEAEs by maximum severity 
 
Any TEAEs at least possibly related to study drug 
 
Any TEAEs at least possibly related to study drug by maximum severity 
 
Any serious adverse events (SAEs)  
 
Any TEAEs leading to dose modification 
 
Any TEAEs leading to interruption of study drug  
 
Any TEAEs leading to discontinuation of study drug 
 
Any TEAEs leading to discontinuation from study 
Data listings will be provided for  
 
All TEAEs 
 
All post treatment AEs 


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SAEs 
 
SAEs for premature physeal closure and bone safety  
 
Deaths 
 
TEAEs leading to dose modification of study drug 
 
TEAEs leading to interruption of study drug 
 
TEAEs leading to discontinuation of study drug 
 
TEAEs leading to discontinuation of study 
 
AEs ongoing at date of informed consent signed in Part C  
Part C Study Day and/or Flare-up Day for AE start and stop dates will be included on AE listings as 
appropriate. 
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).   
Deaths 
Deaths after the first dose of study drug are either on-treatment or post-treatment: 
 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  
The SAE, including death, reporting period for the non-flare-up-based treatment and the flare-up-based 
treatment begins at the time of informed consent and continues through study completion (including Part 
D) + 30 days. 
 
 
7.2 
Safety Laboratory Assessments 
Blood and urine samples will be collected for hematology, biochemistry (includes lipids), and urinalysis 
testing.   
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. A blood or urine 
pregnancy test will be conducted monthly in Part C.  
For females of childbearing status: if pregnancy testing did not continue monthly per protocol 
post the study drug interruption then at a minimum a self-administered urine pregnancy test is to 
be done within 4 weeks before re-starting palovarotene treatment.  
Values and changes from baseline (defined in Section 3.1) for hematology, biochemistry (includes lipids) 
parameters will be summarized at each scheduled visit with descriptive statistics. Both the change from 
baseline (subject based) and the change from Flare-up Cycle Day 1 (flare-up based) will be presented.  
The following plots will be provided:  


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Boxplots for lab parameter over time by scheduled visits and by flare-up visits.  
 
Mean percent of normal high for serum chemistry and lipid lab analytes including: 
 
Aspartate Aminotransferase (AST) 
 
Alanine Aminotransferase (ALT) 
 
Gamma Glutamyl Transferase Gamma Glutamyl Transferase (GGT) 
 
Creatinine 
 
Lipase 
 
Bilirubin  
 
Triglycerides (lipid) 
 
Mean percent of normal low for hematology lab analytes including: 
 
Hematocrit (HCT) 
 
Hemoglobin (HGB) 
 
Bicarbonate (HCO3)  
If multiple records occur within a post-baseline visit, the first non-missing value will be used. Note that 
results obtained locally rather than from the central laboratory will also be used for summaries.  
Potentially clinically significant (PCS) values are predefined criteria/thresholds presented in Table 4. PCS 
values at baseline and new-onset PCS values post-baseline will be summarized with counts and percentages 
of subjects or flare-ups as appropriate. Separate analyses will be performed for the non-flare-up treatment 
visits and the flare-up treatment visits. Percentage of incidence of new-onset PCS laboratory values over 
time will be plotted.  
New-onset PCS values are defined as values that were not PCS at baseline (defined in Section 3.1) and 
were PCS post-baseline. Note that results obtained locally will be included in these summaries.  
Table 4: Potentially Clinically Significant Safety Laboratory Values 
PCS Low
PCS High
Biochemistry 
Aspartate aminotransferase
N/A 
3 x ULN 
Alanine aminotransferase 
N/A 
3 x ULN 
Amylase 
N/A 
3 x ULN 
Lipase, pancreatic
N/A 
3 x ULN 
Bilirubin
N/A 
>2 mg/dL 
AST, ALT and total bilirubin 
N/A 
AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
Thyroxine
<4.0 mcg/dL 
>13.0 mcg/dL
Lipids 
Cholesterol
N/A 
>300 mg/dL 
Triglycerides
N/A 
>400 mg/dL 
Hematology
Leukocytes
<2.8 x 109/L
>16.0 x 109/L
Hemoglobin (females)
<9.5 g/dL
>17.5 g/dL 


