Clinical trial NCT05027802
Conditions: Fibrodysplasia Ossificans Progressiva (FOP)
Sponsor: Ipsen
Start date: 2022-03-14; Completion date: 2024-11-30
Enrollment: 61 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objective of this study is to further evaluate the safety and efficacy of palovarotene in adult and paediatric participants with FOP.

The aim of the study is also to ensure treatment continuity to participants who have completed one of the parent studies (Study PVO-1A-301, Study PVO-1A-202 and Study PVO-1A-204) and who, in the investigator's judgement, may benefit from palovarotene therapy.

Detailed description:

Arms: arm 1: Chronic treatment: participants will receive 5 mg palovarotene or the dose received during participation in the parent study at the time of transition to Study CLIN-60120-452 or prior to interrupting/stopping palovarotene treatment.

Flare-up treatment: at the time of a flare-up (or substantial high-risk traumatic event likely to lead to a flare-up) participants will receive 20 mg palovarotene for 28 days, followed by 10 mg palovarotene for 56 days.
Interventions: intervention 1: Palovarotene
Intervention descriptions: intervention 1: Palovarotene will be taken orally once daily at approximately the same time each day.

Protocol documents:
Prot_000.pdf: 
IPSEN GROUP 
CLIN-60120-452 
CONFIDENTIAL 
PROTOCOL (INCL. AMENDMENT #3): FINAL VERSION 4.0: 13 NOVEMBER 2023 
PAGE 1
 
 
Protocol Title: 
Rollover Study; Multicentre, Phase III, Open-label Study to Further Evaluate the Safety and 
Efficacy of Palovarotene Capsules in Male and Female Participants Aged ≥14 Years with 
Fibrodysplasia Ossificans Progressiva (FOP) Who Have Completed Study PVO-1A-301 or 
PVO-1A-202/PVO-1A-204 and May Benefit from Palovarotene Therapy. 
 
Protocol Number: CLIN-60120-452 
Compound: Palovarotene (IPN60120) 
 
Study Name: PIVOINE 
 
Short Title: 
A Rollover Study to Further Evaluate the Safety and Efficacy of Palovarotene Capsules in Male 
and Female Participants Aged ≥14 Years with Fibrodysplasia Ossificans Progressiva (FOP) 
Who Have Completed the Relevant Parent Studies. 
 
Study Phase: III  
 
Sponsor Name: 
 
Ipsen Pharma SAS 
 
Legal Registered Address: 65, quai Georges Gorse 
92100 Boulogne-Billancourt 
Paris, France 
 
Regulatory Authority Identifier Number(s): 
IND number: 120181 
EudraCT number: 2021-002244-70 
 
Date: 13 November 2023 
Version number: 4.0 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation.


P P D
P P D


IPSEN GROUP 
CLIN-60120-452 
CONFIDENTIAL 
PROTOCOL (INCL. AMENDMENT #3): FINAL VERSION 4.0: 13 NOVEMBER 2023 
PAGE 3
 
 
Principal Investigator Signature Page 
I have read and agree to Protocol CLIN-60120-452 entitled ‘Rollover Study; Multicentre, Phase 
III, Open-label Study to Further Evaluate the Safety and Efficacy of Palovarotene Capsules in 
Male and Female Participants Aged ≥14 Years with Fibrodysplasia Ossificans Progressiva 
(FOP) Who Have Completed Study PVO-1A-301 or PVO-1A-202/PVO-1A-204 and May 
Benefit from Palovarotene Therapy’. I am aware of my responsibilities as an investigator under 
the guidelines of Good Clinical Practice (GCP), local regulations (as applicable) and the study 
protocol. I agree to conduct the study according to these guidelines and to appropriately direct 
and assist the staff under my control, who will be involved in the study. 
 
NAME:  
 
TITLE: 
[PRINCIPAL] 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
 
OFFICE: 
 
 


IPSEN GROUP 
CLIN-60120-452 
CONFIDENTIAL 
PROTOCOL (INCL. AMENDMENT #3): FINAL VERSION 4.0: 13 NOVEMBER 2023 
PAGE 4
 
 
SUMMARY OF CHANGES 
The current version of the protocol was released on 13 November 2023 and includes 
Amendment 3. For the protocol amendment, an amendment form was prepared and is provided 
in Section 10.9. 
 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
01 October 2021 
Section 10.7 
2 
28 April 2022 
Section 10.8 
3 
13 November 2023 
Section 10.9 
 
Amendment #3 (13 November 2023) 
This amendment is considered non-substantial. 
Overall Rationale for the Amendment 
This amendment aimed to: 
• 
Update safety and efficacy background information; 
• 
Provide clarification on remote follow-up and EOS/EW visits; 
• 
Provide clarification on extra bone growth assessment; 
• 
Remove the temporary measures related to the COVID-19 pandemic; 
• 
Add the blister packaging and the packaging format for US patients (15 capsules 
packaged in bottle (5 mg)) 


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PROTOCOL (INCL. AMENDMENT #3): FINAL VERSION 4.0: 13 NOVEMBER 2023 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ................................................................................................... 4 
TABLE OF CONTENTS ......................................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................................ 10 
1 
PROTOCOL SUMMARY ........................................................................................... 13 
1.1 
Synopsis .......................................................................................................................... 13 
1.2 
Schema ........................................................................................................................... 20 
1.3 
Schedule of Activities .................................................................................................... 20 
2 
INTRODUCTION ........................................................................................................ 23 
2.1 
Study Rationale ............................................................................................................. 23 
2.2 
Background ................................................................................................................... 23 
2.2.1 
Disease Background ................................................................................... 23 
2.2.2 
Treatment Background ............................................................................... 24 
2.2.3 
Safety Profile of Palovarotene .................................................................... 25 
2.2.4 
Efficacy of Palovarotene ............................................................................. 26 
2.2.4.1 
Phase II Studies ............................................................................................ 26 
2.2.4.2 
Phase III Study ............................................................................................. 26 
2.3 
Benefit/Risk Assessment ............................................................................................... 27 
2.3.1 
Risk Assessment .......................................................................................... 27 
2.3.2 
Benefit Assessment ...................................................................................... 29 
2.3.3 
Overall Benefit: Risk Conclusion ............................................................... 29 
3 
OBJECTIVES AND ENDPOINTS ............................................................................. 30 
4 
STUDY DESIGN ........................................................................................................... 32 
4.1 
Overall Design ............................................................................................................... 32 
4.2 
Scientific Rationale for Study Design .......................................................................... 33 
4.2.1 
Participant Input into Design ..................................................................... 34 
4.3 
Justification for Dose .................................................................................................... 34 
4.4 
End of Study Definition ................................................................................................ 35 
5 
STUDY POPULATION ............................................................................................... 37 
5.1 
Inclusion Criteria .......................................................................................................... 37 
5.2 
Exclusion Criteria ......................................................................................................... 38 
5.3 
Lifestyle Considerations ............................................................................................... 38 
5.4 
Screen Failures .............................................................................................................. 38 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ............................ 40 
6.1 
Study Intervention Administered ................................................................................ 40 
6.2 
Preparation, Handling, Storage and Accountability ................................................. 42 
6.3 
Measures to Minimise Bias: Randomisation and Blinding ....................................... 43 
6.3.1 
Randomisation ............................................................................................ 43 
6.3.2 
Maintenance of Blinding ............................................................................ 43 
6.4 
Study Intervention Administration/Accountability ................................................... 43 
6.5 
Dose Modification ......................................................................................................... 43 


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6.6 
Continued Access to Study Intervention after the End of the Study ....................... 44 
6.7 
Treatment of Overdose ................................................................................................. 44 
6.8 
Prior and Concomitant Therapy ................................................................................. 44 
6.8.1 
Preventive Medication ................................................................................. 45 
6.8.2 
Rescue Medicine ......................................................................................... 45 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 47 
7.1 
Discontinuation of Study Intervention ........................................................................ 47 
7.1.1 
Liver Chemistry Stopping Criteria ............................................................. 47 
7.1.2 
QTc Stopping Criteria ................................................................................. 47 
7.1.3 
Treatment Interruption ............................................................................... 47 
7.1.4 
Rechallenge ................................................................................................. 47 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................ 47 
7.3 
Lost to Follow-up .......................................................................................................... 48 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................... 49 
8.1 
Efficacy Assessments .................................................................................................... 49 
8.1.1 
FOP-PFQ .................................................................................................... 49 
8.1.2 
PROMIS Global Health Scale .................................................................... 49 
8.1.3 
CAJIS .......................................................................................................... 50 
8.1.4 
FOP Assistive Devices Assessment ............................................................. 50 
8.1.5 
Healthcare Utilisation ................................................................................. 51 
8.1.6 
Lung Function Assessments ....................................................................... 51 
8.1.7 
Flare-up Assessment ................................................................................... 51 
8.1.8 
Extra Bone Growth Assessment (without associated flare-up) ................. 52 
8.1.9 
Qualitative Participant Interviews .............................................................. 52 
8.2 
Safety Assessments ........................................................................................................ 52 
8.2.1 
Spinal Health Assessment ........................................................................... 52 
8.2.2 
C-SSRS and Suicidal Ideation and Behaviour Risk Monitoring .............. 53 
8.2.3 
Biochemistry and Triglycerides .................................................................. 53 
8.2.4 
Linear Height and Body Weight ................................................................. 53 
8.2.5 
Vital Signs ................................................................................................... 54 
8.2.6 
Pregnancy Testing ....................................................................................... 54 
8.3 
AEs and SAEs and Other Safety Reporting ............................................................... 54 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information .... 55 
8.3.2 
Method of Detecting AEs and SAEs ........................................................... 55 
8.3.3 
Follow-Up of AEs and SAEs ...................................................................... 55 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................... 55 
8.3.5 
Pregnancy .................................................................................................... 56 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ......................................................................... 56 
8.3.7 
Adverse Events of Special Interest ............................................................. 56 


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8.3.8 
Reporting of Study Intervention Errors Including Misuse/Abuse ............ 56 
8.4 
Pharmacokinetics .......................................................................................................... 57 
8.5 
Genetics .......................................................................................................................... 57 
8.6 
Biomarkers .................................................................................................................... 57 
8.7 
Immunogenicity Assessments ...................................................................................... 57 
8.8 
Medical Resource Utilisation and Health Economics ................................................ 57 
8.9 
Demographic and Baseline Characteristics ................................................................ 57 
9 
STATISTICAL CONSIDERATIONS ........................................................................ 58 
9.1 
Statistical Hypotheses ................................................................................................... 58 
9.1.1 
Multiplicity Adjustment ............................................................................... 58 
9.2 
Sample Size Determination .......................................................................................... 58 
9.3 
Analysis Sets .................................................................................................................. 58 
9.4 
Statistical Analyses ....................................................................................................... 58 
9.4.1 
General Considerations .............................................................................. 58 
9.4.2 
Analysis of Primary Endpoint .................................................................... 59 
9.4.3 
Analysis of Secondary Endpoints ............................................................... 59 
9.4.3.1 
FOP-PFQ ..................................................................................................... 59 
9.4.3.2 
PROMIS Global Health Scale ..................................................................... 60 
9.4.3.3 
CAJIS ........................................................................................................... 61 
9.4.3.4 
FOP Assistive Devices ................................................................................. 61 
9.4.3.5 
Healthcare Utilization ................................................................................. 61 
9.4.3.6 
Lung Function Parameters .......................................................................... 61 
9.4.3.7 
Flare-ups ...................................................................................................... 61 
9.4.3.8 
Extra Bone Growth ...................................................................................... 61 
9.4.3.9 
Qualitative Participant Interviews ............................................................... 62 
9.4.4 
Other Analyses ............................................................................................ 62 
9.4.4.1 
Demographic and Baseline Characteristics ................................................ 62 
9.4.4.2 
Prior and Concomitant Medication ............................................................. 62 
9.4.4.3 
Concomitant Procedures ............................................................................. 62 
9.4.4.4 
Spinal Health Assessment ............................................................................ 62 
9.4.4.5 
Linear Height and Body Weight .................................................................. 62 
9.4.4.6 
Vital Signs .................................................................................................... 63 
9.4.4.7 
Participant Disposition and Withdrawals ................................................... 63 
9.4.5 
Subgroups Analyses .................................................................................... 63 
9.5 
Interim Analyses ........................................................................................................... 63 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS .................................................................................................... 64 
10.1 Appendix 1: Regulatory, Ethical and Study Oversight Considerations .................. 64 
10.1.1 
Regulatory and Ethical Considerations ..................................................... 64 
10.1.2 
Financial Disclosure ................................................................................... 64 
10.1.3 
Informed Consent and Assent Process ....................................................... 64 


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10.1.4 
Data Protection ........................................................................................... 65 
10.1.5 
Committees Structure .................................................................................. 66 
10.1.5.1 
Independent Data Monitoring Committee ................................................... 66 
10.1.6 
Dissemination of Clinical Study Data ........................................................ 66 
10.1.7 
Data Quality Assurance .............................................................................. 66 
10.1.8 
Source Documents ...................................................................................... 67 
10.1.9 
Study and Site Start and Closure ................................................................ 68 
10.1.10 
Publication Policy ....................................................................................... 68 
10.2 Appendix 2: Contraceptive Guidance and Collection of Pregnancy Information .. 69 
10.2.1 
Definitions ................................................................................................... 69 
10.2.2 
Contraception Guidance ............................................................................. 70 
10.2.3 
Collection of Pregnancy Information ........................................................ 71 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-Up and Reporting ........................................................................ 72 
10.3.1 
Definition of AE .......................................................................................... 72 
10.3.2 
Definition of SAE ........................................................................................ 73 
10.3.3 
Recording and Follow-up of AE and/or SAE ............................................ 74 
10.3.4 
Reporting of SAEs ....................................................................................... 75 
10.4 Appendix 4: Clinical Laboratory Tests ...................................................................... 76 
10.5 Appendix 5: CYP450 3A4 Inducers or Inhibitors - Exclusionary Medications ...... 77 
10.6 Appendix 6: Country-Specific Requirements ............................................................ 78 
10.6.1 
Sweden ......................................................................................................... 78 
10.6.2 
Argentina ..................................................................................................... 78 
10.7 Appendix 7: Protocol Amendment Form No. 1 ......................................................... 79 
10.8 Appendix 8: Protocol Amendment Form No. 2 ....................................................... 103 
10.9 Appendix 9: Protocol Amendment Form No. 3 ....................................................... 120 
11 
REFERENCES ............................................................................................................ 143 
 
LIST OF TABLES 
Table 1 
Schedule of Activities .......................................................................................... 21 
Table 2 
Summary of Potential Risks of Study Participation and Mitigation Strategy
 ............................................................................................................................... 27 
Table 3 
Objectives and Endpoints ................................................................................... 30 
Table 4 
Study Intervention Administered ...................................................................... 41 
Table 5 
Dose Reduction of Palovarotene ........................................................................ 44 
Table 6 
Rescaled Global Physical and Mental Health Scores for the Adult Version 
of the PROMIS Global Health Scale ................................................................. 60 
Table 7 
PROMIS Global Health Scale T-Score Conversions for Global Physical and 
Mental Health Scores .......................................................................................... 61 
Table 8 
Protocol-Required Safety Laboratory Tests ..................................................... 76 


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LIST OF FIGURES 
Figure 1 
Study Schema ....................................................................................................... 20 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
ACVR1 
Activin A Receptor Type-1 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALK2 
Activin Receptor-like-kinase-2 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMP 
Bone Morphogenetic Protein 
CAJIS 
Cumulative Analogue Joint Involvement Scale 
CI 
Confidence Interval 
CIOMS 
Council for International Organisations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP450 
Cytochrome P450 
DLCO 
Diffusion Capacity of the Lung for Carbon Monoxide 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EOS 
End of Study 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
EW 
Early Withdrawal 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in One Second 
FKBP12 
12-kDa FK506-binding Protein 
FOCBP 
Female of Childbearing Potential 
FOP 
Fibrodysplasia Ossificans Progressiva 
FOP-PFQ 
FOP Physical Function Questionnaire 
FSH 
Follicle-stimulating Hormone 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
HEENT 
Head, Eyes, Ears, Nose and Throat 


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ABBREVIATION 
Wording Definition  
HED 
Human Equivalent Dose 
HO 
Heterotopic Ossification 
HRT 
Hormonal Replacement Therapy 
IB 
Investigator’s Brochure 
ICC 
International Clinical Council 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFOPA 
International Fibrodysplasia Ossificans Progressiva Association 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LPLV 
Last Participant Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of available observations 
n 
Number of nonmissing observations 
NHS 
Natural History Study 
OMIM 
Online Mendelian Inheritance in Man 
PI 
Principal Investigator 
PP 
Per Protocol 
PPC 
Premature Physeal Closure 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PT 
Preferred Term 
RARγ 
Retinoic Acid Receptor Gamma 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard Deviation 
SI Unit 
International System of Units 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SP 
Service Provider 


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ABBREVIATION 
Wording Definition  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Events 
TGF-β 
Transforming Growth Factor Beta 
ULN 
Upper Limit of Normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
 


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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title:  
Rollover Study; Multicentre, Phase III, Open-label Study to Further Evaluate the Safety and 
Efficacy of Palovarotene Capsules in Male and Female Participants Aged ≥14 Years with 
Fibrodysplasia Ossificans Progressiva (FOP) Who Have Completed Study PVO-1A-301 or 
PVO-1A-202/PVO-1A-204 and May Benefit from Palovarotene Therapy. 
 
Short Title:  
A Rollover Study to Further Evaluate the Safety and Efficacy of Palovarotene Capsules in Male 
and Female Participants Aged ≥14 Years with Fibrodysplasia Ossificans Progressiva (FOP) 
Who Have Completed the Relevant Parent Studies. 
Rationale: 
The aim of Study CLIN-60120-452 is to provide continued access to palovarotene once the 
ongoing clinical studies have ended. More specifically, the aim is to provide treatment 
continuity to participants who have completed one of the parent studies (Study PVO-1A-301 
or PVO-1A-202 (Parts C and D correspond to Study PVO-1A-204 in France)) and, in the 
investigator’s judgement, may benefit from palovarotene therapy until palovarotene is 
reimbursed in the country where the study is being conducted, or another access programme 
becomes available, or until the study end date of November 2024 is reached, whichever occurs 
first. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
To further evaluate the safety of palovarotene 
in adult and paediatric participants with FOP. 
• 
Incidence 
and 
description 
of 
all 
treatment-emergent adverse events (TEAEs) 
whether or not they are considered as related 
to the study intervention; 
• 
Incidence and description of all serious and 
nonserious treatment-related TEAEs; 
• 
Incidence and description of all serious 
TEAEs, whether or not they are considered as 
related to the study intervention; 
• 
Incidence and description of all nonserious 
TEAEs whether or not they are considered as 
related to the study intervention. 
Secondary 
 
• 
To describe range of motion, as assessed by 
the Cumulative Analogue Joint Involvement 
Scale (CAJIS) for FOP, at the Inclusion Visit 
and over time under palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in CAJIS total score at each Follow-up 
Visit; 
• 
To describe the use of assistive devices and 
adaptations 
for 
daily 
living 
by 
FOP 
participants, at the Inclusion Visit and over 
time under palovarotene treatment; 
• 
Raw values and shift from the Inclusion Visit 
in the use of assistive devices and adaptations 
for daily living at each Follow-up Visit; 
• 
To describe physical function, using the adult 
form of the FOP Physical Function 
Questionnaire (FOP-PFQ), at the Inclusion 
• 
Raw values and change from the Inclusion 
Visit in % of worst score for total score, 
upper extremities subscore and mobility 
subscore using the adult form of the 


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Visit and over time under palovarotene 
treatment; 
FOP-PFQ for all participants, at each 
Follow-up Visit; 
• 
To describe the FOP healthcare utilization in 
patients with FOP 
• 
Type and frequency of healthcare utilization 
• 
To describe the parameters of lung function 
(observed and % predicted forced vital 
capacity (FVC), observed and % predicted 
forced expiratory volume in one second 
(FEV1), absolute and predicted FEV1/FVC 
ratio, observed and % predicted diffusion 
capacity of the lung for carbon monoxide 
(DLCO)) at the Inclusion Visit and over time 
under palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted FVC at each 
Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted FEV1 at 
each Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in absolute and predicted FEV1/FVC 
ratio at each Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted DLCO at 
each Follow-up Visit; 
• 
To describe physical and mental health, using 
the adult form of the Patient Reported 
Outcomes Measurement Information System 
(PROMIS) Global Health Scale, at the 
Inclusion 
Visit 
and 
over 
time 
under 
palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in physical and mental function (mean 
global physical and mental health score 
converted into T-scores), using the adult form 
of the PROMIS Global Health Scale for all 
participants, at each Follow-up Visit; 
• 
To 
describe 
the 
number 
of 
investigator-reported 
flare-ups, 
flare-up 
outcomes (extra bone growth, restricted 
movement) and flare-up duration by body 
location and overall; 
• 
Raw values and change from the Inclusion 
Visit in number of investigator-reported flare-
ups, flare-up outcomes (extra bone growth, 
restricted movement) and flare-up duration at 
each Follow-up Visit by body location and 
overall; 
• 
Percentage of participants with extra bone 
growth associated or not with a flare-up at 
each Follow-up Visit; 
In relation to FOP:  
• 
To 
further 
understand 
and 
describe 
participants’ experiences with FOP symptoms 
(e.g. flare-ups, joints being locked);  
• 
To describe the overall impact of the disease 
on participants living with FOP (e.g. physical 
functioning, emotional health, social 
functioning, work/school/daily life impacts); 
• 
To identify and rank the critical joints from a 
participant’s perspective; 
 
In relation to patient experiences with palovarotene in 
the parent study:  
• 
To further understand and describe 
participant experience with palovarotene (e.g. 
decrease in number of flares up, delay in 
physical disability, overall satisfaction); 
• 
To describe the emotional benefit for 
participants of using palovarotene as a 
treatment for FOP; 
• 
To assess participants’ perceptions of benefits 
and risks of palovarotene.  
• 
Not applicable. 
 


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Overall Design: 
Study CLIN-60120-452 is a multicentre, noncomparative rollover study with the aim of 
continuing to provide palovarotene to participants with FOP who have completed one of the 
parent studies (Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and, in the investigator’s 
judgement, may benefit from palovarotene therapy. Participants who have completed the parent 
study are defined as those who have completed the parent End of Study (EOS) or End of 
Treatment Visit. 
The study is designed primarily to further evaluate the safety of palovarotene and secondly, to 
collect efficacy data in male and female participants aged ≥14 years (qualifying as skeletally 
mature or, based on investigator’s assessment, have reached final adult height) with FOP treated 
with palovarotene. Cross-sectional qualitative interviews will also be conducted by the principal 
investigator (PI)/qualified site staff, within 1 year (ideally within 1 month) following the 
Inclusion Visit, to inform on patient-centred outcomes such as perception of living with FOP 
and perceived treatment benefit of palovarotene. 
Participants are eligible for the study whether they are receiving chronic or flare-up treatment 
in the parent study at the time of transition. Participants who previously interrupted/stopped 
palovarotene treatment and are currently under parent study follow-up due to the premature 
physeal closure (PPC) related partial clinical hold in participants <14 years, are eligible for the 
study if they are ≥14 years of age and skeletally mature/have reached final adult height based 
on investigator’s assessment. There must be a current parent study signed informed consent 
(ICF) form for the participant to be eligible for Study CLIN-60120-452. 
A maximum of 87 participants from studies PVO-1A-301, PVO-1A-202/PVO-1A-204 are 
eligible to be enrolled and will receive palovarotene once daily at the dose received during their 
participation in the parent study at the time of transition to Study CLIN-60120-452 or prior to 
interrupting/stopping palovarotene treatment.  
The study will consist of an Inclusion Visit (Day 1) (which ideally corresponds to the parent 
EOS Visit), a continuous dosing treatment period (including a Follow-up Visit every six 
months), and an EOS/Early Withdrawal (EW) Visit. 
Eligible participants will ideally enter the study directly after completing the EOS Visit of the 
parent study (Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and the ICF is signed. Any 
study assessments already performed at the parent EOS Visit will serve as the Inclusion Visit 
assessment for Study CLIN-60120-452 (maximum of one month allowed between the two 
visits). Treatment initiation for Study CLIN-60120-452 should ideally concur with the EOS 
Visit and the study intervention administration schedule of the parent study in order to ensure 
palovarotene treatment continuity for both chronic and flare-up treatment. 
The Inclusion and EOS/EW Visit can be an in-clinic visit or performed remotely per study 
protocol schedule. However, to enable continued access to the Investigational Product and 
rollover of participants with impaired mobility [in the case(s) when, per investigator’s 
judgement, this is considered as beneficial for the participant’s medical condition], the parent 
EOS Visit, and consenting for CLIN-60120-452 and CLIN-60120-452 Inclusion Visit can be 
conducted remotely. In such case(s), both parts of remote consenting used by the site – i.e., 
Informing/Consenting discussion and ICF signature should be agreed with the IRB/EC, and the 
investigator’s judgement should be sufficiently documented in the patient source notes. Follow-
up Visits can be either in-clinic or performed remotely (e.g., at the participant’s home by 
qualified SP in-home services and/or via video-conference or telephone contact from clinical 
site personnel). In-depth qualitative interviews, conducted in person or by telephone by the 
PI/qualified site staff within 1 year (ideally within 1 month) following the Inclusion Visit, will 
be proposed to all participants. 


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Patient-reported questionnaires (FOP-PFQ, PROMIS Global Health Scale and Healthcare 
Utilization) will be completed by the participant on paper. All other data collected in the study 
will be recorded in an electronic case report form (except for qualitative participant interview 
data).  
Participants will continue to receive palovarotene until it is reimbursed in the country where 
the study is being conducted, or another access programme becomes available, or until the study 
end date of November 2024 is reached, whichever occurs first. At this time, investigational 
palovarotene will be discontinued to allow participants to transition to the commercially 
available drug, physician-prescribed palovarotene, or to another access programme, if available.  
Early access can only take place if it is allowed within the local laws, rules and regulations or 
specifically approved in writing by local authorities. 
Participants can voluntarily withdraw from the study at any time for any reason. 
The study intervention can be discontinued for individual participants by the investigator if 
he/she believes the participants’ safety is at risk. 
In the event of early study withdrawal or early discontinuation of the study intervention, all 
reasonable efforts should be made by the study personnel in-clinic or remotely to have the 
participants complete all study assessments of the EW Visit as per the schedule of activities. 
Participants will be followed-up in-clinic or remotely for safety for 30 days after the last 
palovarotene dose of the study is received. If the study intervention was discontinued due to a 
safety concern, in the case of an adverse event (AE)/serious adverse event (SAE), the participant 
will be monitored until resolution, stabilisation or lost to follow-up and, in the case of 
pregnancy, the participant will be followed throughout the pregnancy and the health status of 
the baby verified up until one year of age. 
An Independent Data Monitoring Committee will be set-up. 
 
Intervention Groups and Duration: 
This is a noncomparative rollover study. 
Participants are eligible for the study whether they are receiving chronic or flare-up treatment 
in the parent study at the time of transition. Participants who previously interrupted/stopped 
palovarotene treatment and are currently under parent study follow-up are also eligible if they 
meet eligibility criteria. The dose of palovarotene administered will be individualised for each 
participant and based on the regimen (chronic or flare-up treatment), the dose received during 
their participation in the parent study at the time of transition to Study CLIN-60120-452 or prior 
to interrupting/stopping palovarotene treatment (to allow for dose modifications made to the 
standard chronic/flare-up regimen during the parent study). 


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Chronic/flare-up regimen: 
Chronic treatment: oral palovarotene once daily, 5 mg, or at the dose received during 
participation in the parent study at the time of transition Study CLIN-60120-452 or prior to 
interrupting/stopping palovarotene treatment. 
Flare-up treatment: increase in dose at the time of a flare-up (or substantial high risk traumatic 
event likely to lead to a flare-up) to 20 mg once daily for 4 weeks (28 days), followed by 10 mg 
once daily for 8 weeks (56 days) for a total of 12 weeks (84 days) even if symptoms resolve 
earlier. 
Participants receiving flare-up treatment at the time of transition to Study CLIN-60120-452 will 
continue and complete the flare-up treatment as was planned in the parent study. 
Flare-up treatment should begin at the onset of the first symptom indicative of a FOP flare-up 
or substantial high risk traumatic event likely to lead to a flare-up. Participants will be instructed 
to report potential flare-up symptoms to study site personnel. Symptoms of a FOP flare-up 
typically include but are not limited to localised pain, soft tissue swelling/inflammation, 
redness, warmth, decreased joint range of motion, and stiffness (only one symptom is required 
to define a flare-up). If these symptoms are consistent with previous flare-ups, include a 
participant-reported onset date, and are confirmed by the investigator as associated with a 
flare-up, participants will be instructed to immediately begin flare-up-based treatment. 
Chronic treatment should cease at the time of initiation of flare-up treatment, re-initiation of the 
chronic daily treatment should occur after completion of the flare-up treatment. 
Flare-ups can occur in the absence of any apparent causative factor, but there is a high risk that 
substantial traumatic events (e.g. surgery, intramuscular immunisation, mandibular blocks for 
dental work, muscle fatigue, blunt muscle trauma from bumps, bruises, falls or influenza-like 
viral illnesses), can lead to a flare-up and result in heterotopic bone formation. Flare-up based 
treatment should also be initiated if the investigator confirms the presence of a substantial 
high-risk traumatic event likely to lead to a flare-up. 
Persistent flare-up symptoms: treatment may be extended in 4-week intervals with 10 mg 
palovarotene and continued until the flare-up symptoms resolve. 
Intercurrent flare-up: if the participant experiences an intercurrent flare-up (new flare-up 
location or marked worsening of the original flare-up) at any time during the flare-up treatment, 
then the 12-week flare-up treatment should be restarted. 
In the case of any intolerable adverse reactions, the daily dose of the chronic/flare-up regimen 
can be reduced (see Table 5). 
Flare-up only regimen: 
If the participant experiences intolerable adverse reactions while taking chronic daily treatment 
and dose reduction does not alleviate the adverse reactions, then the participant may take 
palovarotene only at the time of flare-up (or substantial high-risk traumatic event). 
 
Visit Frequency: 
Every six months. 
 
Study Participant and Intervention Duration: 
Participants will enter ideally this study directly after completing the parent EOS Visit and 
continue to receive palovarotene until it is reimbursed in the country where the study is being 
conducted, or another access programme becomes available, or until the study end date of 


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November 2024 is reached, whichever occurs first. At this time, investigational palovarotene 
will be discontinued to allow participants to transition to the commercially available drug, 
physician-prescribed palovarotene. 
The maximum duration is three years from enrolment to last study visit (November 2021 to 
November 2024). 
 
Number of Participants: 
A maximum of 87 participants from studies PVO-1A-301, PVO-1A-202/PVO-1A-204 are 
eligible to be enrolled. 
 
Statistical Methods: 
No formal statistical testing will be performed. All the analyses will be primarily descriptive in 
nature. 
The Inclusion Visit is the first study visit (Day 1) and first administration of palovarotene in 
Study CLIN-60120-452 (and corresponds ideally to the EOS Visit of the parent study for 
assessments already performed in the parent study). 
Sample Size determination 
No formal sample size calculations have been performed as the sample size is dependent on the 
number of participants in the parent studies who are eligible. A maximum of 87 participants 
from studies PVO-1A-301, PVO-1A-202/PVO-1A-204 are eligible to be enrolled. 
Primary Analysis 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be classified by preferred term (PT) and system organ class (SOC). 
Adverse events listings will be presented by participant, SOC and PT. 
The incidence of all reported TEAEs, serious and nonserious treatment-related TEAEs, serious 
and nonserious TEAEs, TEAEs leading to death and TEAEs leading to treatment 
discontinuation will be tabulated separately. In addition, summary tables for TEAEs will be 
presented by maximum intensity and study intervention relationship (investigator-reported 
causality assessment). 
Secondary Analyses 
All statistical analyses will be descriptive. For descriptive analyses, summary statistics will be 
presented at each scheduled visit. Summary statistics will include sample size, number of 
available observations (N), number of missing observations (missing), mean, 95% confidence 
intervals (CIs) of the mean/median, standard deviation, number of nonmissing observations (n), 
median and range for continuous variables and scores. For categorical or discrete variables, the 
absolute and relative (percentage) numbers based on the nonmissing number of observations 
for each category will be presented, including 95% CIs. 
Participant Interview Analyses 
Participant interviews will be performed within 1 year (ideally within 1 month) following the 
Inclusion Visit. No formal hypotheses will be tested given the qualitative nature of the analyses. 
Initial thoughts will be recorded from each of the completed interviews. Key concepts raised 
by participants and dominant trends in interview data will be identified, with a particular focus 
on the study objectives and other potential insights emerging from the interviews. Additionally, 
once the interview transcripts are available, the interview data will be analysed according to the 
final qualitative analysis plan, using a thematic qualitative data analysis approach. 


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All qualitative and limited quantitative data will be summarised descriptively. Where 
applicable, Ns and %s will be provided. 
Tables displaying the concepts described during the interviews will be developed to document 
the results of the interviews. Additionally, descriptive statistics based on the quantitative data 
obtained during the interviews (e.g. symptom improvements during the clinical study) will be 
computed and summarised. 


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1.2 
Schema 
Figure 1 Study Schema 
 
 
 
1.3 
Schedule of Activities 
The schedule of activities (SoA) planned in this study are presented in Table 1.  
 


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Table 1 
Schedule of Activities 
Assessment/Procedure 
Inclusion Visit[a] 
Day 1 
Follow-Up Visits 
Every 6 months (±1 
month)[b]/ 
EOS/EW Visit[c] 
 
 
Procedures 
already 
performed at 
the parent 
EOS Visit 
that will be 
transferred 
from parent 
study 
database 
Procedures 
already 
performed 
at the parent 
EOS Visit 
to be 
entered in 
CLIN-
60120-452 
eCRF by 
the study 
site 
Procedures 
to be 
performed 
at the 
CLIN-
60120-452 
Inclusion 
Visit 
In-clinic Visit 
Remote visit  
Informed consent[d] 
 
 
X 
 
 
Inclusion/exclusion criteria 
 
 
X 
 
 
Study intervention 
administration/accountability[e] 
 
 
X 
X 
X 
Baseline demographics 
 
 
X 
 
 
Physical examination 
 
 
X 
 
 
Participant interview[f] 
 
 
X 
 
 
Pregnancy testing and 
childbearing potential [g] 
 
X[a]* 
 
X 
X 
Linear height and body weight 
[h] 
 
X[a]* 
 
X 
X 
Vital signs [i]  
 
X[a]* 
 
X 
X 
Spinal health assessment [j] 
 
X [a]** 
 
X 
 
Lung function assessments [k] 
 
 
X 
X 
 
Flare-up assessment [l] 
 
 
X 
X 
X [m] 
Additional Extra bone growth 
assessment (without associated 
flare-up) 
 
 
X 
X 
X 
CAJIS [n] 
X* 
 
 
X 
X 
C-SSRS [n] [o] 
 
 
X 
X 
X 
FOP-PFQ assessment[p] [q] 
X* 
 
X [q]*** 
X 
X 
PROMIS Global Health Scale 
[p][q] 
X* 
 
X [q]*** 
X 
X 
FOP assistive devices 
assessment [p] 
 
 
X 
X 
X 
Healthcare Utilization [p] 
 
 
X 
X 
X 
Biochemistry (amylase, lipase, 
AST, ALT) and triglycerides 
X* 
 
 
 
 
Disease and flare-up history 
X 
 
 
 
 
Prior medications 
X 
 
 
 
 
Concomitant medications 
 
X 
 
X 
X 
Concomitant procedures [r] 
 
X 
 
X 
X 
AEs [s] 
 
X 
 
X 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CAJIS=Cumulative Analogue Joint 
Involvement Scale for FOP; COVID-19=coronavirus disease 2019; C-SSRS=Columbia-Suicide Severity Rating Scale; 
DLCO=diffusion capacity of the lung for carbon monoxide; eCRF=electronic case report form; EOS=End of Study; 
EW=Early Withdrawal; FEV1=forced expiratory volume in one second; FVC=forced vital capacity; FOP=fibrodysplasia 
ossificans progressiva; FOP-PFQ=FOP Physical Function Questionnaire; PROMIS=Patient Reported Outcomes 
Measurement Information System. 
a. 
The Inclusion Visit should be in-clinic and corresponds ideally to the EOS Visit of the parent study (Study PVO-1A-
301 or PVO-1A-202/PVO-1A-204). A maximum of one month is allowed between the two visits. For any assessments 