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PCS Low
PCS High
Hemoglobin (males)
<11.5 g/dL
>19.0 g/dL
Hematocrit (females)
<32%
>54%
Hematocrit (males)
<37%
>60%
Platelets
<75 x 109/L
>700 x 109/L
Urinalysis parameters will be tabulated for Non-Flare-up Treated Population and Flare-up Treated 
Population.  
A listing will be provided for all subjects meeting PCS laboratory criteria that will include all PCS results 
during the study along with associated palovarotene and glucocorticoid dosing data (dose and start and stop 
dates). A by-subject listing of all laboratory parameters will be generated. Listing for subjects with PCS 
lipase values will also be listed separately.  
7.3 
Vital Signs 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature. 
Values and changes from baseline will be summarized at each scheduled visit with descriptive statistics. 
Both the change from baseline (defined Section 3.1) and the change from Flare-up Cycle Day 1 (flare-up 
based) will be presented. If multiple records occur within a post-baseline visit, the first non-missing value 
will be used. 
Potentially clinically significant (PCS) values are predefined criteria/thresholds presented in Table 5. PCS 
values at baseline and new-onset PCS values post-baseline will be summarized with counts and percentages 
of subjects or flare-ups as appropriate. Separate analyses will be performed for the non-flare-up treatment 
visits and the flare-up treatment visits. New-onset PCS values are defined as values that were not PCS at 
baseline (defined in Section 3.1)  and were PCS post-baseline.  
Table 5: Potentially Clinically Significant Vital Sign Values 
7.4 
Body Weight 
Values and changes from baseline for body weight and body weight z-score will be summarized by visit 
with descriptive statistics for Non-flare-up Treated Population and Flare-up Treated Population. Mean 
values will be plotted over time. 
7.5 
Linear Growth Assessment 
A linear growth assessment will be performed for subjects under the age of 18 years at the time of 
enrollment into study with open epiphyseal growth plates using stadiometer and knee height assessments.  
 
PCS Low 
PCS High
Systolic blood pressure 
mmHg 
from baseline 
mmHg from baseline 
Diastolic blood pressure 
from baseline
mmHg from baseline
Heart rate 
baseline 
bpm from baseline 
(2) >125 bpm 
mmHg = millimeters of mercury, bpm = beats per minute. 


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Values and changes from baseline (defined as assessment at screening visit in Part C) will be summarized 
for linear height and knee to heel length by visit with descriptive statistics.  
The values and change from baseline for linear height z-score will also be calculated for each scheduled 
visit.   
Z-scores will be obtained from https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm.
The following spaghetti plots by chronological age at assessment will be provided:  
 
 linear height and linear height z-scores over time 
 
Knee height over time 
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 and premature growth plate closure (PPC) 
status.
 
 
7.6 
Electrocardiogram 
Values and changes from baseline (defined Section 3.1) will be summarized for continuous ECG parameters 
at each scheduled visit with descriptive statistics. The change from baseline (subject based) will be 
presented. If multiple records occur within a post baseline visit, the first non-missing value will be used.  
Abnormal ECG categories will be assigned based on raw findings as shown in Table 6. 
Table 6: Abnormal Electrocardiogram Categories  
Abnormal ECG Category 
Raw Findings 
Rhythm 
* Atrial premature complexes
* Ventricular premature complexes 
* Sinus arrhythmia 
* Sinus tachycardia 
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 




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7.8
Columbia-Suicide Severity Rating Scale  
Suicidal ideation and behavior will be assessed and summarized using the Columbia-Suicide Severity 
Rating Scale (C-SSRS).  
 
Type 1-Type 5 suicidal ideation 
 
Type 1suicidal ideation is passive suicidal ideation (wish to be dead) 
 
Type 2 suicidal ideation is non-specific active suicidal thoughts 
 
Type 3 suicidal ideation is active suicidal ideation without plan or intent 
 
Type 4 suicidal ideation is active suicidal ideation with some intent no plan 
 
Type 5 suicidal ideation is active suicidal ideation with specific plan and intent  
 
Behavior 
 
Non- suicidal self- injurious behavior 
 
Suicidal behaviors include actual attempts, interrupted attempts, aborted attempts, preparatory 
acts or behavior, and suicidal behaviors  
Data listings will be provided for  
 
All C-SSRS results  
 
Subjects reporting any type 4 or type 5 suicidal ideations, suicidal behavior or non- suicidal self- 
injurious behavior 
7.9 
Bone Safety Data 
Bone safety analysis based on WBCT and X-Ray safety imaging data include all phase 2 data (PVO-1A-
202 and PVO-1A-201). Additional details can be found in the Bone Safety Management Plan. 
Baseline is defined as non-missing measures at first assessed timepoint, regardless of which study this was 
performed in. 
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.  
  