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from the parent EOS Visit performed outside this allowed time window, assessments will need to be performed again 
at the Study CLIN-60120-452 Inclusion Visit (flagged with *). However, to enable continued access to the 
Investigational Product and rollover of participants with impaired mobility [in the case(s) when per investigator’s 
judgement this is considered as beneficial for the participant’s medical conditions], the parent EOS Visit and 
consenting for CLIN-60120-452 and CLIN-60120-452 Inclusion Visit can be conducted remotely. In such case(s) both 
parts of remote consenting used by the site – i.e. Informing/Consenting discussion and ICF signature should be agreed 
with the IRB/EC, and the investigator’s judgement should be sufficiently documented in the patient source notes.  
For the spinal health assessment, a time window of 3 months post parent visit is allowed (flagged with **). 
b. 
Follow-up Visits will be either in-clinic or performed remotely (e.g. at the participant’s home by qualified SP in-home 
services, and/or via video-conference or telephone contact from clinical site personnel).  
c. 
The EOS/EW Visit will be ideally an in-clinic visit (or remotely when permitted by the IRB/IEC) and will occur at the 
time of last study intervention intake. The EOS Visit must take place before the participant transitions to commercial 
treatment. 
d. 
For participants <18 years, assent and legal guardian’s consent will also be required. 
e. 
Palovarotene status (treated or not treated) and regimen (chronic or flare-up treatment) at the time of transition to Study 
CLIN-60120-452 will be collected at the Inclusion Visit. Participants will be supplied with chronic treatment as well 
as the appropriate dose of palovarotene to initiate flare-up treatment when a flare-up or traumatic event is confirmed 
by the investigator. Participants will be instructed to report potential flare-up symptoms to study site personnel, only 
one symptom is required to define a flare-up (see Section 6.1). In the presence of persistent flare-up symptoms, 
treatment may be extended in 4-week intervals until the flare-up symptoms resolve. If the participant experiences an 
intercurrent flare-up, or substantial high-risk traumatic event likely to lead to a flare-up, at any time during the flare-
up treatment, the 12-week flare-up treatment should be restarted. 
f. 
Participant interviews will be conducted in person or by telephone by the PI/qualified site staff and can be carried out 
anytime within 1 year (ideally within 1 month) following the Inclusion Visit. 
g. 
Participants will be assessed for child-bearing status and pregnancy prevention measures (females only). According to 
local practice, medically documented blood or urine pregnancy tests should be carried out prior to starting therapy, 
monthly as long as the participant receives palovarotene and one month after stopping (the results of pregnancy tests 
will be recorded in the eCRF). See Section 8.2.6 and 8.3.5 for procedure in case of a positive pregnancy test during 
the study. 
h. 
For linear height, data from the parent EOS Visit will be used for the Study CLIN-60120-452 Inclusion Visit when 
available. Height at 6 to 12 months prior to the Inclusion Visit will be transferred from parent study database. 
i. 
Vital signs to be collected are respiratory rate, blood pressure and heart rate. 
j. 
The spinal health assessment must be performed at the Study CLIN-60120-452 Inclusion Visit ONLY if not already 
performed within the time window allowed (ie,, 3 months post-parent EOS Visit). The spinal health assessment will 
then be performed annually. The spinal health assessment should be performed using radiological imaging (e.g., CT, 
x-ray, scintigraphy, etc). This assessment may be performed locally. 
k. 
Includes spirometry and the DLCO test. Spirometry obtains the lung function parameters of observed and % predicted 
FVC and FEV1 and the absolute and predicted FEV1/FVC ratio. The DLCO test obtains observed and % predicted 
DLCO which provides information on the efficiency of gas transfer from alveolar air into the bloodstream. 
l. 
Includes extra bone growth assessment when associated with a flare-up 
m. 
During remote visit performed at home by the SP in-home services, the participant will be asked if any flare-ups 
occurred since last visit. If yes, the homecare clinician will attempt to facilitate a call between the participant and the 
site to provide details. 
n. 
In case of remote visit, the CAJIS and C-SSRS will be assessed via video-conference if possible or feasible or 
telephone contact from clinical site personnel. The homecare clinician will facilitate the call between the participant 
and Investigator.  
o. 
‘Baseline’ version of C-SSRS will be used at the Study CLIN-60120-452 Inclusion visit. ‘Since Last Visit’ version of 
C-SSRS will be used at Follow-Up Visits. 
p. 
In case of remote visit, the questionnaires will be provided by the SP in-home services and completed by the 
participants. 
q. 
Paper patient-reported questionnaires. Questionnaires completed at the parent EOS Visit will be used for the Study 
CLIN-60120-452 Inclusion Visit. The adult form (developed for participants ≥15 years old) of the FOP-PFQ and 
PROMIS Global Health Scale will be used for all participants. At in-clinic visits when multiple assessments are to be 
performed, the FOP-PFQ and the PROMIS Global Health Scale should be completed first, and in that order, before 
any other assessments are completed. Participants who completed the paediatric versions of the questionnaires at the 
EOS Visit of the parent study are required to complete the adult versions of the questionnaires at the CLIN-60120-452 
Inclusion Visit (flagged with ***). 
r. 
Any vaccinations received during the study (including COVID-19) should be recorded as concomitant procedures. 
s. 
AEs first occurring during participation in the parent study and ongoing at the time of the Study CLIN-60120-452 
Inclusion Visit will be entered again in the Study CLIN-60120-452 eCRF. 


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2 
INTRODUCTION 
Palovarotene is an orally bioavailable retinoic acid receptor gamma (RARγ) selective agonist 
that is being developed by Ipsen for the prevention of heterotopic ossification (HO) in adults 
and children with fibrodysplasia (myositis) ossificans progressiva (FOP). 
2.1 
Study Rationale 
Currently there are no commercially available effective treatments to prevent the formation of 
heterotopic bone in FOP. Therapeutic approaches are limited to symptom management and 
flare-up prevention (Kaplan et al., 2019a; Meyers et al., 2019). 
The clinical safety and efficacy of palovarotene in reducing new HO in FOP has been evaluated 
and demonstrated in: 
• 
Study 
PVO-1A-201 
(complete), 
a 
phase 
II, 
randomised, 
double-blind, 
placebo-controlled study; 
• 
Study PVO-1A-202 (Part A and B complete, Part C and D complete; Parts B, C and D 
correspond to Study PVO-1A-204 in France), an open-label extension of Study 
PVO-1A-201; 
• 
Study PVO-1A-301 (Part A, B and C complete), a phase III, single-arm, open-label 
study. 
The aim of this study is to provide continued access to an effective treatment for FOP for which 
there is no alternative once the ongoing clinical studies have ended. More specifically, the aim 
is to provide treatment continuity to participants who have completed one of the parent studies 
(Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and, in the investigator’s judgement, may 
benefit from palovarotene therapy until palovarotene is reimbursed in the country where the 
study is being conducted, or another access programme becomes available, or until the study 
end date of November 2024 is reached, whichever occurs first. 
2.2 
Background 
2.2.1 
Disease Background 
Fibrodysplasia ossificans progressiva (Online Mendelian Inheritance in Man (OMIM) 
#135100) is an ultra-rare genetic disorder, with an estimated prevalence of 1.36 per million 
individuals (Baujat et al., 2017). 
FOP is caused by a spontaneous missense mutation in the activin A receptor type-1 
(ACVR1)/activin receptor-like-kinase-2 (ALK2) gene, which encodes a receptor in the bone 
morphogenetic protein (BMP) signalling pathway (Pignolo et al., 2013; Zhang et al., 2013). 
Bone morphogenetic proteins are extracellular ligands belonging to the transforming growth 
factor beta (TGF-β) superfamily. Signal transduction studies show that receptor-regulated Smad 
proteins 1/5/8 are the immediate downstream molecules of BMP receptors and play a central 
role in BMP signal transduction (Sanchez-Duffhues et al., 2016; Shen et al., 2009). 
Following ligand binding to BMP receptors, there is downstream activation of genes involved 
in the differentiation and activation of osteoblast and chondrocyte-like cells via phosphorylation 
of Smad proteins 1/5/8; this is regulated by the inhibitory factor 12-kDa FK506-binding protein 
(FKBP12), which binds to the BMP type 1 receptor and stabilises the inactive form 
(Sanchez-Duffhues et al., 2016; Shen et al., 2009). In the presence of the mutated ACVR1/ALK2 
gene, FKBP12 binding is reduced, leading to enhanced BMP signalling (Sanchez-Duffhues et 
al., 2016). 
Patients with FOP experience sporadic and unpredictable episodes of soft‐tissue swelling, pain, 
reduced movement, stiffness and fever, referred to as ‘flare‐ups’ (Di Rocco et al., 2017; 
Kaplan et al., 2019a; Pignolo et al., 2013; Pignolo et al., 2016). Flare‐ups appear spontaneously 


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or after muscle fatigue, minor trauma, intramuscular injections or influenza‐like viral illnesses, 
and develop rapidly over several hours (Kaplan et al., 2019a); these inciting events induce local 
inflammation, which is followed by recruitment of bone progenitor cells that differentiate into 
chondrocytes (Shimono et al., 2011). Although some flare-ups regress spontaneously, many 
appear to lead to HO, which transforms soft and connective tissues (including aponeuroses, 
fascia, ligaments, tendons and skeletal muscles) into heterotopic bone (Kaplan et al., 2019a; 
Pignolo et al., 2013). Of patients with FOP, 95% manifest HO before reaching 15 years of age 
(Qi et al., 2017). 
FOP is characterised by congenital malformation of the great toes and progressive HO in soft 
and connective tissues; it is a severely disabling HO disorder (Baujat et al., 2017; 
Pignolo et al., 2016). Other clinical features observed in patients with FOP are shortened 
thumbs, cervical spine malformations, short broad femoral necks and proximal medial tibial 
osteochondromas (Kaplan et al., 2009; Pignolo et al., 2013). Typically, HO begins in the dorsal, 
proximal, axial and cranial regions of the body (neck, shoulders and back) and progresses into 
ventral, caudal and distal regions (trunk and limbs) (Hüning and Gillessen-Kaesbach, 2014). 
Heterotopic ossifications develop into ribbons, sheets and plates of extra bone throughout the 
body and across joints, thereby progressively restricting movement (Baujat et al., 2017). Once 
ossification occurs, it is permanent; consequently, disability in FOP is cumulative, with most 
patients becoming immobilised and confined to a wheelchair by their third decade of life and 
requiring lifelong assistance in performing activities of daily living (ADL) (Baujat et al., 2017; 
Mattera et al., 2015; Ortiz-Agapito and Colmenares-Bonilla, 2015; Pignolo et al., 2013; 
Pignolo et al., 2020a). 
FOP is not only an extremely disabling disease but also a condition of considerably shortened 
lifespan (Kaplan et al., 2010). Morbidity associated with FOP includes fractures (due to the 
increased risk of falls, immobility and prednisone use), limb swelling, pressure sores, hearing 
impairment, gastrointestinal issues and pain (Kaplan et al., 2019b; Peng et al., 2019). Patients 
with FOP reach a median survival of 56 (95% confidence interval (CI): 51; 60) years; death is 
often due to cardiorespiratory failure (as a result of respiratory insufficiency, which is usually 
caused by progressive restrictive chest-wall HO) or thrombosis (Baujat et al., 2017; 
Di Rocco et al., 2017; Kaplan et al., 2010; Pignolo et al., 2013). 
There are currently no effective treatments to prevent the formation of heterotopic bone in FOP, 
with therapeutic approaches being limited to symptom management and flare-up prevention; 
consequently, there is a critical unmet need for definitive therapies for patients with FOP 
(Kaplan et al., 2019a; Meyers et al., 2019). 
2.2.2 
Treatment Background 
Palovarotene is an orally bioavailable RARγ selective agonist. 
RARγ is a nuclear hormone receptor that has a role in regulating skeletal development and 
growth; it is expressed in chondrogenic cells and chondrocytes (Koyama et al., 1999), where it 
operates as a transcriptional repressor (Williams, et al., 2009). Activation of the retinoid 
signalling pathway and RARγ has been demonstrated to inhibit both chondrogenesis and HO 
(Kaplan et al., 2017a). Given that chondrogenesis requires a decrease in retinoid signalling 
concurrent with upregulation of pro-chondrogenic pathways, including BMP signalling 
(Weston et al., 2002; Hoffman et al., 2006), RARγ agonists are likely to elicit anti-chondrogenic 
and anti-HO effects by maintaining retinoid signalling while reducing BMP signalling 
(Shimono et al., 2011).  
RARγ agonists potently impede heterotopic endochondral ossification by inhibiting 
downstream effectors (namely Smad 1/5/8) of the mutated ACVR1/ALK2 gene and by 


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redirecting pre chondrogenic mesenchymal stem cells from an osteoblast fate to a nonosseous 
soft‑tissue fate (Shimono et al., 2011; Kaplan et al., 2011). 
Palovarotene has been found to reduce new HO in animal models, and participants with FOP 
in phase II and III studies. A brief summary of clinical safety and efficacy of palovarotene in 
participants aged ≥8/10 years is provided in the sections that follow. To note, the target 
population for this study is ≥14 years which is aligned with the age of treated participants in the 
completed parent studies (Study PVO-1A-301 and PVO-1A-202/PVO-1A-204). A detailed 
description of the chemistry, pharmacology, nonclinical and clinical efficacy and safety of 
palovarotene is available in the Investigator’s Brochure (IB). 
2.2.3 
Safety Profile of Palovarotene 
Safety data from the FOP clinical studies reflect exposure to palovarotene in a total of 
164 participants, including 139 participants aged 8 years and above for females and 10 years 
and above for males (≥8/10 years) for a mean duration of 94.1 weeks, to a maximum of 
3.8 years. Participants received either:  
• 
chronic/flare-up regimen: 5 mg daily dose of palovarotene with a 20/10 mg dose for 
12 weeks at the time of flare-up (4 weeks of 20 mg once daily followed by 10 mg once 
daily for 8 weeks); 
• 
flare-up regimen only: either the 20/10 mg dose for 12 weeks, a 10/5 mg dose for 6 weeks 
(10 mg once daily for 2 weeks followed by 5 mg once daily for 4 weeks) or a 5/2.5 mg 
dose for 6 weeks (5 mg once daily for 2 weeks followed by 2.5 mg once daily for 
4 weeks). 
In palovarotene-treated participants aged ≥8/10 years, the most commonly reported adverse 
reactions were in the Skin and subcutaneous disorders (98.8%), Gastrointestinal disorders 
(86.6%) and Infections and infestations (82.3%) System Organ Classes (SOC). The majority of 
adverse events (AEs) were mild or moderate (19.5% and 56.7% of participants, respectively) 
across all palovarotene FOP studies. 
Serious adverse reactions reported in palovarotene-treated participants aged ≥8/10 years 
included PPC (preferred term (PT): epiphysis premature fusion) and cellulitis (13 participants 
each; 1.2%).  
Adverse events leading to permanent discontinuation occurred in 9.8% of palovarotene-treated 
participants aged ≥8/10 years. No study discontinuations were reported in placebo/untreated 
participants due to AEs. Mucocutaneous AEs leading to dose reductions were more common 
during palovarotene 20/10 mg flare-up treatment than during chronic treatment. 
Participants <18 years with open epiphyses were assessed for growth during the clinical studies. 
Twenty-seven of 87 skeletally immature FOP participants <18 years of age experienced PPC. 
In participants who received only chronic dosing, PPC, when observed, typically occurred 
between 12 and 18 months after exposure to palovarotene. The higher proportion of younger 
participants with PPC is expected given that pre-adolescent individuals are not expected to have 
physiologic growth plate closure. Thus, any narrowing, partial closure, or closure are likely to 
be assessed as premature by the clinician. However, the possibility that younger participants 
with specific risk factors are predisposed to developing PPC or are more sensitive to the effects 
of palovarotene cannot be excluded. 
No pregnancies or deaths were reported during the clinical development programme. One death, 
due to restrictive lung disease from complications of FOP, occurred two and a half months after 
discontinuing palovarotene treatment. Efficacy of Palovarotene 


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2.2.4 
Efficacy of Palovarotene 
2.2.4.1 
Phase II Studies 
The flare-up only regimen was assessed in the phase II programme, including the double-blind, 
placebo-controlled Study PVO-1A-201 and the open-label extension, Study PVO-1A-202. 
In Study PVO-1A-201, participants were randomised in a 3:3:2 fashion to palovarotene 10 mg 
for 2 weeks, then 5 mg for 4 weeks (10/5 mg treatment), palovarotene 5 mg for 2 weeks, then 
2.5 mg for 4 weeks (5/2.5 mg treatment), or placebo for 6 weeks, followed by a 6-week 
observation period for all groups. The clinical endpoint of mean volume of new HO following 
a flare-up at Week 12 in evaluable flare-ups was assessed. 
In Study PVO-1A-202 Part A, participants experiencing another flare-up received palovarotene 
10/5 mg treatment in an open-label manner. In Part B, participants who were at least 90% 
skeletally mature received chronic 5 mg daily treatment with increased dosing at the time of a 
flare-up to 20 mg for 4 weeks followed by 10 mg for 8 weeks (chronic/flare-up regimen), with 
continuation of treatment in 4-week increments for persistent symptoms. Skeletally immature 
participants received the 20/10 mg flare-up treatment (weight-adjusted) in Part B. 
The comparator group includes flare-ups imaged in untreated participants from the Natural 
History Study (NHS) (an international, 3-year, longitudinal, noninterventional study) and 
placebo-treated flare-ups from Study PVO-1A-201. These two sources of participants were 
similar with respect to demographics and baseline disease characteristics. 
Based on pooled data from Studies PVO-1A-201, PVO-1A-202/Parts A and B, and PVO-1A-
001 (NHS), there was a statistically significant 72% decrease (approximated P value of 0.02) 
in the new HO volume in the 15 flare-ups treated with the 20/10-mg flare-up only regimen 
(3045 mm3) compared with the volume observed in untreated/placebo flare-ups (10,780 mm3).  
Combining all flare-ups treated with the 20/10-mg regimen, regardless of whether they were 
preceded by chronic treatment with 5 mg, resulted in a 55% reduction in new HO (4818 mm3 
in 48 flare-ups) relative to untreated/placebo flare-ups (approximated P value of 0.24). 
2.2.4.2 
Phase III Study 
The phase III study, PVO-1A-301, evaluated the efficacy and safety of the chronic/flare-up 
palovarotene treatment regimen in preventing new HO as compared to data from the NHS. 
Participants received palovarotene 5 mg daily with increased dosing at the time of a flare-up 
defined as at least one symptom (e.g. pain, swelling, redness) consistent with a previous flare-up 
or a substantial high-risk traumatic event likely to lead to a flare-up to 20 mg once daily for 
4 weeks followed by 10 mg once daily for 8 weeks (denoted as the chronic/flare-up regimen), 
with flare-up treatment extension in 4-week increments for persistent symptoms. Anytime 
during flare-up treatment, the 12-week treatment restarted if the participant had another flare-up 
or substantial high-risk traumatic event. The dosing was adjusted according to body weight in 
skeletally immature children (children who had not reached at least 90% skeletal maturity 
defined as a bone age of ≥12 years 0 months for girls and ≥14 years 0 months for boys). 
The treatment groups assessed in the chronic/flare-up regimen were well matched for baseline 
demographics. 
Post-hoc analyses showed that, for participants aged ≥8/10 years, the mean annualised new HO 
volume was 56% lower in palovarotene-treated participants (11 419 mm3) (N=77) than that 
observed in untreated participants (25 796 mm3) (N=79). 
The weighted linear mixed effects analysis showed a 49% lower fitted mean annualised new 
HO volume in palovarotene treated participants (11 033 mm3) versus untreated participants in 
the NHS (21 476 mm3), yielding 2-sided nominal p-value p=0.1124. 


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2.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of palovarotene may be found in the IB. 
2.3.1 
Risk Assessment 
The key potential risks of clinical significance of participating in this study with palovarotene 
are summarised in Table 2 and are based on the current palovarotene IB, which is the safety 
reference document for this study. The list of potential risks may be revised if necessary, 
according to each new IB version published during Study CLIN-60120-452. 
Table 2 
Summary of Potential Risks of Study Participation and Mitigation Strategy 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study Intervention 
Contraindications 
Teratogenicity 
 
The teratogenic potential of systemic 
retinoids 
is 
well 
established 
regarding the risk to the developing 
embryo and foetus. Although there 
were 
no 
pregnancies 
in 
the 
palovarotene 
development 
programme, findings in toxicology 
studies demonstrate characteristic 
patterns of foetal malformations 
typical of retinoids (e.g. cleft palate, 
misshapen skull bones, short/long 
bones). At higher dosages, these 
effects resulted in reduced foetal 
survival. Similar to other systemic 
retinoids, palovarotene is assumed to 
be a potent teratogen and has the 
potential 
to 
adversely 
affect 
development of an embryo or foetus 
if given to a pregnant female patient 
and lead to adverse pregnancy 
outcomes. 
Participant selection: Participants who 
are pregnant or breastfeeding will not be 
included in the study. FOCBP are only 
eligible to participate in the study if they 
have met all the conditions of pregnancy 
prevention (Section 5.1). 
Participant monitoring: During the 
study, pregnancy testing will be carried 
out monthly until one month after stopping 
treatment (Section 8.2.6). 
Study intervention withdrawal criteria: 
If a participant becomes pregnant during 
the 
study, 
palovarotene 
will 
be 
immediately discontinued (Section 8.3.5). 
Radiological 
vertebral 
fracture 
In clinical trials, palovarotene has 
resulted in decreased vertebral bone 
mineral content, decreased bone 
density and decreased bone strength 
as well as an increased risk of 
radiologically observed vertebral (T4 
to L4) fractures in treated adult and 
paediatric patients compared with 
untreated patients. 
Participant selection: Participants who 
have any symptomatic vertebral fracture 
will not be included in the study (Section 
5.2). 
 