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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
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 
ruption period.  
Note that bone safety analysis will also be performed based on premature physeal closure status. 
 
7.9.1 
Knee and Hand/Wrist Radiographs 
Subjects under the age of 18 years at the time of enrollment into Study PVO-1A-202 or PVO-1A-201 with 
open epiphyseal growth plates will undergo knee and hand/wrist radiographs (AP view) for assessment of 
epiphyseal growth plate. 
Knee and hand/wrist radiographs will be performed remotely (eg, at a local medical facility) for subjects 
who are unable or unwilling to attend site visits. Once a subject has achieved 100% skeletal maturity (as 
confirmed by radiography), knee and hand/wrist radiographs will no longer be required.  
Summary statistics of bone age and chronological age (values and changes from baseline) for subjects < 18 
years will be calculated at each scheduled visit for Enrolled Population. Changes in bone age will be plotted 
over time.  
Two independent radiology reviewers will qualitatively assess the hand/wrist and knee growth plate for 
abnormalities listed below.  Discrepancies in the reads will be adjudicated. 
The following abnormalities of the Epiphyseal Growth Plates assessed from X-ray will be assessed: 
 
EGP Abnormality Location: Wrist or Knee 
 
Calcinosis 
 
Cupping 
 
Dense Metaphyseal Lines 
 
Frayed Metaphyseal Edge 
 
Under Mineralisation or Osteopenia of the Adjacent Growing Bone 
 
Sclerosis of the Adjacent Growing Bone 
 
Widening of the Epiphyses 
 
Other 
Summary tables of growth plate abnormalities identified in radiographs will include the following: 


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Number and percent of subject with epiphyseal growth plates open (by hand/wrist and/or knee). 
 
Number and proportion of subjects with any abnormality at each visit, for each specific abnormality 
(e.g. growth recovery lines, Sclerosis, Under mineralization, etc.). 
 
Number and proportion of subjects with any change from baseline and from prior timepoint for 
hand/wrist and knee by each abnormality for each visit. 
 
Number and proportion of subjects with any change from baseline and from prior timepoint for 
hand/wrist and knee by each abnormality across all post-screening visits. For summaries across all 
timepoints, the worst case for a given subject will be used in the analysis. 
 
Number and proportion of subjects with any change from baseline and from prior timepoint for 
hand/wrist and knee across all abnormalities and post-screening visits. For summaries across all 
abnormalities and timepoints, the worst case for a given subject will be used in the analysis.  
Premature growth plate closure 
Listings of all subjects with premature growth plate closure will be provided. 
Analyses of Knee Alignment
Distal femoral angle  and premature closure of the growth plate will also be summarized for subjects < 18 
years old in Enrolled Population.  
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. 
7.9.2 
WBCT Bilateral Hand/Wrist and Knee Growth Plate Morphology Assessment  
Imaging was performed for pediatric subjects, i.e. subjects <18 years old who underwent WBCT scan at 
study enrollment and during regularly scheduled follow-up visits thereafter. Although the WBCT scans 
obtained in the trial are used primarily to quantify change in HO volume, they will also be used to assess 
bone safety, including bilateral hand/wrist and knee growth plate abnormalities on all subjects age < 18 
years. 
The following abnormalities of the Epiphyseal Growth Plates assessed from WBCT will be assessed: 
 
EGP Abnormality Location: Wrist or Knee 
 
Calcinosis 
 
Cupping 
 
Dense Metaphyseal Lines 
 
Frayed Metaphyseal Edge 
 
Under Mineralisation or Osteopenia of the Adjacent Growing Bone 
 
Sclerosis of the Adjacent Growing Bone 


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Widening of the Epiphyses 
 
Other 
Counts of abnormalities of epiphyseal growth plates (yes/no/not evaluable) detected will be summarized 
for each timepoint. (selecting the “last case” in the hierarchy for each abnormality, in order of the terms 
listed below): 
Open Epiphyseal Growth Plates 
 
Yes, Open  
 
Yes, Partially Closed  
 
No (Closed)  
 
Not Evaluable  
 
Missing  
 
Open Epiphyseal Growth Plates Location  
 
Wrist or Knee  
 
Wrist and Knee  
 
Wrist Only  
 
Knee Only  
 
Not Evaluable  
 
Closed  
Counts of abnormalities detected will be summarized as follows: 
 