Instruction: 
Assessment 
of 
25-OH 
Vitamin D levels is recommended and 
supplementation with Vitamin D for good 
bone health should be considered as per 
the ICC on FOP guideline [ICC FOP 
2022] and local guidelines. 
 
Participant monitoring: Spinal health 
assessment will be performed annually 
using radiological imaging (e.g., CT, x-
ray, scintigraphy, etc). 
 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Hypersensitivity 
to 
palovarotene 
Not applicable 
Participant selection: Participants with a 
known allergy to palovarotene will not be 
included in the study (Section 5.2). 
Participant monitoring: During the 
study, participants will be monitored for 
signs of hypersensitivity/allergy and any 
events 
will 
be 
recorded 
as 
AEs 
(Section 8.3). 
Study intervention withdrawal criteria: 
The daily dose of palovarotene can be 
reduced for any intolerable adverse 
effects. If already receiving the lowest 
dose, palovarotene can be temporarily or 
permanently 
discontinued 
or 
the 
participant switched to flare-up treatment 
only (Section 6.5). 
Special warnings and precautions for use 
Mucocutaneous effects 
Mucocutaneous toxicities are the 
most 
common 
side 
effects 
of 
systemic retinoids and are generally 
treatable, 
dose-dependent, 
and 
reversible. The most frequently 
reported AEs during FOP clinical 
studies with palovarotene were 
primarily mucocutaneous in nature, 
including cheilitis/dry lips, dry skin, 
pruritus and alopecia, and were 
generally assessed as related to 
palovarotene. 
Participant selection: Participants who 
were intolerant to prior treatment with 
palovarotene will not be included in the 
study (Section 5.2). 
Instruction: 
Participants 
will 
be 
instructed to utilise symptomatic therapy 
(e.g. analgesics, skin emollients, lip 
moisturisers, artificial tears, or other 
helpful treatments), to minimize these side 
effects, or as prophylaxis in the study. 
Participant monitoring: During the 
study, participants will be monitored for 
signs of mucocutaneous effects and any 
events 
will 
be 
recorded 
as 
AEs 
(Section 8.3). 
Study intervention withdrawal criteria: 
The daily dose of palovarotene can be 
reduced for any intolerable adverse 
effects. If already receiving the lowest 
dose, palovarotene can be temporarily or 
permanently 
discontinued 
or 
the 
participant switched to flare-up treatment 
only (Section 6.5). 
Photosensitivity 
Photosensitivity reactions, such as 
exaggerated sunburn reactions (e.g. 
burning, 
erythema, 
blistering) 
involving areas exposed to the sun 
have been associated with the use of 
retinoids. 
Although palovarotene has not been 
proven 
to 
be 
phototoxic, 
precautionary 
measures 
for 
phototoxicity are recommended. 
Participant selection: Participants who 
were intolerant to prior treatment with 
palovarotene, or any other medical 
condition 
that 
would 
expose 
the 
participant to undue risk, will not be 
included in the study (Section 5.2). 
Instructions: Participants should avoid 
excessive exposure to sun and use 
protection from sunlight when it cannot be 
avoided (use of sunscreens, protective 
clothing, and use of sunglasses).  
Participant monitoring: During the 
study, participants will be monitored for 
signs of photosensitivity and any events 
will be recorded as AEs (Section 8.3). 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study intervention withdrawal criteria: 
The daily dose of palovarotene can be 
reduced for any intolerable adverse 
effects. If already receiving the lowest 
dose, palovarotene can be temporarily or 
permanently 
discontinued 
or 
the 
participant switched to flare-up treatment 
only (Section 6.5). 
Psychiatric disorders 
Systemic 
retinoids 
have 
been 
associated with psychiatric side 
effects, 
including 
depression, 
suicide, aggression and psychosis. 
During FOP clinical studies, AEs 
related to psychiatric disorders were 
reported in a third of all participants 
with 
irritability, 
anxiety 
and 
depressed 
mood 
reported 
most 
frequently. 
Participant selection: Participants with 
suicidal ideation (type 4 or 5) or any 
suicidal behaviour at the Study CLIN-
60120-452 Inclusion Visit defined by the 
C-SSRS, will not be included in the study 
(Section 5.2). 
Participant monitoring: During the 
study, will be monitored appropriately and 
observed closely for suicidal ideation and 
behaviour or any other unusual changes in 
behaviour and any events will be recorded 
as AEs (Section 8.2.1). 
Study intervention withdrawal criteria:  
If participants experience signs of suicidal 
ideation 
or 
behaviour, 
consideration 
should be given to discontinuing the study 
intervention. 
AE=adverse event; C-SSRS=Columbia-Suicide Severity Rating Scale; EOS=End of Study; FOCBP=female 
of childbearing potential; FOP=fibrodysplasia ossificans progressiva. 
2.3.2 
Benefit Assessment 
Palovarotene has been demonstrated in clinical studies to be effective in reducing new HO in 
FOP participants. Currently, available therapeutic approaches for FOP are limited to symptom 
management and flare-up prevention. None of them have demonstrated reduction in HO 
formation. 
Therefore, the benefit afforded to participants with FOP enrolled in this study is continued 
access to a definitive, effective treatment for FOP for which there is no alternative, until 
palovarotene is reimbursed in the said participants country or another access programme 
becomes available.  
2.3.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimise risk to participants, the potential risks 
identified in association with palovarotene are justified by the anticipated benefits that may be 
afforded to participants with FOP. 


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3 
OBJECTIVES AND ENDPOINTS 
Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To further evaluate the safety of palovarotene 
in adult and paediatric participants with FOP. 
• 
Incidence and description of all treatment-
emergent adverse events (TEAEs) whether or 
not they are considered as related to the study 
intervention; 
• 
Incidence and description of all serious and 
nonserious treatment-related TEAEs; 
• 
Incidence and description of all serious 
TEAEs, whether or not they are considered as 
related to the study intervention; 
• 
Incidence and description of all nonserious 
TEAEs whether or not they are considered as 
related to the study intervention. 
Secondary 
 
• 
To describe range of motion, as assessed by 
the Cumulative Analogue Joint Involvement 
Scale (CAJIS) for FOP, at the Inclusion Visit 
and over time under palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in CAJIS total score at each Follow-up 
Visit; 
• 
To describe the use of assistive devices and 
adaptations 
for 
daily 
living 
by 
FOP 
participants, at the Inclusion Visit and over 
time under palovarotene treatment; 
• 
Raw values and shift from the Inclusion Visit 
in the use of assistive devices and adaptations 
for daily living at each Follow-up Visit; 
• 
To describe physical function, using the adult 
form 
of 
the 
FOP 
Physical 
Function 
Questionnaire (FOP-PFQ), at the Inclusion 
Visit and over time under palovarotene 
treatment; 
• 
Raw values and change from the Inclusion 
Visit in % of worst score for total score, upper 
extremities subscore and mobility subscore 
using the adult form of the FOP-PFQ for all 
participants, at each Follow-up Visit; 
• 
To describe the FOP healthcare utilization in 
patients with FOP 
• 
Type and frequency of healthcare utilization 
• 
To describe the parameters of lung function 
(observed and % predicted forced vital 
capacity (FVC), observed and % predicted 
forced expiratory volume in one second 
(FEV1), absolute and predicted FEV1/FVC 
ratio, observed and % predicted diffusion 
capacity of the lung for carbon monoxide 
(DLCO)) at the Inclusion Visit and over time 
under palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted FVC at each 
Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted FEV1 at each 
Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in absolute and predicted FEV1/FVC ratio 
at each Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted DLCO at 
each Follow-up Visit; 
• 
To describe physical and mental health, using 
the adult form of the Patient Reported 
Outcomes Measurement Information System 
(PROMIS) Global Health Scale, at the 
Inclusion 
Visit and over time under 
palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in physical and mental function (mean 
global physical and mental health score 
converted into T-scores), using the adult form 
of the PROMIS Global Health Scale for all 
participants, at each Follow-up Visit; 


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• 
To 
describe 
the 
number 
of 
investigator-reported 
flare-ups, 
flare-up 
outcomes (extra bone growth, restricted 
movement) and flare-up duration by body 
location and overall; 
• 
Raw values and change from the Inclusion 
Visit in number of investigator-reported flare-
ups, flare-up outcomes (extra bone growth, 
restricted movement) and flare-up duration at 
each Follow-up Visit by body location and 
overall; 
• 
Percentage of participants with extra bone 
growth associated or not with a flare-up at each 
Follow-up Visit; 
In relation to FOP:  
• 
To 
further 
understand 
and 
describe 
participants’ 
experiences 
with 
FOP 
symptoms (e.g. flare-ups, joints being 
locked);  
• 
To describe the overall impact of the disease 
on participants living with FOP (e.g. physical 
functioning, 
emotional 
health, 
social 
functioning, work/school/daily life impacts); 
• 
To identify and rank the critical joints from a 
participant’s perspective; 
 
In relation to patient experiences with palovarotene in 
the parent study:  
• 
To 
further 
understand 
and 
describe 
participant experience with palovarotene (e.g. 
decrease in number of flares up, delay in 
physical disability, overall satisfaction); 
• 
To describe the emotional benefit for 
participants of using palovarotene as a 
treatment for FOP; 
• 
To assess participants’ perceptions of benefits 
and risks of palovarotene. 
• 
Not applicable. 


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4 
STUDY DESIGN 
4.1 
Overall Design 
Study CLIN-60120-452 is a multicentre, noncomparative rollover study with the aim of 
continuing to provide palovarotene to participants with FOP who have completed one of the 
parent studies (Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and, in the investigator’s 
judgement, may benefit from palovarotene therapy. Participants who have completed the parent 
study are defined as those who have completed the parent End of Study (EOS) or End of 
Treatment Visit. 
The study is designed primarily to further evaluate the safety of palovarotene and secondly, to 
collect efficacy data in male and female participants aged ≥14 years (qualifying as skeletally 
mature or, based on investigator’s assessment, have reached final adult height) with FOP treated 
with palovarotene. Cross-sectional qualitative interviews will also be conducted by the principal 
investigator (PI)/qualified site staff, within 1 year (ideally within 1 month) following the 
Inclusion Visit, to inform on patient-centred outcomes such as perception of living with FOP 
and perceived treatment benefit of palovarotene. 
Participants are eligible for the study whether they are receiving chronic or flare-up treatment 
in the parent study at the time of transition. Participants who previously interrupted/stopped 
palovarotene treatment and are currently under parent study follow-up due to the PPC related 
partial clinical hold in participants <14 years, are eligible for the study if they are ≥14 years of 
age and skeletally mature/have reached final adult height based on investigator’s assessment. 
There must be a current parent study signed informed consent form (ICF) for the participant to 
be eligible for Study CLIN-60120-452. 
A maximum of 87 participants from studies PVO-1A-301, PVO-1A-202/PVO-1A-204 are 
eligible to be enrolled and will receive palovarotene once daily at the dose received during their 
participation in the parent study at the time of transition to Study CLIN-60120-452 or prior to 
interrupting/stopping palovarotene treatment.  
The study will consist of an Inclusion Visit (Day 1) (which corresponds ideally to the parent 
EOS Visit), a continuous dosing treatment period (including a Follow-up Visit every six 
months), and an EOS/Early Withdrawal (EW) Visit. The study design is illustrated in Figure 1. 
Eligible participants will ideally enter the study directly after completing the EOS Visit of the 
parent study (Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and the ICF is signed. Any 
study assessments already performed at the parent EOS Visit will serve as the Inclusion Visit 
assessment for Study CLIN-60120-452 (maximum of one month allowed between the two 
visits). For assessments not performed in the parent study (i.e. spirometry), assessments will be 
performed at the Study CLIN-60120-452 Inclusion Visit. 
Treatment initiation (at the Inclusion Visit) for Study CLIN-60120-452 should ideally concur 
with the EOS Visit and the study intervention administration schedule of the parent study in 
order to ensure palovarotene treatment continuity for both chronic and flare-up treatment. 
The Inclusion and EOS/EW Visit can be an in-clinic visit or performed remotely per study 
protocol schedule.  However, to enable continued access to the Investigational Product and 
rollover of participants with impaired mobility [in the case(s) when per investigator’s 
judgement this is considered as beneficial for the participant’s medical conditions], the parent 
EOS, consenting for CLIN-60120-452 and CLIN-60120-452 Inclusion Visit can be conducted 
remotely. In such case(s) both parts of remote consenting used by the site – i.e. 
Informing/Consenting discussion and ICF signature should be agreed with the IRB/EC, and the 
investigator’s judgement should be sufficiently documented in the patient source notes. Follow-
up Visits can be either in-clinic or performed remotely (e.g., at the participant’s home by 


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qualified SP in-home services, or via video-conference or telephone contact from clinical site 
personnel). In-depth qualitative interviews, conducted in person or by telephone by the 
PI/qualified site staff within 1 year (ideally within 1 month) following the Inclusion Visit, will 
be proposed to all participants.  
Participants will undergo the procedures and assessments specified in the SoA (Table 1). 
Patient-reported questionnaires (FOP-PFQ, PROMIS Global Health Scale, Healthcare 
Utilization and FOP Assistive Device Assessment) will be completed by the participant on 
paper. All other data collected in the study will be recorded in an electronic case report form 
(eCRF) (except for qualitative participant interview data).  
Participants will continue to receive palovarotene until it is reimbursed in the country where 
the study is being conducted, or another access programme becomes available, or until the study 
end date of November 2024 is reached, whichever occurs first. At this time, investigational 
palovarotene will be discontinued to allow participants to transition to the commercially 
available drug, physician-prescribed palovarotene, or to another access programme, if available. 
Early access can only take place if it is allowed within the local laws, rules and regulations or 
specifically approved in writing by local authorities. 
Participants can voluntarily withdraw from the study at any time for any reason. 
The study intervention can be discontinued for individual participants by the investigator if 
he/she believes the participants’ safety is at risk. 
In the event of early study withdrawal or early discontinuation of the study intervention, all 
reasonable efforts should be made by the study personnel in-clinic or remotely to have the 
participants complete all study assessments of the EW Visit as per the SoA. 
Participants will be followed-up in-clinic or remotely for safety for 30 days after the last 
palovarotene dose of the study is received. If the study intervention was discontinued due to a 
safety concern, the participant will be monitored for safety (see Section 8.3.3 for follow-up of 
AEs/serious adverse events (SAEs) and Section 8.3.5 for follow-up of pregnancies). 
The EOS for an individual participant will be the date of study completion due to palovarotene 
becoming reimbursed in the country where the study is being conducted, or another access 
programme becoming available, or the study end date of November 2024 being reached, 
whichever occurs first. 
The maximum duration of the study is three years from enrolment to last study visit 
(November 2021 to November 2024). 
An Independent Data Monitoring Committee (IDMC) will be set-up, as described in Section 
10.1.5. 
4.2 
Scientific Rationale for Study Design 
Firstly, this study was designed to provide treatment continuity to participants who have 
completed one of the parent studies (Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and, 
in the investigator’s judgement, may benefit from palovarotene therapy until palovarotene is 
reimbursed in the country where the study is being conducted, or another access programme 
becomes available. 
In addition, the study will primarily further evaluate the safety of palovarotene and secondly, 
collect efficacy data in participants with FOP treated with palovarotene. Cross-sectional 
qualitative interviews will also be conducted by the principal investigator (PI)/qualified site 
staff, within 1 year (ideally within 1 month) following the Inclusion Visit, to inform on 
patient-centred outcomes such as perception of living with FOP and perceived treatment benefit 
of palovarotene. 


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The primary endpoint is the standard description and incidence of all TEAEs, serious and 
nonserious treatment-related TEAEs, all serious TEAEs and all nonserious TEAEs, which will 
permit the AE profile of palovarotene to be further characterised. 
As secondary endpoints, this study will continue to collect efficacy data which was collected in 
the parent studies; range of motion, physical impairment, physical and mental health and the 
number of flare-ups experienced and their outcome and duration. As in the parent studies, range 
of motion will be assessed by CAJIS, physical impairment by the FOP-PFQ and physical and 
mental function by the PROMIS Global Health Scale. 
The CAJIS is a disease-specific, objective measure of joint movement completed by the 
investigator to document total joint involvement. CAJIS scores have been shown to provide an 
accurate and reproducible overview of total body and regional mobility burden of FOP that 
correlates with age and functional status (Kaplan et al., 2017b; Pignolo et al., 2019). 
The FOP-PFQ is a disease-specific patient-reported outcome measure of physical impairment. 
It was developed by Clementia (an Ipsen Company) based on the FDA Guidance for Industry, 
‘Patient Reported Outcome Measures: Use in Medical Product Development to Support 
Labeling Claims’ to assess the relationship between patient reports of physical impairment due 
to HO, thereby providing evidence of HO as a clinically meaningful endpoint. FOP-PFQ scores 
have been shown to provide a consistent and reproducible measure of physical function and 
ability to conduct ADL, correlated with age, functional status and HO volume (Pignolo et al., 
2019; Pignolo et al., 2020b). 
The PROMIS Global Health Scale is a patient-reported outcome measure of physical and 
mental function. HO burden substantially impacts quality of life and physical functioning. A 
strong, statistically significant association between total PROMIS Global Health Scale scores 
and the number of anatomic sites subjectively reported as being affected by HO has been shown. 
In addition, a statistically significant association between the total PROMIS score and the FOP-
PFQ has been shown. When stratified by gender, this relationship holds only for females 
(Pignolo et al., 2020c). 
The lung function parameters of FVC, FEV1 and FEV1/FVC ratio as well as the DLCO, a 
measure of the efficiency of gas transfer from alveolar air into the bloodstream, has not been 
collected in previous clinical studies but will inform on the effect of palovarotene on lung 
function. Patients with FOP often experience respiratory insufficiency, which is usually caused 
by progressive restrictive chest-wall HO and is often the cause of death (Kaplan et al., 2010). 
Further information on the use of assistive devices and adaptations for daily living will be 
collected using a list compiled by the International Fibrodysplasia Ossificans Progressiva 
Association (IFOPA) of assistive devices and adaptations for daily living used by patients with 
FOP. 
The target population for this study is ≥14 years (at the time the informed consent is signed) 
which is aligned with the age of treated participants in the completed parent studies 
(Study PVO-1A-301 and PVO-1A-202/PVO-1A-204). 
4.2.1 Participant Input into Design 
None. 
4.3 
Justification for Dose 
The proposed dosing for palovarotene consists of 5 mg once daily (chronic treatment) with an 
increase in dose at the time of a flare-up to 20 mg once daily for 4 weeks (28 days), followed 
by 10 mg once daily for 8 weeks (56 days) for a total of 12 weeks (84 days) (20/10 mg flare-up 
treatment) even if symptoms resolve earlier. In the presence of persistent flare-up symptoms, 
treatment may be extended in 4-week intervals with 10 mg palovarotene and continued until 


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the flare-up symptoms resolve. Should the participant experience an intercurrent flare-up (new 
flare-up location or marked worsening of the original flare-up) at any time during flare-up 
treatment, the flare-up 12-week treatment should be restarted (see Section 6.1). In the case of 
adverse reactions, the daily dose can be reduced (see Section 6.5). If dose reduction does not 
alleviate the adverse reactions, then the participant may take palovarotene only at the time of a 
flare-up (or substantial high-risk traumatic event) (Section see 6.1). 
Participants are eligible for the study whether they are receiving chronic or flare-up treatment 
in the parent study at the time of transition. Participants who previously interrupted/stopped 
palovarotene treatment and are currently under parent study follow-up are also eligible if they 
meet eligibility criteria. As this is a rollover study with the aim of providing treatment 
continuity, the dose of palovarotene administered will be individualised for each participant 
and based on the regimen (chronic or flare-up treatment) and dose they received during their 
participation in the parent study at the time of transition to Study CLIN-60120-452 or prior to 
interrupting/stopping palovarotene treatment (to allow for dose modifications made to the 
standard chronic/flare-up during the parent study). 
The proposed chronic/flare-up regimen was selected based on nonclinical and clinical data. 
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 a human equivalent dose (HED) of approximately 5 mg prevented HO 
formation. Importantly, in this animal model, the dosing regimen did not impair long bone 
growth but partially normalised 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 optimised clinical dosing strategy. 
The rationale for increasing the chronic palovarotene dose at the time of a flare-up comes from 
nonclinical data from two different mouse models of FOP which 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 chronic/flare-up regimen was assessed in Study PVO-1A-301. The flare-up only regimen 
was assessed in the phase II studies PVO-1A-201 and PVO-1A-202. Both regimens were 
demonstrated to significantly reduce new HO volume versus untreated/placebo-treated 
participants (see Section 2.2.4) 
While it is recognised 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 
immunisations, 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 (Kaplan et al., 2008). In one survey of patients with FOP, flare-ups were induced in 
two-thirds of falls and resulted in permanent loss of movement in 93% of patients 
(Glaser et al., 1998). Therefore, flare-up-based treatment should also be initiated if the 
investigator confirms the presence of a substantial high-risk traumatic event likely to lead to a 
flare-up. 
4.4 
End of Study Definition 
The EOS for an individual participant will be the date of study completion; the participant is 
considered to have completed the study if he/she has stopped study intervention due to 
palovarotene becoming reimbursed in the country where the study is being conducted, or 
another access programme becoming available, or the study end date of November 2024 being 
reached, whichever occurs first. 