Any Abnormality of Epiphyseal Growth Plates 
 
Yes 
 
No 
 
Not Evaluable 
Frequency of each abnormality for each timepoint and changes from baseline and from prior timepoint will 
also be summarized. 
7.9.3 
WBCTs Measurements of Femur and Tibia Lengths 
Although the WBCT scans obtained in the 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 age <18 years. 
Two independent radiology reviewers will measure the femur and tibia lengths.   The summary statistics of 
femur and tibia lengths (values and changes from baseline) for subjects < 18 years will be calculated for 
each visit for Enrolled Population.  Femur and tibia length will be summarized for four different subgroups: 
 
Male, Age < 10, 10 - <14, 14 - < 18 
 
Female, Age  < 8, 8 - <14, 14 - <18 
Figures will include plots of the femur and tibia length by chronological age at assessment by gender. 


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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 
(ie, >1.5 cm difference) will be provided in a listing.
7.9.4 
Evaluation of Bilateral Hips by WBCT Safety Read 
Although the WBCT scans obtained in the 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) in all subjects.   
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 by specific abnormalities (i.e. cysts, subchondral lucency, subchondral 
collapse, osteosclerosis, flattening/collapse femoral head, …), if present, the degree of change from the 
baseline scan and previous scan. 
WBCT Hip abnormalities identified in WBCT safety reads will be summarized for Enrolled Population 
include the following: 
 
Number and proportion of subjects with No, Yes (possible, probable, or definite) AVN or not 
evaluable at baseline, and by specific abnormality  
 
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 
Listings of any subject with possible, probable, definite AVN present will be provided. 
7.9.4.1 
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. Additionally descriptive statistics will be provided for each 
timepoint.   
8 
Pharmacokinetics Data 
Pharmacokinetics of palovarotene dosing will 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, PK blood samples can be obtained during any subsequent flare-up dosing cycle. 
Pharmacokinetic blood samples will be collected at pre-dose and 3, 6, 10, and 24 hours post-dose. Subjects 
who underwent PK assessment under PVO-1A-202 Protocol Amendment 3 will not have PK assessed again 
under PVO-1A-202 Amendment 4. 


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Blood samples for PK assessment of non-flare-up dosing will be collected at the first 3-month safety 
assessment at pre-dose and 3, 6, 10, and 24 hours post-dose; if samples cannot be or were not obtained at 
the 3-month safety assessment, or if a subject is on flare-up based treatment, then the PK blood sample for 
non-flare-up based treatment can be obtained during any subsequent 3-month safety visit.  
The allowed time deviation windows for pre-dose blood sample is 1 hour before dosing. The concentrations 
outside the sampling window will be listed but not used for PK parameter calculation and summary 
statistics. Plasma palovarotene concentrations will be summarized with descriptive statistics (number of 
non-missing values, arithmetic mean, standard deviation, standard error, coefficient of variation, geometric 
mean, median, minimum, and maximum).  
All plasma concentrations below the limit of quantification (LOQ) will be set to zero for the purpose of 
calculating descriptive statistics. If at any time point, 1/3 or more of subjects have <LOQ values, descriptive 
statistics will not be calculated at that time point. PK concentrations will be imputed using the following: 
 
If 0-hour concentration missing, then 24-hour concentration used to replace the missing 
concentration. 
 
If 24-hour concentration missing, then 0-hour concentration used to replace the missing 
concentration. 
 
Invalid 24-hour concentrations replaced with the 0-hour concentrations. Twenty-four-hour 
concentrations are determined to be invalid if concentration is greater than the 10-hour value (i.e. 
assumed to have been obtained after next day dose instead of before next day dose). 
For some subject who has both 0-hour and 24-hour concentration missing, the missing values will not be 
imputed. Data will be listed but excluded from PK parameter calculation. 
If any other blood sample collections are missing, PK parameters will not be assessed. Actual sampling 
times will be used for the PK analysis, if available. Nominal sampling times will be used for descriptive 
statistics. 
Individual concentration-time profiles for palovarotene will be presented (linear and semi-logarithmic 
scales). Arithmetic means (+/- standard deviation) concentration-time profiles will also be presented (linear 
and semi-logarithmic scales). 
An exploration of the effects of body weight on PK will be performed as the data allows.  
The PK analysis of palovarotene will be conducted using model-independent methods as implemented in 
WinNonlinTM. The PK parameters analyzed will include AUC0-24(ss), Cmax(ss), Cmin(ss), Tmax(ss), Tmin(ss), CLss/F, 
z, and t1/2 at steady-state. The PK parameters are defined as follows in Table 8: 
Table 8: PK Parameters 
AUC0-24(ss) 
Area under the concentration versus time curve over the 24-hour dosing interval; 
calculated using linear trapezoid rule. 
Cmax(ss)
Maximum measured plasma concentration at steady-state. 
Cmin(ss) 
Minimum measured plasma concentration at steady-state. 
Tmax(ss) 
Time of maximum measured plasma concentration at steady-state, obtained by 
inspection. 