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The EOS Visit can be an in-clinic visit or performed remotely and must take place before the 
participant transitions to commercial treatment. 
Study end is defined as the date of last contact with the last participant in the study (Last 
Participant Last Visit (LPLV)). 
Criteria for study intervention discontinuation and participant discontinuation/withdrawal from 
the study are described in Section 7.1 and Section 7.2, respectively. Loss to follow-up is 
described in Section 7.3. 


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5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Participants enrolling will have fulfilled the inclusion and exclusion criteria for 
Study PVO-1A-301 or PVO-1A-202/PVO-1A-204. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Participant has completed the EOS or End of Treatment Visit of Study PVO-1A-301 or PVO-
1A-202 (PVO-1A-202 Parts C and D correspond to Study PVO-1A-204 in France) and did not 
previously withdraw consent from any of the parent studies to be eligible for Study CLIN-
60120-452. 
In the investigator’s judgment, the participant may benefit from continued participation in a 
palovarotene study. 
Age 
1. Participant must be ≥14 years of age (aligned with the age of treated participants in the 
ongoing parent studies PVO-1A-301 and PVO-1A-202/PVO-1A-204) and qualify as 
100% skeletally mature (if <18 years, based on assessments carried out at parent EOS 
Visit; if ≥18 years, automatically considered 100% skeletally mature) or have reached 
final adult height based on investigator’s assessment*, at the time the Study CLIN-
60120-452 informed consent is signed. 
*The above criteria can be reached at any point after parent study end for the participant to be 
eligible for Study CLIN-60120-452, as long as it is prior to palovarotene becoming reimbursed 
in the country where the study is being conducted. 
Sex 
2.  Male, or female who is not pregnant or breastfeeding and has met all of the following 
conditions: 
• 
Females of child-bearing potential (FOCBP) (defined in Section 10.2.1) must have 
a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) 
prior to administration of palovarotene; 
• 
FOCBP must agree to remain abstinent from heterosexual sex during treatment 
and for one month after treatment or, if sexually active, to use two effective 
methods of birth control (described in Section 10.2.2) during and for one month 
after treatment; 
• 
Additionally, sexually active FOCBP must already be using two effective methods 
of birth control one 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 participant or legally authorised representatives (e.g. 
parents, caregivers or legal guardians) must specifically sign this section. 
Contraceptive use by women should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies. 
Guidance for contraception and collection of pregnancy information is provided in 
Section 10.2. 
Requirements for pregnancy testing are located in Section 8.2.6. 


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Informed Consent and Assent 
3. Capable of giving signed informed consent or providing assent as described in 
Section 10.1.3. 
5.2 
Exclusion Criteria 
Participants will not be included in the study if any of the following criteria apply: 
Medical conditions 
1. History of allergy or hypersensitivity to retinoids, gelatin, lactose (note that lactose 
intolerance is not exclusionary) or palovarotene, or unresponsiveness to prior treatment 
with palovarotene. 
2. Uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, 
metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease. 
3. Symptomatic vertebral fracture. 
4. Any other medical condition/clinically significant abnormalities that would expose the 
participant to undue risk or interfere with study assessments. 
5. Amylase or lipase >2× above the upper limit of normal (ULN) or with a history of 
chronic pancreatitis. 
6. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× 
ULN. 
7. Fasting triglycerides >400 mg/dL with or without therapy. 
8. Suicidal ideation (type 4 or 5) or any suicidal behaviour at the Inclusion Visit as defined 
by the Columbia-Suicide Severity Rating Scale (C-SSRS). 
Prior/concomitant therapy (see Section 6.8) 
9. Current use of 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. 
10. Exposure to synthetic oral retinoids other than palovarotene within 4 weeks of the 
Inclusion Visit. 
11. Concurrent treatment with tetracycline or any tetracycline derivatives due to the 
potential increased risk of pseudotumor cerebri. 
12. Use of concomitant medications that are strong inhibitors or inducers of 
cytochrome P450 (CYP450) 3A4 activity (see Section 6.8 and 10.5); or kinase 
inhibitors such as imatinib. 
Other exclusion criteria 
13. Palovarotene is reimbursed in the country where the study is being conducted. 
14. Any reason that, in the opinion of the investigator, would lead to the inability of the 
participant and/or family to comply with the protocol. 
5.3 
Lifestyle Considerations 
No lifestyle restrictions are required for this study. 
5.4 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 


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regulatory authorities. Minimal information includes date of informed consent, demography, 
reason for screen failure, eligibility criteria and any SAE at the time. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 


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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Study intervention is defined as the investigational intervention intended to be administered to 
the study participant according to the study protocol. 
6.1 
Study Intervention Administered 
The study intervention administered is palovarotene. Participants are eligible for the study 
whether they are receiving chronic or flare-up treatment in the parent study at the time of 
transition. Participants who previously interrupted/stopped palovarotene treatment and are 
currently under parent study follow-up are also eligible if they meet eligibility criteria. As this 
is a rollover study with the aim of providing treatment continuity, the dose of palovarotene 
administered will be individualised for each participant and based on the regimen (chronic or 
flare-up treatment) and the dose they received during their participation in the parent study at 
the time of transition to Study CLIN-60120-452 or prior to interrupting/stopping palovarotene 
treatment (to allow for dose modifications made to the standard chronic/flare-up regimen during 
the parent study). 
In the completed parent studies PVO-1A-202/PVO-1A-204 and PVO-1A-301, participants 
received the chronic/flare-up regimen detailed in Table 4 below (or the weight-based equivalent 
for <90% skeletally immature participants), with flare-up treatment extension in 4-week 
increments for persistent symptoms. In Study PVO-1A-301, anytime during flare-up treatment, 
the 12-week treatment restarts if the participant has another flare-up or a substantial high-risk 
traumatic event. In both parent studies, the daily dose of palovarotene can be reduced if the 
participant experiences AEs that are not tolerated. 
Participants receiving flare-up treatment at the time of transition to Study CLIN-60120-452 will 
continue and complete the flare-up treatment as was planned in the parent study. Chronic daily 
treatment should then be re-initiated at 5 mg, or the dose received during participation in the 
parent study prior to the flare-up. 
Treatment initiation (at the Inclusion Visit) for Study CLIN-60120-452 should ideally concur 
with the EOS Visit and the study intervention administration schedule of the parent study in 
order to ensure palovarotene treatment continuity for both chronic and flare-up treatment. 
Details of the study intervention are provided in Table 4. 


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Table 4 
Study Intervention Administered 
Intervention Name 
Palovarotene 
Intervention Description 
Palovarotene hard capsules, taken once daily as chronic/flare-up treatment 
Type  
Drug 
Dose Formulation 
Capsule 
Unit Dose Strength(s) 
Each capsule contains 1 mg, 1.5 mg, 2.5 mg, 5 mg or 10 mg of palovarotene as 
active ingredient 
Dosage Level(s) 
Chronic/flare-up regimen: 
Chronic treatment 
5 mg once daily (or at the dose received during participation in the parent 
study at the time of transition to Study CLIN-60120-452, or prior to 
interrupting/stopping palovarotene treatment) 
Flare-up treatment 
20 mg once daily for 4 weeks (28 days) 
10 mg once daily for 8 weeks (56 days) 
Persistent flare-up symptoms: extension of 10 mg once daily in 4-week 
increments 
Intercurrent flare-ups (new flare-up location or marked worsening of 
original flare-up): 12-week flare-up treatment should be restarted 
Chronic treatment: once daily, 5 mg or at the dose received during 
participation in the parent study at the time of transition to Study 
CLIN-60120-452 or prior to interrupting/stopping palovarotene treatment. 
Flare-up treatment: increase in dose at the time of a flare-up (or substantial 
high risk traumatic event likely to lead to a flare-up) to 20 mg once daily for 
4 weeks (28 days), followed by 10 mg once daily for 8 weeks (56 days) for a 
total of 12 weeks (84 days) (20/10 mg flare-up treatment) even if symptoms 
resolve earlier. 
Flare-up treatment should begin at the onset of the first symptom indicative of a 
FOP flare-up or substantial high-risk traumatic event likely to lead to a flare-up. 
Symptoms of a FOP flare-up typically include but are not limited to localised 
pain, soft tissue swelling/inflammation, redness, warmth, decreased joint range 
of motion, and stiffness. Chronic treatment should cease at the time of initiation 
of flare-up treatment, re-initiation of the chronic daily treatment should occur 
after completion of the flare-up treatment. 
Flare-ups can occur in the absence of any apparent causative factor, but there is 
a high risk that substantial traumatic events (e.g. surgery, intramuscular 
immunisation, mandibular blocks for dental work, muscle fatigue, blunt muscle 
trauma from bumps, bruises, falls or influenza-like viral illnesses), can lead to a 
flare-up and result in heterotopic bone formation. Flare-up treatment should be 
initiated at the time of such events. 
Persistent flare-up symptoms: treatment may be extended in 4-week intervals 
with 10 mg palovarotene and continued until the flare-up symptoms resolve. 
Intercurrent flare-up: if the participant experiences an intercurrent flare-up 
(new flare-up location or marked worsening of the original flare-up) at any time 
during the flare-up treatment, then the 12-week flare-up treatment should be 
restarted. 
In the case of any intolerable adverse reactions, the daily dose of the 
chronic/flare-up regimen can be reduced (see Section 6.5). 
Flare-up only regimen: 
If the participant experiences intolerable adverse reactions while taking chronic 
daily treatment and dose reduction does not alleviate the adverse reactions, then 
the participant may take palovarotene only at the time of flare-up (or substantial 
high-risk traumatic event). 
Route of Administration 
Oral 
Use 
Active study intervention 
IMP and NIMP/AMP. 
IMP 
Sourcing 
Centrally by sponsor 


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Packaging and Labelling 
Study intervention will be provided in bottle or blister packaging: 
- 
 90 capsules packaged in a bottle (1 mg, 1.5 mg, 2.5 mg, 5 mg and 
10 mg). 
- 
14 capsules packaged in a blister (1 mg, 1.5 mg and 5 mg) 
- 
15 capsules packaged in a bottle (5 mg) for US patients only. 
 
Each carton will be labelled as required per country requirement. 
Storage requirements 
To be stored at room temperature (between 15°C and 30°C) and protected from 
light and humidity. 
Former Names/Alias(es) 
None 
AMP=auxiliary medicinal product; FOP= fibrodysplasia ossificans progressiva; IMP=investigational medicinal product; 
NIMP=non investigational medicinal product. 
Participants will be instructed to report potential flare-up symptoms to study site personnel. 
Only one symptom is required to define a flare-up. If these symptoms are consistent with 
previous flare-ups, include a participant-reported onset date, and are confirmed by the 
investigator as associated with a flare-up, participants will immediately begin flare-up-based 
treatment. Flare-up based treatment should also be initiated if the investigator confirms the 
presence of a substantial high-risk traumatic event likely to lead to a flare-up. 
Based on clinical signs and symptoms as determined by the investigator, flare-up treatment may 
be extended in 4-week intervals while on-treatment with 10 mg palovarotene and continue until 
the flare-up resolves and the 4-week extension treatment has been completed. 
Participants will be supplied with chronic treatment as well as the appropriate dose of 
palovarotene to initiate flare-up treatment when a flare-up or traumatic event is confirmed by 
the investigator (during in-clinic or remote visit, or by telephone contact). 
Participants will be instructed to contact study site personnel immediately in case of intolerable 
adverse reactions during palovarotene treatment. The investigator will assess the adverse 
reaction and, if appropriate, will instruct the participant to reduce the daily dose of palovarotene 
as described in Section 6.5. If the participant does not have the appropriate dose in his/her 
possession, the study site will make immediate arrangements to ship the appropriate 
palovarotene dose to the participant. 
Palovarotene should be taken with food preferably at the same time each day. Palovarotene may 
be swallowed whole, or capsules may be opened and the contents emptied onto a teaspoon of 
soft food and taken immediately. 
6.2 
Preparation, Handling, Storage and Accountability 
Women who are pregnant or intend to become pregnant should avoid contact with palovarotene. 
Additionally, to avoid unintended exposure, caregivers administering palovarotene by 
emptying the capsule contents onto soft food should wear disposable gloves when handling and 
use disposable paper towels and a container to collect waste (e.g. a resealable bag). 
Palovarotene capsules may be opened, and the contents emptied on a teaspoon of soft food and 
taken immediately. If not taken immediately, it can be taken after a maximum of one hour after 
the sprinkling provided it was maintained at room temperature and not exposed to direct 
sunlight. 
• 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention and only 
authorised site staff may supply study intervention. All study intervention must be stored 
in a secure, environmentally controlled and monitored (manual or automated) area in 


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accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
• 
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition records). 
• 
The sponsor will provide guidance on the destruction of unused study intervention. If 
destruction is authorised to take place at the investigational site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy and any special instructions provided by the sponsor. All 
destruction must be adequately documented.  
Further guidance and information for the receipt, preparation, management and disposal/return 
of the study intervention are provided in the ‘Investigational Medicinal Product Handling 
Manual’. 
At each dispensation (at scheduled and unscheduled visits, if applicable), treatment number(s) 
will be assigned by the Interactive Web Response System (IWRS). The IWRS will also manage 
all logistical aspects of the study treatment (e.g. replacement, drug supplies and expiry dates) 
and the recording of drug accountability/destruction. This service provides the investigator, 
investigational site coordinators and project team members with a service that is available 
24 hours a day, 7 days a week. Additional details may be found in the IWRS reference manual 
provided to each investigational site. In case of technical or dispensation queries, a 24-hour 
helpline is available. If a participant discontinues the study before any intake of study treatment, 
his/her assigned treatment number(s) will not be reused. 
In addition to the information provided in the IWRS, drug accountability paper records will be 
maintained by the investigator. 
6.3 
Measures to Minimise Bias: Randomisation and Blinding 
6.3.1 
Randomisation 
Not applicable as this is a nonrandomised study. 
6.3.2 
Maintenance of Blinding 
This is an open-label study therefore no procedures for blinding are applicable. 
6.4 
Study Intervention Administration/Accountability 
Study intervention bottles and blisters will be brought back to the site and accountability 
performed. Accountability will be documented in the source documents and IWRS. 
A record of the quantity of palovarotene dispensed to and administered by each participant must 
be maintained and reconciled with study intervention and accountability records.  
Palovarotene status (treated or not treated) and regimen (chronic or flare-up or intercurrent 
flare-up or persistent flare up symptoms treatment) at the time of transition to Study 
CLIN-60120-452 will be collected at the Inclusion Visit. 
6.5 
Dose Modification 
Participants will be instructed to contact study site personnel immediately in case of intolerable 
adverse reactions during palovarotene treatment. The investigator will assess the adverse 
reaction and, if appropriate, will instruct the participant to reduce the daily dose to the next 
lower dosage as shown in Table 5; additional dose reduction should occur if adverse reactions 
continue to be intolerable. If the participant is already receiving the lowest possible dose, then 
consideration should be given to discontinue therapy temporarily or permanently or switching 


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to flare-up treatment only (see Section 6.1). Subsequent flare-up treatment should be initiated 
at the same reduced treatment that was tolerated previously. 
Table 5 
Dose Reduction of Palovarotene 
Dose Prescribed 
Reduced Dose 
20 mg 
15 mg  
15 mg 
12.5 mg 
12.5 mg 
10 mg 
10 mg 
7.5 mg 
7.5 mg 
5 mg 
5 mg 
2.5 mg 
2.5 mg 
1 mg 
6.6 
Continued Access to Study Intervention after the End of the Study 
The aim of this rollover study is to provide continued access to treatment to participants who 
have completed one of the parent studies until palovarotene is reimbursed in the country where 
the study is being conducted, or another access programme becomes available, or until the study 
end date of November 2024 is reached, at which point the study will end. Therefore, participants 
will not receive any additional study intervention following the EOS. 
6.7 
Treatment of Overdose 
For this study, any dose of palovarotene greater than those specified in Section 6.1 will be 
considered an overdose. 
The sponsor does not recommend specific treatment for an overdose; any overdose should be 
treated with supportive care according to the signs and symptoms exhibited by the participant. 
In the event of an overdose, the investigator/treating physician should: 
• 
Contact the medical monitor immediately. 
• 
Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
palovarotene can no longer be detected systemically (at least 30 days). 
• 
Document the quantity of the excess dose as well as the duration of the overdose. See 
Section 10.3.1 for reporting requirements concerning overdose. 
6.8 
Prior and Concomitant Therapy 
The following medications are not allowed during palovarotene treatment (chronic or 
flare-up-based treatment): 
• 
Vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal 
preparations, or fish oil are not permitted from the day before the start of treatment until 
the last day of treatment. 
• 
Synthetic oral retinoids other than palovarotene are not permitted in the 30 days prior to 
treatment until the last day of treatment. 
• 
Concomitant use of tetracyclines and retinoids has been associated with benign 
intracranial hypertension. Therefore, use of tetracycline or tetracycline derivatives is 
prohibited during the study. If the participant experiences a medical condition that 
requires treatment with tetracycline and/or doxycycline, the study intervention 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. 


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• 
Strong inhibitors of CYP450 3A4 are known to alter the metabolism of palovarotene. 
Thus, concurrent oral medications identified as strong inhibitors of CYP450 3A4 (see 
Section 10.5) are excluded. If during the study, the participant must take a strong inhibitor 
of CYP450 3A4, the study intervention 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 Section 10.5). 
• 
Strong inducers of CYP450 3A4 are also known to alter the metabolism of palovarotene. 
Thus, concurrent oral medications identified as strong inducers of CYP450 3A4 (see 
Section 10.5) are excluded. If during the study, the participant must take a strong inducer 
of CYP450 3A4, the study intervention may continue, but the medical monitor should be 
notified. 
• 
Kinase inhibitors such as imatinib, and other drugs used off-label as potential treatments 
for FOP such as rapamycin, as reported in the literature. A washout period of 5 half-lives 
is required prior to enrolment into the study. 
Prior medications will not be collected or recorded in the Study CLIN-60120-452 eCRF. These 
data will be transferred from the final parent study database and summarised at the Inclusion 
Visit. 
Any medication (including over-the-counter or prescription medicines, recreational drugs, 
vitamins, herbal supplements and vaccines (e.g. COVID-19)) or other specific categories of 
interest that the participant receives during the study will be collected at the Inclusion Visit, the 
Follow-up Visits and the EOS/EW Visit along with: 
• 
Reason for use; 
• 
Dates of administration including start and end dates; 
• 
Dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The following data on concomitant procedures will be collected at the Inclusion Visit and at the 
Follow-up/EOS/EW Visits: 
• 
Surgical procedure name; 
• 
Indication; 
• 
Reason for concomitant surgery; 
• 
Date of surgery. 
6.8.1 
Preventive Medication 
Assessment of 25-OH Vitamin D level is recommended and supplementation with Vitamin D 
for good bone health should be considered as per the ICC on FOP guideline [ICC FOP 2022] 
and local guidelines. 
6.8.2 
Rescue Medicine 
Mucocutaneous toxicities are the most common side effects of systemic retinoids. The most 
frequently reported AEs during FOP clinical studies with palovarotene were primarily 
mucocutaneous in nature, including cheilitis/dry lips, dry skin, pruritus and alopecia, and were 
generally assessed as related to palovarotene. 
Participants will be instructed to utilise symptomatic therapy (e.g. analgesics, skin emollients, 
lip moisturisers, artificial tears, or other helpful treatments), to minimize these side effects, or 
as prophylaxis in the studies. 


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Although palovarotene has not been proven to be phototoxic, precautionary measures for 
phototoxicity are recommended. Participants should avoid excessive exposure to sun and use 
protection from sunlight when it cannot be avoided (use of sunscreens, protective clothing, and 
use of sunglasses). 


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7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or of the study as a whole are detailed in Section 10.1.9. 
7.1 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention before the EOS. Palovarotene treatment for individual participants can be 
discontinued by the investigator if he/she believes the participants’ safety is at risk. In the event 
of pregnancy, palovarotene treatment must be discontinued (Section 8.3.5). 
If palovarotene is permanently discontinued, the participant will be withdrawn from the study. 
All reasonable efforts should be made by the study personnel to have the participants complete 
all study assessments of the EW Visit as per the SoA (see Table 1). 
If palovarotene is permanently discontinued due to a safety concern, the participant will be 
monitored for safety (see Section 8.3.3 for follow-up of AEs/SAEs and Section 8.3.5 for 
follow-up of pregnancies). 
7.1.1 
Liver Chemistry Stopping Criteria 
Not applicable to this study. 
7.1.2 
QTc Stopping Criteria 
Not applicable to this study. 
7.1.3 
Treatment Interruption 
Palovarotene can be temporarily discontinued if, after the daily dose of palovarotene has already 
been reduced to the lowest possible dose (see Section 6.5), the participant continues to 
experience intolerable adverse effects. 
If palovarotene is temporarily interrupted, the participant will remain in the study and 
assessments performed as planned per the SoA. 
If palovarotene is permanently discontinued, the participant will be withdrawn from the study 
and all reasonable efforts should be made by the study personnel to have the participant 
complete all study assessments of the EW Visit as per the SoA. 
In case of suspected or confirmed COVID-19 (SARS-CoV-2) infection, the intervention 
administration may be temporarily discontinued depending on the participant clinical 
presentation. In some cases, the investigator may request a participant be retested before the 
intervention administration is resumed.  
7.1.4 
Rechallenge 
If palovarotene is temporarily interrupted due to a safety related event, once the event resolves, 
treatment can resume at the discretion of the investigator. If the event reoccurs, palovarotene 
treatment may be temporarily interrupted again or permanently discontinued. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
compliance reasons. Participants meeting exclusion criteria during the course of the study 
will be withdrawn. 
• 
The legal guardian and the paediatric participant have the right to withdraw permission 
(consent or assent, respectively) at any time during the study. If the study staff identify 
any reluctance in the legal guardian or paediatric participant (e.g. signs of verbal or 
physical dissent) about continued participation in the study, the paediatric participant’s 


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continuation in the study should be re-evaluated. The same principles that govern 
permission/assent/consent also govern its withdrawal. A participant will be withdrawn 
from the study if consent or assent if applicable (a paediatric participant’s dissent should 
be respected) is withdrawn. 
• 
At the time of discontinuing from the study, all reasonable efforts should be made by the 
study personnel to have the participants complete all study assessments of the EW Visit 
if possible, as shown in the SoA. See SoA (Table 1) for data to be collected at the time 
of study discontinuation and any evaluations that need to be completed. 
• 
The reason for discontinuation will be recorded in the eCRF. 
• 
The participant will be permanently discontinued from the study intervention and the 
study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such withdrawal of consent. 
• 
If the participant requests to permanently discontinue the study intervention, they will be 
withdrawn from the study. In the case of ongoing AE/SAEs or pregnancy, they will be 
asked to be followed for safety (see Section 8.3.3 for follow-up of AEs/SAEs and Section 
8.3.5 for follow-up of pregnancies). 
• 
If the participant withdraws consent for any further contact, the investigator will explain 
in the medical records as to whether the withdrawal is only from further receipt of study 
intervention or also from study procedures and/or post-study intervention follow-up. This 
information must be entered in the eCRF.  
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return/be present 
for scheduled in-clinic or remote visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic or be present 
remotely for a required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible. The site should counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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8 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarised in the SoA (see Table 1). Protocol 
waivers and exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
Procedures conducted as part of the participant’s parent EOS Visit will be utilised for 
screening and Inclusion Visit assessments. All evaluations must be reviewed to confirm 
that potential participants meet all eligibility criteria. 
Eligible participants will enter this study ideally directly after completing the EOS Visit of the 
parent study (Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and after having signed the 
ICF. Any study assessments already performed at the parent EOS Visit will serve as the 
Inclusion Visit assessment for Study CLIN-60120-452; the data will be either transferred from 
the parent study database or will be entered again in the Study CLIN-60120-452 eCRF by the 
study site (see details in Table 1). For assessments not performed in the parent study (i.e. 
spirometry) or assessments performed out of allowed time window, assessments will be 
performed in-clinic or remotely at the Study CLIN-60120-452 Inclusion Visit. 
8.1 
Efficacy Assessments 
At in-clinic visits when multiple assessments are to be performed, the FOP-PFQ and the 
PROMIS Global Health Scale should be completed first, and in that order, before any other 
assessments are completed. 
8.1.1 
FOP-PFQ 
Physical function will be assessed using the FOP-PFQ at the Inclusion Visit, Follow-up Visits 
and the EOS/EW Visit. 
The FOP-PFQ is a disease-specific patient-reported outcome measure of physical impairment 
which includes questions related to ADL and physical performance. The adult form (developed 
for participants ≥15 years old) will be used for all participants. 
The adult FOP-PFQ consists of 28 questions which are scored on a scale of 1 to 5, with lower 
scores indicating that the participant has more difficulty completing those tasks. A total score, 
upper extremities subscore and a mobility subscore is calculated. Score calculations are 
described in Section 9.4.3.1. 
8.1.2 
PROMIS Global Health Scale 
Physical and mental function will be assessed using the PROMIS Global Health Scale at the 
Inclusion Visit, at the Follow-up Visits and the EOS/EW Visit. 
The PROMIS Global Health Scale is a patient-reported outcome measure of physical and 
mental function. The adult form (developed for participants ≥15 years old) will be used for all 
participants. 
The PROMIS Global Health Scale consists of 10 questions from which two scores are 
calculated: the global physical health score and the global mental health score, both ranging 
from 4 (worse health) to 20 (better health). Scores are converted to T-scores, with a higher 
T-score value indicating better health. Score calculations and conversion to T-scores are 
described in Section 9.4.3.2. 


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8.1.3 
CAJIS 
The CAJIS for FOP will be performed at the Inclusion Visit, Follow-up Visits and the EOS/EW 
Visit. 
The CAJIS is an objective measure of joint movement completed by the investigator to 
document total joint involvement (Kaplan et al., 2017b). This scale, which was developed by 
the investigators from the Center for Research in FOP and Related Disorders, assesses 
functional disability by categorising range of motion across 12 joints (both right and left 
shoulder, elbow, wrist, hip, knee and ankle joints) and three body regions (cervical spine, 
thoracic/lumbar spine and jaw), with each joint/region assessed as: 0=normal (<10% deficit); 
1=partially impaired (10% to 90% deficit); 2=functionally ankylosed (>90% deficit). The 
CAJIS total score is calculated as the sum of the scores of all joints/regions and ranges from 0 
(no involvement) to 30 (maximally involved). 
The examiner must also note and record (yes/no) if the participant: 
• 
Can walk; 
• 
Uses a wheelchair; 
• 
Needs some help with ADL; 
• 
Needs complete help with ADL. 
8.1.4 
FOP Assistive Devices Assessment 
The use of assistive devices and adaptations for daily living will be collected using the FOP 
assistive devices assessment at the Inclusion Visit, Follow-up Visits and the EOS/EW Visit. 
Assistive devices and adaptations for daily living include: 
• 
Mobility aids (cane/crutch, walker, manual wheelchair, motorised scooter, customised 
motorised wheelchair, adapted vehicle for driving or for motorised wheelchair); 
• 
Eating tools (adapted eating utensils, customised height table for eating/customised chair 
for eating, customised table for eating attached to wheelchair, straws for drinking, 
blender for pureeing foods, adapted cooking utensils); 
• 
Personal care tools (hearing aids, reaching stick, dressing stick, compression socks, 
customised clothing, standard shoe lift for support, customised shoe soles, portable urinal 
for male and females, adapted comb/brush/bathing tools/toothbrush/shaver/cosmetic 
application tools, pill crusher, medical alert bracelet with annual emergency membership, 
‘In Case of Emergency’ Taggisar with annual membership and label for emergency care, 
customised dental care tools); 
• 
Bathroom aids and devices (barrier-free roll in shower, shower seat/chair, handicap 
height toilet, washlet toilet, portable commode, lift seat on toilet, adapted sink 
counter/height/faucet handles/piping, shower grab bars, shower handheld sprayer, tub 
lift, bathroom grab bars); 
• 
Bedroom aids and devices (memory foam bed mattress/pillows, bed with motorised lift 
system, airflow mattress, waterbed, bed safety rails, bed pull/strap for self-positioning, 
remote control devices for lights/window treatment/shades); 
• 
Home adaptions (floor level threshold on all doorways, wide doorways to allow 
wheelchair access, transfer lift for bathing and mobility around the house, portable 
transfer lift, permanent built in ramp for home, portable ramp for use in 
home/office/travel, automatic light switches, customised furniture, customised counters 
in your kitchen/bathroom/work area, lift chair, durable/easy care flooring due to 
wheelchair weight, padded flooring for protection for children, handicapped emergency 


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exits, sliding/pocket interior doors, remote control/hands free exterior door opener and 
closer, combination emergency fire/carbon monoxide detectors and alert) 
• 
Work environment adaptions (customised desk/office chair/workstation/office tools, use 
of handicapped bathroom facilities); 
• 
Technology adaptions (adapted keyboard, voice activated computer software, wireless 
keyboard and mouse, trackball, adapted stand for computer use, typing stick, onscreen 
keyboard that is not normally part of the device); 
• 
Sports and recreation adaptions (protective helmet/body gear, adapted bicycle, other 
adapted recreational gear); 
• 
School adaptions (adapted desk, adapted chair, reaching tools, special electronics for 
learning, adapted curriculum); 
• 
Medical therapies for daily living (supplemental oxygen, physical therapy, hydrotherapy, 
energy medicine therapy, occupational therapy, lymphoedema massage treatments and 
wraps, wound care specialist, positive expiratory pressure mask or spirometer for 
breathing exercises). 
8.1.5 
Healthcare Utilisation 
The healthcare utilisation information that will be collected does not rely on specific validated 
questionnaires, but on tailored questions which will assess the type and frequency of health 
services used in the past 6 months/since the last visit.  
8.1.6 
Lung Function Assessments 
Lung function will be assessed at the Inclusion Visit, Follow-up Visits and at the EOS/EW 
Visit. 
The lung function parameters of observed FVC (litres) and % predicted FVC, observed FEV1 
(litres) and % predicted FEV1 and the absolute and predicted FEV1/FVC ratio are obtained by 
spirometry. 
The parameters of observed (traditional unit of mL/min/mmHg or International System of Units 
(SI unit) of mmol/min/kPa) (Graham et al., 2017) and % predicted DLCO is obtained by the 
DLCO test. This provides information on the efficiency of gas transfer from alveolar air into 
the bloodstream. Carbon monoxide has a high affinity for haemoglobin, and it follows the same 
pathway as that of oxygen to finally bind with haemoglobin. Inhaled carbon monoxide is used 
for this test due to its high affinity for haemoglobin which is 200-250 times that of oxygen 
(Modi and Cascella, 2020). 
8.1.7 
Flare-up Assessment 
For each flare-up, the location of the flare-up, flare-up cause, flare-up start and stop date, 
whether it is ongoing, flare-up concomitant medication, symptoms and outcome (resulted in 
extra bone growth, restricted movement) will be collected at the Inclusion Visit (for ongoing 
flare-up, data from parent EOS Visit will be entered again in the Study CLIN-60120-452 
eCRF), the Follow-up Visits and the EOS/EW Visits. 
Symptoms of a flare-up typically include, but are not limited to, localised pain, soft tissue 
swelling/inflammation, redness, warmth, decreased joint range of motion and stiffness. Only 
one symptom is required to define a flare-up. Flare-ups can occur in the absence of any apparent 
causative factor, but there is a high risk that substantial traumatic events (e.g. surgery, 
intramuscular immunisation, mandibular blocks for dental work, muscle fatigue, blunt muscle 
trauma from bumps, bruises, falls or influenza-like viral illnesses) can lead to a flare-up and 
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At each visit, the investigator will ask the participant if they experienced any flare-ups since 
their last visit, the location of the flare-ups, the start and stop date or whether it is ongoing, if 
any flare-up concomitant medication was taken and whether the flare-up resulted in extra bone 
growth and/or restricted movement. When extra bone growth occurred, the location will be 
specified and the investigators will ask the participant how the extra bone growth affected their 
movement. 
Bone growth, loss of mobility and audiology impact that occurs as a consequence of a flare-up 
will be reported as an AE or SAE (see Section 10.3.1). 
8.1.8 
Extra Bone Growth Assessment (without associated flare-up) 
For each extra bone growth (without associated flare-up) the location of the extra bone growth, 
whether it was preceded by injury, illness, vaccination and/or other events (“yes”, “no” or 
“unknown”), extra bone growth start date, duration and whether it is ongoing, will be collected 
at the Inclusion Visit and Follow-up/EOS/EW Visits. 
At each visit, the investigator will ask the participant if they experienced any extra bone growth 
(without associated flare-up) since their last visit and the details of these extra bone growths. 
8.1.9 
Qualitative Participant Interviews 
In-depth qualitative interviews will be proposed to all participants and will be conducted in 
person or by telephone by the PI/qualified site staff. Interviews can be carried out anytime 
within 1 year (ideally within 1 month) following the Inclusion Visit with consenting 
participants. 
Participants will be asked to describe her/his past experience with FOP (e.g. symptoms, joint 
being locked) and with palovarotene (e.g. decrease in number of flare-ups, delay in physical 
disability, overall satisfaction). 
Participants will also be asked to describe: 
• 
the overall impact of the disease on them (e.g. physical functioning, emotional health, 
social functioning, work/school/daily life impacts); 
• 
the critical joints involved; 
• 
the emotional benefit of using palovarotene as a treatment for FOP; 
• 
the perceptions of benefits and risks of palovarotene. 
The conduct of the qualitative interviews and all related procedures will be described in the 
interview guide. For the collection and reporting processes of the AEs/SAEs during the 
qualitative interviews, please refer to Section 8.3. 
8.2 
Safety Assessments 
The assessment of AEs/SAEs is detailed in Section 8.3. 
8.2.1 
Spinal Health Assessment 
Participants’ spinal health should be assessed for the risk of ‘radiological vertebral fracture’.  
The spinal health will be assessed using radiological imaging (e.g., CT, x-ray, scintigraphy, etc) 
at the Inclusion Visit, at the Follow-Up Visit annually and at the EOS/EW Visit. This 
assessment may be performed locally. 
The data from the spinal health assessment performed in the parent study (less than 3 months 
before entry in CLIN-60120-452 study) should be entered in the CLIN-60120-452 eCRF by the 
study site for the Inclusion Visit. If the spinal health assessment was performed more than 3 
months before entry in CLIN-60120-452 study, a new spinal health assessment should be 
performed at the Inclusion Visit. Spinal health assessment should then be performed annually. 


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The radiological imaging can be done locally and the spinal health assessment will be done by 
the PI and the data should be collected in the eCRF. If any vertebral fractures are identified, 
these should be reported as AEs and the corresponding eCRF page should be completed. 
8.2.2 
C-SSRS and Suicidal Ideation and Behaviour Risk Monitoring 
Suicidal ideation and behaviour will be collected using the C-SSRS (‘Baseline’ version) at the 
Inclusion Visit for screening purposes. At Follow-up visits, the C-SSRS ‘Since Last Visit’ 
version will be used. 
The adult form (designed for participants ≥12 years of age) will be used for all participants. 
Any participant reporting type 4 or 5 suicidal ideation or any suicidal behaviour within the past 
month prior to the Inclusion Visit, will not be eligible to participate in the study. 
Although there was no treatment-related increase in suicidal ideation, suicidal behaviour or 
psychiatric disorders overall relative to untreated participants with FOP in clinical trials, 
depression, depression aggravated, anxiety, mood alterations and suicidal thoughts and 
behaviours have been reported in patients treated with systemic retinoids. In addition, there is 
a relatively high background prevalence (24%) of depression in untreated patients with FOP. 
Therefore, participants being treated with palovarotene should be monitored appropriately and 
observed closely for suicidal ideation and behaviour or any other unusual changes in behaviour, 
especially at the beginning and end of the course of intervention, or at the time of dose changes, 
either increases or decreases. Participants who experience signs of suicidal ideation or 
behaviour should undergo a risk assessment. All factors contributing to suicidal ideation and 
behaviour should be evaluated and consideration should be given to discontinuation of the study 
intervention. 
When informed consent or assent has been given, families and caregivers of participants being 
treated with palovarotene should be alerted about the need to monitor participants for the 
emergence of unusual changes in behaviour, as well as the emergence of suicidal ideation and 
behaviour and to report such symptoms immediately to the study investigator. Suicidal ideation 
and behaviour will be captured as an AE/SAE. 
8.2.3 
Biochemistry and Triglycerides 
Amylase, lipase, AST, ALT and triglyceride levels from the EOS of parent studies and centrally 
measured will be used at the Inclusion Visit for screening purposes. 
For participants being screened more than one month after EOS visit of parent study, blood 
samples will be collected under fasting conditions when possible and testing preformed at a 
local, qualified laboratory. 
The participant will not be eligible to participate in the study if: 
• 
Any of the exclusion criteria apply (Section 5.2); 
• 
Amylase or lipase is >2× above the ULN; 
• 
AST or ALT is >2.5× above the ULN; 
• 
Fasting triglycerides levels are >400 mg/dL with or without therapy. 
8.2.4 
Linear Height and Body Weight 
Linear height and body weight will be collected for all participants at the Inclusion Visit, the 
Follow-up Visits and the EOS/EW Visit. 
Height at 6 to 12 months prior to the Inclusion Visit will also be collected. 