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28 February 2020, i.e. cutoff for the interim 
CSR.
dosing regimens in each part of 
the study.
8.3 Study Populations 
This SAP amendment adds Restart Full 
Analysis Set (RFAS) includes all enrolled 
subjects in the FAS who restarted 
palovarotene therapy after January 2020 
and have at least two HO volume 
measurements in Part C trial on or after 
restart, with the first such WBCT imaged at 
least 30 days after the end of the previous 
flare-up. 
The Per-Protocol Set (PPS) is not intended 
to be summarized.  
 
The RFAS population is most 
similar to those described in 
other palovarotene studies. 
Due to the small sample size, 
particularly when the additional 
restriction that baseline WBCT 
must be taken at least 30 days 
after the end of the previous 
flare-up (as was the case for 
Study 301 and NHS), formal per-
protocol analyses are not planned 
to be performed. 
8.7.1 Primary Efficacy 
Per the protocol, the primary efficacy 
analysis was to be a wLME comparing 
annualized HO volume collected in Study 
202 Parts B and C with that in Study 001 
(NHS). In the final CSR, propensity-score 
based comparisons of Study 202 Part B and 
Part C vs NHS, as well as Study 202 Part C 
alone vs NHS, will be performed. 
Additional analyses more similar to those 
specified in the protocol, e.g. GEE, will 
also be performed. 
Efficacy summaries will be 
based on analyses prepared at the 
request of regulators. 
8.8.1 Adverse Events 
Per the protocol, retinoid associated 
adverse events were to be summarized. 
Consistent with the interim CSR, this is no 
longer planned. 
 The pre-specified retinoid AEs 
outlined in the protocol did not 
encompass all AEs which might 
be considered retinoid associated 
AEs. SMQ analysis was more 
comprehensive. 
 
11 Changes from SAP Version 0.3 (13 July 2020) introduced in SAP Version 1.1 (16 Dec. 
2022) 
The following key substantive changes from SAP Version 0.3 are documented: 


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Location/Section 
Number 
Change 
Rationale 
1.1 
Context 
for 
Version 1.1
Amendment is preparation for final CSR. 
Version 0.3 described the data 
summaries to be used for the 
interim CSR. 
3.1.4 
Baseline 
for 
Subjects 
who 
Restarted Palovarotene 
after 
dosing 
interruption in Part C 
Definition added. 
Needed for RFAS summaries. 
3.4 
Adjustment 
for 
Covariates 
Efficacy analyses comparing annualized 
new HO in Study 202 vs NHS requested by 
FDA are described. 
Efficacy 
was 
summarized 
descriptively in the interim CSR. 
4.4 
Flare-up 
Per 
Protocol Population 
Formal per-protocol analyses are not 
planned to be performed. 
See Section 10 
4.6 
Restart 
Full 
Analysis Set 
RFAS added. 
See Section 10 
4.7 Part D Analysis Set Part D Analysis Set added. 
Needed to summarize post-
interruption data for skeletally 
immature subjects who stopped 
taking 
palovarotene 
before 
completion and had imaging to 
allow for their study. 
7 Safety Data 
Safety data summaries in the final CSR will 
be based on the safety data presentations in 
recent documents, including the Safety 
Update included in the NDA and the Day 
90 Safety Update; the primary difference 
will be that those summaries included data 
from all palovarotene studies, while the 
Study 202 presentations will only include 
data collected in Study 202. 
Given the complicated history of 
palovarotene, basing the CSR 
summary 
on 
previous 
discussions 
will 
ensure 
consistency. 


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12
References
1. Hays RD, Spritzer KL, Amtmann D, et al. Upper-extremity and mobility subdomains from the Patient-
Reported Outcomes Measurement Information System (PROMIS) adult physical functioning item 
bank. Arch Phys Med Rehabil. 2013;94(11):2291-2296. doi:10.1016/j.apmr.2013.05.014. 


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13
APPENDIX
Appendix 1. PROMIS T-Score Conversions
The following conversion tables 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. 
Table 9: PROMIS T-Score Conversions for Adult Global Physical and Mental Health 
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 
3.8
18
57.7
4.9 
 
18
59 
3.9
19
61.9
5.2 
19
62.5
4.2
20
67.7
5.9
 
20
67.6
5.3
 


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Table 10: PROMIS T-Score Conversions for Pediatric Global Health  
Pediatric Self-Completed Total
Pediatric Proxy-Completed Total
Raw Score
T-Score 
Standard Error
Raw Score
T-Score
Standard Error 
7 
16
3.4 
7
14.7
2.9
8
17.1
3.6
8
15.3
3.1
9 
18.3
3.7 
9
16
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
3.8
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
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
25
43.9
3.7 
25
41.7
4
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
33
61.1
4.9 
33
60.2
5.4
34
64.2
5.4 
34
63.2
6
35
67.5
6.1 
35
66.1
6.5


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Appendix 2.  Flare-up Location Mapping 
Table 11: Flare-up Location Mapping 
List
Flare Location
Flare Other Specify
Adjusted Location: Combine Left 
and Right
1
ABDOMEN
Lower spine/abdomen
2 
ANTERIOR NECK 
Head/Neck
3
CERIVCAL SPINE
Cerivcal spine
4
CHEST
Upper Spine/Chest
5 
HEAD 
Head/Neck
6
JAW
Jaw
7 
LEFT ANKLE OR FOOT 
Distal lower extremities 
8 
LEFT DISTAL LOWER 
EXTREMETIES 
Distal lower extremities 
9 
LEFT DISTAL LOWER 
EXTREMITIES
Distal lower extremities 
10 
LEFT DISTAL UPPER 
EXTREMETIES 
Distal upper extremities 
11 
LEFT ELBOW 
Elbow 
12 
LEFT HIP
Hip 
13 
LEFT KNEE
Knee 
14 
LEFT SHOULDER
Shoulder 
15 
LEFT WRIST OR HAND 
Distal upper extremities 
16 
LOWER BACK
Lower spine/abdomen 
17 
LOWER SPINE/ABDOMEN
Lower spine/abdomen 
18 
LUMBAR SPINE
Lower spine/abdomen 
19 
NECK
Head/Neck
20 
OTHER
ABOVE LEFT KNEE
Knee 
21 
OTHER
BOTH RIGHT KNEE AND RIGHT HIP
Hip 
22 
OTHER
LEFT ANTERIOR THIGH 
Hip 
23 
OTHER
LEFT KNEE/ LEFT CALF
Knee 
24 
OTHER
LEFT NECK
Head/Neck
25
OTHER
LEFT NECK AND 
SUBMANDIBULAR AREA
Head/Neck
26 
OTHER
LEFT POSTERIOR CALF, FOCUS OF 
TENDERNESS 8 CM BELO 
Knee 
27 
OTHER
LEFT TRICEPS 
Shoulder 
28 
OTHER
NECK (RIGHT AND BELOW THE 
CLIN)
Head/Neck
29 
OTHER
NECK RIGHT AND RIGHT ARM
Shoulder 
30 
OTHER
RIGHT ARM
Shoulder 
31 
OTHER
RIGHT BICEP 
Shoulder 
32 
OTHER
RIGHT PECTORAL AND AXILLARY 
AREA 
Upper Spine/Chest 
33 
OTHER
RIGHT THIGH AND CERVICAL 
SPINE
Hip 
34 
OTHER
RIGHT TRICEP
Shoulder 