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8.2.5 
Vital Signs 
Respiratory rate, blood pressure and heart rate will be collected at the Inclusion Visit, the 
Follow-up Visits and the EOS/EW Visit. 
• 
Blood pressure and pulse measurements will be assessed by manual techniques. An 
automated device should not be used due to the risk of over-inflation and potential tissue 
injury in participants with FOP. To minimise the potential for a flare-up at the cuff site 
when measuring blood pressure, the cuff should be pumped slowly to a maximum of 
140 mm Hg. Blood pressure should not be measured on an arm with a flare-up. 
• 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (e.g. television, cell phones). 
• 
Vital signs will be measured after 5 minutes rest and will include respiratory rate, systolic 
and diastolic blood pressure and pulse. 
8.2.6 
Pregnancy Testing 
Female participants are assessed for child-bearing status and pregnancy prevention measures 
prior to receiving palovarotene. Refer to Section 5.1 for pregnancy testing entry criteria. 
Pregnancy tests may be performed either with the assistance from a study nurse at home or self-
administered by the participant.  
 
According to local practice, medically documented blood or urine pregnancy tests should be 
performed, as follows (the results of which will be recorded in the eCRF): 
• 
Prior to starting therapy: at least one month after the participant has started using 
contraception, and shortly (preferably a few days) prior to the first prescription, the 
participant should undergo a pregnancy test. This test should ensure the participant is not 
pregnant when she starts treatment with palovarotene and should be documented within 
the patient medical records. 
• 
Follow-up pregnancy testing during treatment: follow-up pregnancy tests should be 
done monthly. The need for repeated medically documented pregnancy tests every month 
is required and should be determined according to local practice including consideration 
of the participant's sexual activity and extent of FOP disease burden. 
• 
End of treatment: one month after stopping treatment, women should undergo a final 
pregnancy test. 
Palovarotene is strictly contraindicated during pregnancy, therefore if the pregnancy test is 
positive at the Inclusion Visit, the participant will not be eligible to participate in the study. Any 
positive pregnancy test during the study will result in immediate discontinuation of 
palovarotene. If a participant becomes pregnant during the study, she will be followed 
throughout her pregnancy and the health status of the baby will be verified up until one year of 
age (see Section 8.3.5). 
8.3 
AEs and SAEs and Other Safety Reporting 
The definitions of AEs and SAEs can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legal guardian). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs or their sequelae (any AE, based on the investigator’s opinion, not only those assessed 


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as related) that persist after the date of palovarotene discontinuation, or that caused the 
participant to discontinue palovarotene (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs (including SAEs) will be collected from the signing of the ICF until last study 
intervention intake + 30 days at the time points specified in the SoA (Table 1). 
All AEs that first occurred during participation in the parent study and are ongoing at the time 
of transition to Study CLIN-60120-452 will be collected and entered again as ongoing 
AEs/SAEs in the Study CLIN-60120-452 eCRF at the signing of the ICF. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of awareness of the event, as indicated in Section 10.3. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation (unless any AEs/SAEs or their sequelae persist after this date, follow-up 
is required until the event or its sequelae resolve or stabilise, or the participant is lost to follow-
up). However, if the investigator learns of any SAE, at any time after a participant has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the sponsor (through 
pharmacovigilance). 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-Up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. Follow‑up of the AE/SAE after the date of 
palovarotene discontinuation is required until the event or its sequelae resolve or stabilise at a 
level acceptable to the investigator and the sponsor’s clinical monitor or his/her designated 
representative, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 10.3. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, institutional review board 
(IRB)/independent ethics committee (IEC), and investigators. 
• 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 


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• 
Investigator safety reports must be prepared by the sponsor for suspected unexpected 
serious adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor’s policy and forwarded to investigators as necessary. 
8.3.5 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected from the signing of the 
ICF and until one year after the end of treatment within Study CLIN-60120-452. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue the study intervention and be withdrawn from the study. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate forms (AE form, in the eCRF and 080479-FOR Drug Exposure for 
Pregnancy Form – paper form) and submit it to the sponsor within 24 hours of learning 
of the female participant’s pregnancy (detailed in Section 10.2). 
• 
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and follow-up 
information on the neonate up until one year of age and the information will be forwarded 
to the sponsor using the appropriate forms. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• 
For female participants who have not reached legal age and who become pregnant, this 
information will be shared with the participant’s legal guardian if and as required by local 
regulations. 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
8.3.7 
Adverse Events of Special Interest  
No Adverse Events of Special Interest have been formally defined during palovarotene clinical 
development. 
8.3.8 
Reporting of Study Intervention Errors Including Misuse/Abuse 
• 
Medication errors are unintentional errors in the prescribing, dispensing, administration 
or monitoring of a study intervention (medicinal product) while under the control of a 
healthcare professional, participant or consumer (EMA definition). 
• 
Misuse refers to situations where the study intervention is intentionally and 
inappropriately used not in accordance with the protocol. 
• 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
• 
Study intervention errors and uses outside of what is foreseen in the protocol will be 
recorded in the eCRF in the AE section. It will be reported in the safety database only if 
associated with an SAE.  


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• 
Misuse or abuse will be collected and reported (via SAE form) in the safety database, 
whether associated or not with an AE/SAE, within 24 hours of investigator’s or qualified 
designees’ awareness. 
8.4 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.5 
Genetics 
Genetics are not evaluated in this study. 
8.6 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.7 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 
8.8 
Medical Resource Utilisation and Health Economics 
Medical resource utilisation and health economics parameters are not evaluated in this study. 
8.9 
Demographic and Baseline Characteristics 
The following data will not be collected or recorded in the Study CLIN-60120-452 eCRF; these 
data will be transferred from the final parent study database and summarised: 
• 
Disease history including the date of symptom onset, date of diagnosis by a physician, 
method of diagnosis, date of genetic test if performed and type of FOP genetic mutation. 
• 
Flare-up history over the past 12 months prior to the Inclusion Visit including: location 
of flare-ups, cause, flare-up start and stop date, flare-up concomitant medication and 
outcome (resulted in extra bone growth, restricted movement). Symptoms of a flare-up 
typically include, but are not limited to, localised pain, soft tissue swelling/inflammation, 
redness, warmth, decreased joint range of motion and stiffness. 
The following will be collected at the Inclusion Visit: 
• 
Baseline demographics including age, gender and race. 
• 
Physical examination including a general assessment, skin, lymph nodes, head, eyes, 
ears, nose and throat (HEENT), thorax, lung, cardiovascular system, abdomen, 
extremities, musculoskeletal system, neurological system and other. 
Any post-Inclusion Visit abnormal findings considered clinically significant by the investigator 
will be collected as an AE/SAE. 


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9 
STATISTICAL CONSIDERATIONS 
The first draft of the statistical analysis plan (SAP) will be made available within the first three 
months following the first participant first visit and will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the primary and secondary endpoints. 
9.1 
Statistical Hypotheses 
No hypotheses are planned to be tested as the primary endpoint of this study is descriptive. 
9.1.1 
Multiplicity Adjustment 
Adjustment for multiplicity is not applicable to this study. 
9.2 
Sample Size Determination 
No formal sample size calculations have been performed as the sample size is dependent on the 
number of participants in the parent studies who are eligible. A maximum of 87 participants 
from studies PVO-1A-301, PVO-1A-202/PVO-1A-204 are eligible to be enrolled. 
9.3 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Screened Set 
All participants who signed the ICF 
Enrolled Set 
The Enrolled Set will contain all participants who were assigned to receive 
palovarotene in Study CLIN-60120-452. 
Full Analysis Set 
(FAS)/Safety Set 
The FAS/Safety Set will contain all participants who received at least one 
dose of palovarotene during Study CLIN-60120-452.  
Per Protocol (PP) Set 
The PP set will contain all participants from the FAS who did not experience 
any major protocol deviations that may interfere with safety/efficacy 
evaluations 
9.4 
Statistical Analyses 
9.4.1 
General Considerations 
Statistical evaluation will be performed using Statistical Analysis System (SAS®) (Version 9.4 
or higher). 
No formal statistical testing will be performed. All the analyses will be primarily descriptive in 
nature. If p-values are presented, they will be for exploratory purposes only. 
For descriptive analyses, summary statistics will be presented at each scheduled visit and will 
include sample size, number of available observations (N), number of missing observations 
(missing), mean, 95% CIs of the mean/median, standard deviation (SD), number of nonmissing 
observations (n), median and range for continuous variables and scores. For categorical or 
discrete variables, the absolute and relative (percentage) numbers based on the nonmissing 
number of observations for each category will be presented, including 95% CIs. 
Missing data will not be replaced but will be displayed in all relevant tables. 
The Inclusion Visit is the first study visit (Day 1) and first administration of palovarotene in 
Study CLIN-60120-452 (and corresponds to the EOS Visit of the parent study for assessments 
already performed in the parent study). 
All analyses will be performed by parent study (PVO-1A-301 or PVO-1A-202/PVO-1A-204), 
by palovarotene status at the time of transition to Study CLIN-60120-452 (treated, not treated) 
and treatment regimen (chronic treatment only, flare-up treatment only, chronic & flare-up 
treatment) and overall. 


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9.4.2 
Analysis of Primary Endpoint 
The primary endpoint is the incidence and description of all TEAEs, serious and nonserious 
treatment-related TEAEs, all serious TEAEs and all nonserious TEAEs. 
A TEAE is defined as any AE that occurs after signing the ICF of Study CLIN-60120-452 or 
an ongoing AE from the parent study with a worsening in severity or relationship to the study 
intervention following transition to Study CLIN-60120-452. 
Ongoing AEs from the parent study with no change in severity or relationship to the study 
intervention following transition to Study CLIN-60120-452 will not be considered TEAEs. 
Any event that first occurred during participation in the parent study and is ongoing at the time 
of transition to Study CLIN-60120-452 will therefore be a (non-TEAE) AE. 
All ongoing AEs from the parent study and all TEAEs that occur following the signing of the 
ICF until last study intervention intake + 30 days will be included in the participant data listings 
using the Full Analysis Set (FAS)/Safety Set. Primary endpoint analyses and summary tables 
will be presented by parent study, by palovarotene status at the time of transition to Study CLIN-
60120-452 and treatment regimen and overall for the FAS/Safety Set. 
Adverse events/TEAEs will be coded according to Medical Dictionary for Regulatory 
Activities (MedDRA) and will be classified by PT and SOC. Adverse events/TEAE listings 
will be presented by participant, SOC and PT. 
The incidence of all reported TEAEs, serious and nonserious treatment-related TEAEs, all 
serious TEAEs, all nonserious TEAEs, TEAEs leading to death and TEAEs leading to treatment 
discontinuation will be tabulated separately. In addition, summary tables for TEAEs will be 
presented by maximum intensity and study intervention relationship (investigator-reported 
causality assessment). 
9.4.3 
Analysis of Secondary Endpoints 
Data related to the secondary endpoints will be included in the participant data listings using 
the FAS/Safety Set. Secondary endpoint analyses and summary tables will be presented by 
parent study, by palovarotene status at the time of transition to Study CLIN-60120-452 and 
treatment regimen and overall for the FAS/Safety Set. 
Analyses of the secondary endpoints will be repeated on the Per Protocol (PP) Set if ≥10% of 
participants are excluded from the FAS/Safety Set. 
Data will be tabulated descriptively, i.e. the number and percentage of participants for each 
category for categorical parameters, and the number, mean, SD, 95% CIs of the mean/median, 
median, minimum and maximum for continuous parameters will be tabulated. 
9.4.3.1 
FOP-PFQ 
The adult FOP-PFQ consists of 28 questions which are scored on a scale of 1 to 5. A total score, 
upper extremities subscore and a mobility subscore is calculated as follows: 
• 
Total score: the sum of the scores from each question which will range from 28 × 1 = 28 
to 28 × 5 = 140. 
• 
Upper extremities subscore: the sum of the scores from 15 questions (Questions 1-12, 
14, 25 and 26) which will range from 15 × 1 = 15 to 15 × 5 = 75. 
• 
Mobility subscore: the sum of the scores from 13 questions (Questions 13, 15-24, 27 and 
28) which will range from 13 × 1 = 13 to 13 × 5 = 65. 
Missing scores for individual questions will not be imputed, but they will be taken into account 
according to the rules described below: 


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(1) 
If more than 20% of the questions contributing to the total score are missing, the total 
score will not be calculated. It will be considered as missing. 
(2) 
If less than 20% of the questions contributing to the total score are missing, the total score 
will be calculated by summing all observed question scores, divided by the number of 
questions that were answered and by multiplying this average score by the total number 
of questions that were meant to be answered (i.e. × 28). 
The two rules described above also apply to the upper extremities subscore and the mobility 
subscore. 
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. 
The % of worst scores (for total score, upper extremities subscore and mobility subscore) as 
well as the change from the Inclusion Visit will be presented for each visit. 
9.4.3.2 
PROMIS Global Health Scale 
The PROMIS Global Health Scale consists of 10 questions from which the global physical 
health score and the global mental health score, both ranging from 4 (worse health) to 20 (better 
health), is calculated as follows: 
• 
Global physical health score: the sum of scores from Questions 3, 6, 7 and 8 and will 
range from 4 (worse health) to 20 (better health). 
• 
Global mental health score: 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 above scores, the Question 7, 8 and 10 will be rescaled as shown in 
Table 6. 
If a participant is missing any of the contributing raw scores, the corresponding score (global 
physical health or global mental health score) will not be calculated for that participant. 
Table 6 
Rescaled Global Physical and Mental Health Scores for the Adult Version of the PROMIS 
Global Health Scale 
Questions 
Raw 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 
PROMIS=Patient Reported Outcomes Measurement Information System. 
The global physical health score and the global mental health score will be converted into 
T-scores (see Table 7). T-score distributions are standardised such that a value of 50 represents 
the average (mean) for the general population and increments of ±10 points represent ±1 SD 
away from the norm. Higher T-scores indicate better physical/mental health. A T-score <50 
indicates worse health than the general population, while a T-score >50 indicates better health. 
For example, a participant who has a T-score of 60 is 1 SD better (healthier) than the general 
population. 


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Table 7 
PROMIS Global Health Scale T-Score Conversions for Global Physical and Mental Health 
Scores 
Global Physical Health 
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 
PROMIS=Patient Reported Outcomes Measurement Information System. 
Actual values as well as the change from the Inclusion Visit in mean global physical and mental 
health score converted into T-scores will be presented for each visit. 
9.4.3.3 
CAJIS 
Actual values as well as the change from the Inclusion Visit in CAJIS total score will be 
presented for each visit. 
9.4.3.4 
FOP Assistive Devices 
Actual values as well as the shift from the Inclusion Visit in the use of assistive devices and 
adaptions for daily living will be presented for each visit. 
9.4.3.5 
Healthcare Utilization 
Descriptive statistics will be presented for each visit. 
9.4.3.6 
Lung Function Parameters 
Actual values as well as the change from the Inclusion Visit in observed and % predicted FVC, 
observed and % predicted FEV1, absolute and predicted FEV1/FVC ratio and observed and % 
predicted DLCO will be presented for each visit. 
The DLCO value is reported in either traditional units (mL/min/mmHg) or SI units 
(mmol/min/kPa). Values in SI units can be multiplied by 2.987 to obtain values in traditional 
units (Graham et al., 2017). 
9.4.3.7 
Flare-ups 
Actual values as well as the change from the Inclusion Visit in number of investigator-reported 
flare-ups, flare-up outcomes (extra bone growth, restricted movement) and flare-up duration 
will be presented for each visit by body location and overall. 
9.4.3.8 
Extra Bone Growth 
The percentage of participants with extra bone growth (associated with a flare-up and not 
associated with a flare-up) will be presented for each visit. 


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9.4.3.9 
Qualitative Participant Interviews 
No formal hypotheses will be tested given the qualitative nature of the analyses. 
The service Provider (SP) will begin the analysis process based on the PI/qualified site staff 
debrief and record of initial thoughts from each of the completed interviews. Specifically, using 
field notes (where available), the PI/qualified site staff will identify key concepts raised by 
participants and dominant trends in interview data with a particular focus on the study 
objectives and other potential insights emerging from the interviews. Additionally, once the 
interview transcripts are available, the SP will analyse the interview data according to the final 
qualitative analysis plan, using a thematic qualitative data analysis approach. 
All qualitative and limited quantitative data will be summarised descriptively. Where 
applicable, Ns and %s will be provided. 
Tables displaying the concepts described during the interviews will be developed to document 
the results of the interviews. Additionally, descriptive statistics based on the quantitative data 
obtained during the interviews (e.g. symptom improvements during the clinical study) will be 
computed and summarised. 
9.4.4 
Other Analyses 
9.4.4.1 
Demographic and Baseline Characteristics 
Disease and flare-up history will be summarised using the data transferred from the final parent 
study database. 
Baseline demographic and physical examination data will be included in the participant data 
listings and descriptive statistics presented using the FAS/Safety Set. 
Physical examination findings will be coded using MedDRA and summarised. 
9.4.4.2 
Prior and Concomitant Medication 
Prior medication will be summarised at the Inclusion Visit using the data transferred from the 
final parent study database. 
Concomitant medication will be included in the participant data listings using the FAS/Safety 
Set. 
Descriptive statistics of concomitant medication will be presented for the FAS/Safety Set. 
Concomitant medication will be coded using the World Health Organization Drug Dictionary 
(WHODD) and summarised by drug categories. 
9.4.4.3 
Concomitant Procedures 
Concomitant procedure data will be included in the participant data listings using the 
FAS/Safety Set. 
Descriptive statistics of concomitant procedures will be presented for the FAS/Safety Set. 
9.4.4.4 
Spinal Health Assessment 
Spinal health assessment data will be included in the participant data listings using the 
FAS/Safety Set. 
Descriptive statistics of spinal health assessment will be presented for the FAS/Safety Set. 
9.4.4.5 
Linear Height and Body Weight 
Linear height and body weight will be included in the participant data listings using the 
FAS/Safety Set.  
Actual values and mean changes from the Inclusion Visit in linear height and body weight will 
be presented at each visit for the FAS/Safety Set. 