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List
Flare Location
Flare Other Specify
Adjusted Location: Combine Left 
and Right
35 
OTHER
UPPER BACK AND RIGHT SCAPULA
Upper back
36 
OTHER
LEFT SHOULDER AND LEFT SIDE 
OF NECK
Shoulder 
37
OTHER
RIGHT THIGH
Hip
38
OTHER
RIGHT TRICEPS
Shoulder
39 
OTHER
LEFT DISTAL MEDIAL THIGH
Knee 
40
OTHER
LEFT SCAPULA
Upper back
41
OTHER
LEFT HAMSTRING
Hip
42 
OTHER
LEFT HAMSTRING
Hip 
43
OTHER
LEFT FOREARM
Elbow
44 
OTHER
LEFT ANTERIOR THIGH 
Hip 
45 
OTHER
LEFT FOREARM 
Elbow 
46
OTHER
LEFT HAMSTRING
Hip
47 
OTHER
RIGHT THIGH, NOT INCLUDING HIP 
OR KNEE 
Hip 
48 
OTHER
R THIGH
Hip 
49 
OTHER
RIGHT UPPER THIGH
Hip 
50 
OTHER
SOURCE ONLY STATED "BACK" 
 missing 
51 
OTHER
LEFT CHEEK 
Head/Neck
52 
OTHER
LEFT ARM
Elbow 
53 
OTHER
3 SITES: NECK, SKULL, SHOULDER 
Head/Neck
54 
OTHER
RIGHT GROIN 
Hip 
55 
OTHER
RIGHT CHEEK 
Head/Neck
56 
OTHER
HEAD, NECK, ARM
Head/Neck
57 
OTHER
RIGHT GREAT TOE
Distal lower extremities 
58 
OTHER
RIGHT LOWER BACK 
Lower spine/abdomen 
59 
OTHER
BICEPS, RIGHT SIDE
Shoulder 
60 
OTHER
THUMB (RIGHT)
Distal upper extremities 
61
OTHER
RIGHT CALF
Knee
62 
OTHER
SUBMAXILAR AREA
Jaw
63 
OTHER
THE FLARE UP IS LOCATED IN THE 
RIGHT THUMB. 
Distal upper extremities 
64 
OTHER
RIGHT SHOULDER 
Shoulder 
65 
OTHER
THIGH AND LEFT LEG
Hip 
66 
OTHER
HEAD AND RIGHT ARM
Head/Neck
67 
OTHER
RIGHT SHOULDER, RIGHT ELBOW, 
LEFT ELBOW AND LEFT ARM 
Shoulder 
68 
OTHER
UPPER BACK (LEFT SIDE) AND 
CERVICAL SPINE (LEFT SIDE) 
Upper back
69 
OTHER
BELOW THE CHIN
Head/Neck
70 
OTHER
NECK - RIGHT SIDE
Head/Neck




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List
Flare Location
Flare Other Specify
Adjusted Location: Combine Left 
and Right
105 
RIGHT FOREARM 
Elbow 
106 
RIGHT ILIAC CREST
Hip 
107
RIGHT THIGH
Hip
108 
RIGHT UPPER ARM 
Shoulder 
109 
RIGHT UPPER THIGH 
Hip 
110
Other Location, Specify
AROUND RIGHT SCAPULA
Upper back
111 
Other Location, Specify
BETWEEN SHOULDER BLADES
Upper back
112 
Other Location, Specify
CERVICAL SPINE AND THORACIC 
SPINE
Upper Spine/Chest 
113
Other Location, Specify
FRONTAL
missing
114 
Other Location, Specify
HEAD - FOREHEAD
Head/Neck
115 
Other Location, Specify
INNER RIGHT ARM EXTENDING 
FROM ELBOW TO SHOULDER. 
TRANSIENT SWELLINGS OVER 
BACK AND BACK OF HEAD 
CONSTANTLY HAPPENING; FALL 
2012 SWELLING OVER OCCIPUT. 
Elbow 
116 
Other Location, Specify
LEFT LEG (11/2016) AND 
BILATERAL BUTTOCKS (11/2016) 
Hip 
117 
Other Location, Specify
LEFT SHOULDER, EXTENDING TO 
LEFT ELBOW
Shoulder 
118 
Other Location, Specify
LEFT SHOULDER, LEFT ELBOW
Shoulder 
119 
Other Location, Specify
LEFT THIGHT
Hip 
120 
Other Location, Specify
LOWER BACK AND CERVICAL 
SPINE
Lower spine/abdomen 
121 
Other Location, Specify
NECK 
Head/Neck
122 
Other Location, Specify
NECK (RIGHT SIDE)
Head/Neck
123 
Other Location, Specify
RIGHT FIRST DIGIT
missing 
124 
Other Location, Specify
RIGHT SHOULDER AND LEFT 
SHOULDER. FLARES ARE 
SYMMETRICAL AND TEND TO 
OCCUR ON BOTH SIDES. FIRST 
FLARES WERE TOPS OF 
SHOULDERS, LOOKED LIKE AN 
OFFENSIVE LINEMAN. 
Shoulder 
125 
Other Location, Specify
RIGHT SHOULDER, LEFT 
SHOULDER, AND CHEST
Shoulder 
126 
Other Location, Specify
THIGH FOLLOWING VACCINATION 
INTO RIGHT THIGH 
Hip 
127 
Other Location, Specify
THORACIC SPINE AND LUMBAR 
SPINE
Lower spine/abdomen 
128 
Other Location, Specify
TOE (AFTER SURGERY FUSED 
TOGETHER)
Distal lower extremities 
129 
Other Location, Specify
UNDER CHIN 
Head/Neck
130 
Other Location, Specify
UPPER BACK, NECK, ABDOMEN
Upper back
131 
Other Location, Specify
UPPER BACK/ NECK, ANTERIOR
Upper back
132 
Other Location, Specify
UPPER LEG (RIGHT SIDE)
Hip 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
List
Flare Location
Flare Other Specify
Adjusted Location: Combine Left 
and Right
133 
OTHER
ANTERIOR NECK AND ANTERIOR 
RIGHT THORAX 
Head/Neck
134 
OTHER
ANTEROLATERAL RIGHT THIGH
hip 
135
OTHER
BACK
missing
136 
OTHER
BACK OF HEAD
Head/Neck 
137 
OTHER
BACK OF NECK
Head/Neck
138
OTHER
BILATERAL ANKLES
Distal lower extremities
139
OTHER
BILATERAL ANKLES, CAN'T 
REMEMBER WHICH WAS FIRST
Distal lower extremities
140 
OTHER
BILATERAL GROIN 
hip 
141 
OTHER
BOTH LOW LEGS
Distal lower extremities 
142 
OTHER
CENTRAL MID-BACK ALONG THE 
SPINE
lower spine/abdomen 
143
OTHER
CLAVICULA
Upper Spine/Chest
144 
OTHER
FACE
Head/Neck 
145 
OTHER
FEMUR, RIGHT SIDE 
hip 
146 
OTHER
FORE HEAD
Head/Neck 
147 
OTHER
FOREHEAD
Head/Neck 
148 
OTHER
FOREHEAD AND PERIORBITAL
Head/Neck 
149 
OTHER
JAW AND NECK
jaw 
150 
OTHER
L CALF
knee
151 
OTHER
L POSTERIOR RIBCAGE
Upper back
152 
OTHER
L SCAPULA
Upper back
153 
OTHER
LEFT AXILLA
shoulder 
154 
OTHER
LEFT LEG
missing 
155 
OTHER
LEFT POSTERIOR THIGH
hip 
156 
OTHER
LEFT SHOULDER AND THORACIC 
SPINE
shoulder 
157 
OTHER
LEFT SUPERIOR MEMBER 
missing 
158 
OTHER
LEFT UPPER BACK
Upper back
159
OTHER
MIDDLE BACK
lower spine/abdomen
160 
OTHER
MOUTH
jaw 
161 
OTHER
NECK (SIDE)
Head/Neck 
162 
OTHER
NECK AND SHOULDERS
Head/Neck 
163 
OTHER
NECK/THROAT 
Head/Neck 
164 
OTHER
ONE HIP, CANNOT REMEMBER 
SIDE
hip 
165 
OTHER
R LOWER ABDOMEN/R UPPER 
THIGH
lower spine/abdomen 
166 
OTHER
R SUBSCAPULAR REGION
Upper back
167 
OTHER
R UPPER THIGH/LEG
hip 
168 
OTHER
RIGHT BACK SIDE, SHOULDER 
shoulder 
169 
OTHER
RIGHT BACK, SHOULDER
shoulder 
170 
OTHER
RIGHT HEEL
Distal lower extremities 


STATISTICAL ANALYSIS PLAN                     
PROTOCOL PVO-1A-202 PART C 
PALOVAROTENE
 
 
 
CLEMENTIA PHARMACEUTICALS INC. 
 
16 DECEMBER 2022
PROPRIETARY AND CONFIDENTIAL
List
Flare Location
Flare Other Specify
Adjusted Location: Combine Left 
and Right
171 
OTHER
RIGHT LATEROCERVICAL
Head/Neck
172
OTHER
RIGHT NECK
Head/Neck
173
OTHER
RIGHT SIDE NECK
Head/Neck 
174 
OTHER
RIGHT THIGH/KNEE
hip 
175 
OTHER
SACRAL SPINE AREA
lower spine/abdomen 
176
OTHER
SHOULDERS, ELBOWS, CHEST AND 
BACK
shoulder
177 
OTHER
SKULL 
Head/Neck 
178 
OTHER
TOE (AFTER SURGERY, FUSED 
TOGETHER)
Distal lower extremities 
179 
OTHER
UPPER AND LOWER BACK
Upper back
180
OTHER
UPPER BACK/HEAD/NECK 
(OCCIPITAL REGION)
Upper back