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Height velocity and z-scores will be derived for participants <18 years of age. Actual values 
and mean changes from the Inclusion Visit in height velocity and z-scores will be presented at 
each visit for the FAS/Safety Set. 
9.4.4.6 
Vital Signs 
Vital signs (respiratory rate, blood pressure and heart rate) will be included in the participant 
data listings using the FAS/Safety Set.  
Actual values and mean changes from the Inclusion Visit in respiratory rate, blood pressure and 
heart rate will be presented at each visit for the FAS/Safety Set. 
9.4.4.7 
Participant Disposition and Withdrawals 
The numbers and percentages of participants included in the analysis sets will be tabulated 
overall, by parent study and by country and site. The reasons for participant exclusions from 
each of the analysis sets will also be tabulated. 
In addition, the number of participants who discontinued treatment or withdrew from the study 
will be presented with the primary reasons for discontinuation/withdrawal. 
9.4.5 
Subgroups Analyses 
Subgroup analyses will be performed by parent study (PVO-1A-301 or PVO-1A-202/PVO-1A-
204), palovarotene status at the time of transition to study CLIN-60120-452 (treated, not 
treated), and treatment regimen (chronic treatment only, flare-up treatment only, chronic & 
flare-up treatment). 
Further details on the statistical analysis will be provided in the SAP. 
9.5 
Interim Analyses 
No interim analyses are planned. 
A stand-alone final report for the qualitative participant interview will be made available once 
enrolment and all interviews have been completed at the Inclusion Visit. 


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SAP_001.pdf: 
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PAGE 1/37 
 
 
080091-FOR SAP Template version 6.0 
STATISTICAL ANALYSIS PLAN 
 
ROLLOVER STUDY; MULTICENTRE, PHASE III, OPEN-LABEL STUDY TO 
FURTHER EVALUATE THE SAFETY AND EFFICACY OF PALOVAROTENE 
CAPSULES IN MALE AND FEMALE PARTICIPANTS AGED ≥14 YEARS WITH 
FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP) WHO HAVE 
COMPLETED STUDY PVO-1A-301 OR PVO-1A-202/PVO-1A-204 AND MAY 
BENEFIT FROM PALOVAROTENE THERAPY  
[CLIN-60120-452] 
 
This statistical analysis plan is based on: 
PROTOCOL VERSION AND DATE: VERSION 4.0 – 13 OCTOBER 2023 
ORIGINAL PROTOCOL: 03 AUGUST 2021 
 
SAP Version 
Date 
Final 1.0 
24 January 2025 
 
 
 
 
 
 


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080091-FOR SAP Template version 6.0 
APPROVAL PAGE 
STUDY NUMBER: 
CLIN-60120-452 
PROTOCOL TITLE: 
Rollover Study; Multicentre, Phase III, Open-label 
Study to Further Evaluate the Safety and Efficacy of 
Palovarotene Capsules in Male and Female Participants 
Aged ≥14 Years with Fibrodysplasia Ossificans 
Progressiva (FOP) Who Have Completed Study PVO-
1A-301 or PVO-1A-202/PVO-1A-204 and May 
Benefit from Palovarotene Therapy 
SAP VERSION: 
Final 1.0 
SAP DATE: 
24 January 2025  
 


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HISTORY OF CHANGES 
  
 
Version Number  
Date 
Description/Rational for 
change 
Version 1.0 
24 January 2024 
Original Version 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
APPROVAL PAGE .................................................................................................................. 2 
HISTORY OF CHANGES ...................................................................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 6 
1 
INTRODUCTION .......................................................................................................... 8 
2 
PROTOCOL OVERVIEW ............................................................................................ 8 
2.1 
Study Objectives and Hypotheses ................................................................................. 8 
2.2 
Overall Study Design and Investigational Plan ........................................................... 9 
2.3 
Sample Size Determination and Power ....................................................................... 11 
2.4 
Randomisation and Blinding ....................................................................................... 12 
2.5 
Schedule of Assessments ............................................................................................... 12 
2.6 
Change from Statistical Section of the Protocol ........................................................ 16 
3 
PLANNED ANALYSES ............................................................................................... 16 
3.1 
Data Monitoring ............................................................................................................ 16 
3.2 
Interim Analysis ............................................................................................................ 16 
3.3 
Final Analysis ................................................................................................................ 16 
4 
ANALYSIS SETS ......................................................................................................... 16 
5 
STATISTICAL METHODS/ANALYSES .................................................................. 16 
5.1 
General Considerations ................................................................................................ 16 
5.1.1 
Outputs Presentation ................................................................................... 17 
5.1.1.1 
Tables Header .............................................................................................. 17 
5.1.1.2 
Presentation of Groups ................................................................................ 17 
5.1.1.3 
Presentation of Visits / Timepoints .............................................................. 17 
5.1.1.4 
Subgroups .................................................................................................... 17 
5.1.2 
Descriptive Statistics ................................................................................... 17 
5.1.3 
Baseline value ............................................................................................. 18 
5.1.4 
Reference Start Date and Study Day .......................................................... 18 
5.2 
Disposition and Analysis Sets ....................................................................................... 18 
5.3 
Protocol Deviations ....................................................................................................... 18 
5.4 
Demography and Other baseline characteristics ....................................................... 19 
5.5 
Non-drug therapies, medications and surgical procedures ...................................... 19 
5.6 
Compliance .................................................................................................................... 20 
5.7 
Primary and Secondary Analysis ................................................................................ 21 
5.7.1 
General Considerations .............................................................................. 21 
5.7.1.1 
Significance Testing and Estimations .......................................................... 21 
5.7.1.2 
Handling of Dropouts and missing data ...................................................... 21 
5.7.1.3 
Statistical/analytical issues .......................................................................... 21 
5.7.2 
Analysis of Primary Endpoint .................................................................... 21 


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5.7.2.1 
Endpoints ..................................................................................................... 21 
5.7.2.2 
Primary Analysis – Adverse Events ............................................................. 21 
5.7.3 
Analysis of Secondary Endpoints ............................................................... 24 
5.7.3.1 
FOP Physical Function Questionnaire (FOP-PFQ) ................................... 24 
5.7.3.2 
PROMIS Global Health Scale ..................................................................... 25 
5.7.3.3 
Cumulative Analogue Joint Involvement Scale (CAJIS) .............................. 25 
5.7.3.4 
FOP Assistive Devices ................................................................................. 26 
5.7.3.5 
Healthcare Utilisation ................................................................................. 26 
5.7.3.6 
Lung Function Parameters .......................................................................... 27 
5.7.3.7 
Flare-ups ...................................................................................................... 27 
5.7.3.8 
Extra Bone Growth ...................................................................................... 28 
5.7.4 
Analysis of Exploratory Endpoints ............................................................. 28 
5.8 
Safety .............................................................................................................................. 28 
5.8.1 
General Consideration ................................................................................ 28 
5.8.2 
Extent of exposure ...................................................................................... 28 
5.8.2.1 
Total Duration of Treatment ........................................................................ 28 
5.8.2.2 
Duration of Flare-up Treatment .................................................................. 29 
5.8.2.3 
Duration of Chronic Treatment ................................................................... 29 
5.8.3 
Laboratory Data .......................................................................................... 29 
5.8.4 
C-SSRS ........................................................................................................ 29 
5.8.5 
Linear Height and Body Weight ................................................................. 30 
5.8.6 
Vital Signs ................................................................................................... 30 
5.8.7 
Physical Examination ................................................................................. 31 
5.8.8 
Spinal Health Assessment ........................................................................... 31 
6 
DATA HANDLING ...................................................................................................... 31 
6.1 
Visit window .................................................................................................................. 31 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit ............................................................ 31 
7 
DERIVED DATA .......................................................................................................... 31 
7.1 
PROMIS T-Score Conversions .................................................................................... 31 
7.2 
Linear Height Z-scores ................................................................................................. 32 
8 
REFERENCES .............................................................................................................. 32 
9 
APPENDICES ............................................................................................................... 33 
A1. SAS code ........................................................................................................................ 33 
A2. List of PCSA criteria .................................................................................................... 33 
A3. Partial/Missing Date Convention ................................................................................ 34 
A4. Programming Convention for Outputs ....................................................................... 36 
A5. Listings conventions ...................................................................................................... 36 
A6. EudraCT categories for age ......................................................................................... 37 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
Wording Definition 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Class 
C 
Concomitant  
CAJIS 
Cumulative Analogue Joint Involvement Scale 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
Diffusion Capacity of the Lung for Carbon Monoxide 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EOS 
End of Study 
EudraCT 
European Clinical Trials Database 
EW 
Early Withdrawal 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in One Second 
FOP 
Fibrodysplasia Ossificans Progressiva 
FOP-PFQ 
FOP Physical Function Questionnaire 
FVC 
Forced Vital Capacity 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Regulatory Activities 
P 
Prior 
PC  
Prior and Concomitant  
PCSA 
Potentially Clinically Significant Abnormalities 


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ABBREVIATION 
Wording Definition 
PN 
Preferred Name 
PP 
Per Protocol 
PROMIS 
Patient Reported Outcomes Measurement Information 
System 
PT 
Preferred Term 
RARγ 
Retinoic Acid Receptor Gamma 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI Unit 
International System of Units 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Events 
TFLs 
Tables, Figures and Listings 
ULN 
Upper Limit of Normal 
WHODD 
World Health Organization Drug Dictionary 
 
 


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1 
INTRODUCTION 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
completion of the Clinical Study Report (CSR) for protocol CLIN-60120-452. It describes the 
rules and conventions to be used in the analysis and presentation of data, the data to be 
summarised and analysed, including specificities of the statistical analyses to be performed.  
A separate shell will be provided for tables, figures and listings.  
The SAP is to be finalised prior to database lock (DBL). Any deviations from the SAP after 
database lock will be documented in the CSR (section 9.8 “Changes in the conduct of the study 
or planned analyses” as per International Conference on Harmonisation (ICH) E3).  
2 
PROTOCOL OVERVIEW 
The aim of Study CLIN-60120-452 is to provide continued access to palovarotene once the 
ongoing clinical studies have ended. More specifically, the aim is to provide treatment 
continuity to participants who have completed one of the parent studies (Study PVO-1A-301 
or PVO-1A-202 (Parts C and D correspond to Study PVO-1A-204 in France)) and, in the 
investigator’s judgement, may benefit from palovarotene therapy until palovarotene is 
reimbursed in the country where the study is being conducted, or another access programme 
becomes available, or until the study end date of November 2024 is reached, whichever occurs 
first. 
2.1 
Study Objectives and Hypotheses 
The objectives of the study are as per the table below:  
Objectives 
Endpoints 
Primary 
 
• 
To further evaluate the safety of palovarotene 
in adult and paediatric participants with FOP. 
• 
Incidence and description of all treatment-
emergent adverse events (TEAEs) whether or 
not they are considered as related to the study 
intervention; 
• 
Incidence and description of all serious and 
nonserious treatment-related TEAEs; 
• 
Incidence and description of all serious 
TEAEs, whether or not they are considered 
as related to the study intervention; 
• 
Incidence and description of all nonserious 
TEAEs whether or not they are considered as 
related to the study intervention. 
Secondary 
 
• 
To describe range of motion, as assessed by the 
Cumulative Analogue Joint Involvement Scale 
(CAJIS) for FOP, at the Inclusion Visit and 
over time under palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in CAJIS total score at each Follow-up 
Visit; 
• 
To describe the use of assistive devices and 
adaptations 
for 
daily 
living 
by 
FOP 
participants, at the Inclusion Visit and over 
time under palovarotene treatment; 
• 
Raw values and shift from the Inclusion 
Visit in the use of assistive devices and 
adaptations for daily living at each Follow-
up Visit; 
• 
To describe physical function, using the adult 
form 
of 
the 
FOP 
Physical 
Function 
Questionnaire (FOP-PFQ), at the Inclusion 
Visit and over time under palovarotene 
treatment; 
• 
Raw values and change from the Inclusion 
Visit in % of worst score for total score, 
upper extremities subscore and mobility 
subscore using the adult form of the FOP-
PFQ for all participants, at each Follow-up 
Visit; 


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• 
To describe the FOP healthcare utilization in 
patients with FOP 
• 
Type and frequency of healthcare utilization 
• 
To describe the parameters of lung function 
(observed and % predicted forced vital 
capacity (FVC), observed and % predicted 
forced expiratory volume in one second 
(FEV1), absolute and predicted FEV1/FVC 
ratio, observed and % predicted diffusion 
capacity of the lung for carbon monoxide 
(DLCO)) at the Inclusion Visit and over time 
under palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted FVC at 
each Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted FEV1 at 
each Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in absolute and predicted FEV1/FVC 
ratio at each Follow-up Visit; 
• 
Raw values and change from the Inclusion 
Visit in observed and % predicted DLCO at 
each Follow-up Visit; 
• 
To describe physical and mental health, using 
the adult form of the Patient Reported 
Outcomes Measurement Information System 
(PROMIS) Global Health Scale, at the 
Inclusion Visit and over time under 
palovarotene treatment; 
• 
Raw values and change from the Inclusion 
Visit in physical and mental function (mean 
global physical and mental health score 
converted into T-scores), using the adult 
form of the PROMIS Global Health Scale 
for all participants, at each Follow-up Visit; 
• 
To describe the number of 
investigator-reported flare-ups, flare-up 
outcomes (extra bone growth, restricted 
movement) and flare-up duration by body 
location and overall; 
• 
Raw values and change from the Inclusion 
Visit in number of investigator-reported 
flare-ups, flare-up outcomes (extra bone 
growth, restricted movement) and flare-up 
duration at each Follow-up Visit by body 
location and overall; 
• 
Percentage of participants with extra bone 
growth associated or not with  a flare-up 
status at each Follow-up Visit; 
In relation to FOP (via interviews):  
• 
To further understand and describe 
participants’ experiences with FOP symptoms 
(e.g. flare-ups, joints being locked);  
• 
To describe the overall impact of the disease 
on participants living with FOP (e.g. physical 
functioning, emotional health, social 
functioning, work/school/daily life impacts); 
• 
To identify and rank the critical joints from a 
participant’s perspective; 
 
In relation to patient experiences with palovarotene in 
the parent study :  
 
• 
To further understand and describe participant 
experience with palovarotene (e.g. decrease in 
number of flares up, delay in physical 
disability, overall satisfaction) 
• 
To describe the emotional benefit for 
participants of using palovarotene as a 
treatment for FOP; 
• 
To assess participants’ perceptions of benefits 
and risks of palovarotene.  
• 
Not applicable. 
 
2.2 
Overall Study Design and Investigational Plan 
Study CLIN-60120-452 is a multicentre, noncomparative rollover study with the aim of 
continuing to provide palovarotene to participants with FOP who have completed one of the 


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parent studies (Study PVO-1A-301 or PVO 1A 202/PVO 1A 204) and, in the investigator’s 
judgement, may benefit from palovarotene therapy. Participants who have completed the parent 
study are defined as those who have completed the parent End of Study (EOS) or End of 
Treatment Visit. 
The study is designed primarily to further evaluate the safety of palovarotene and secondly, to 
collect efficacy data in male and female participants aged ≥14 years (qualifying as skeletally 
mature or, based on investigator’s assessment, have reached final adult height) with FOP treated 
with palovarotene. 
Participants are eligible for the study whether they are receiving chronic or flare-up treatment 
in the parent study at the time of transition. Participants who previously interrupted/stopped 
palovarotene treatment and are currently under parent study follow-up due to the premature 
physeal closure (PPC) related partial clinical hold in participants <14 years, are eligible for the 
study if they are ≥14 years of age and skeletally mature/have reached final adult height based 
on investigator’s assessment. There must be a current parent study signed informed consent 
(ICF) form for the participant to be eligible for Study CLIN-60120-452. 
A maximum of 87 participants from studies PVO-1A-301, PVO-1A-202/PVO-1A-204 are 
eligible to be enrolled and will receive palovarotene once daily at the dose received during their 
participation in the parent study at the time of transition to Study CLIN-60120-452 or prior to 
interrupting/stopping palovarotene treatment. 
The study will consist of an Inclusion Visit (Day 1) (which ideally corresponds to the parent 
EOS Visit), a continuous dosing treatment period (including a Follow-up Visit every six 
months), and an EOS/Early Withdrawal (EW) Visit. The maximum duration is three years from 
enrolment to last study visit (November 2021 to November 2024). The study schema is below: 
 
Figure 1 Study Schema 
 


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Eligible participants will ideally enter the study directly after completing the EOS Visit of the 
parent study (Study PVO-1A-301 or PVO-1A-202/PVO-1A-204) and the ICF is signed. Any 
study assessments already performed at the parent EOS Visit will serve as the Inclusion Visit 
assessment for Study CLIN-60120-452 (maximum of one month allowed between the two 
visits). Treatment initiation for Study CLIN-60120-452 must concur with the EOS Visit and 
the study intervention administration schedule of the parent study in order to ensure 
palovarotene treatment continuity for both chronic and flare-up treatment. 
The dose of palovarotene administered will be individualised for each participant and based on 
the regimen (chronic or flare-up treatment), the weight and the dose received during their 
participation in the parent study at the time of transition to Study CLIN-60120-452 or prior to 
interrupting/stopping palovarotene treatment (to allow for dose modifications made to the 
standard chronic/flare-up regimen during the parent study) 
Chronic/flare-up regimen: 
Chronic treatment: oral palovarotene once daily, 5 mg, or at the dose received during 
participation in the parent study at the time of transition Study CLIN-60120-452 or prior to 
interrupting/stopping palovarotene treatment. 
Flare-up treatment: increase in dose at the time of a flare-up (or substantial high risk traumatic 
event likely to lead to a flare-up) to 20 mg once daily for 4 weeks (28 days), followed by 10 mg 
once daily for 8 weeks (56 days) for a total of 12 weeks (84 days) even if symptoms resolve 
earlier. 
Participants receiving flare-up treatment at the time of transition to Study CLIN-60120-452 will 
continue and complete the flare-up treatment as was planned in the parent study. 
Flare-up treatment should begin at the onset of the first symptom indicative of a FOP flare-up 
or substantial high risk traumatic event likely to lead to a flare-up. Chronic treatment should 
cease at the time of initiation of flare-up treatment, re-initiation of the chronic daily treatment 
should occur after completion of the flare-up treatment. 
Persistent flare-up symptoms: treatment may be extended in 4-week intervals with 10 mg 
palovarotene and continued until the flare-up symptoms resolve. 
Intercurrent flare-up: if the participant experiences an intercurrent flare-up (new flare-up 
location or marked worsening of the original flare-up) at any time during the flare-up treatment, 
then the 12-week flare-up treatment should be restarted. 
In the case of any intolerable adverse reactions, the daily dose of the chronic/flare-up regimen 
can be reduced. 
2.3 
Sample Size Determination and Power 
No formal sample size calculations have been performed as the sample size is dependent on the 
number of participants in the parent studies who are eligible. A maximum of 87 participants 
from studies PVO-1A-301, PVO-1A-202/PVO-1A-204 are eligible to be enrolled. 


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2.4 
Randomisation and Blinding 
This is a non-randomised open-label study therefore no procedures for blinding are applicable. 
2.5 
Schedule of Assessments 
The schedule of Activities (SoA) planned in this study are presented in Table 1. 


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Table 1 
Schedule of Activities 
 
Assessment/Procedure 
Inclusion Visit[a] 
Day 1 
Follow-Up Visits 
Every 6 months (±1 
month)[b]/ 
EOS/EW Visit[c] 
 
 
Procedures 
already 
performed at 
the parent 
EOS Visit 
that will be 
transferred 
from parent 
study 
database 
Procedures 
already 
performed 
at the parent 
EOS Visit 
to be 
entered in 
CLIN-
60120-452 
eCRF by 
the study 
site 
Procedures 
to be 
performed 
at the 
CLIN-
60120-452 
Inclusion 
Visit 
In-clinic Visit 
Remote visit  
Informed consent[d] 
 
 
X 
 
 
Inclusion/exclusion criteria 
 
 
X 
 
 
Study intervention 
administration/accountability[e] 
 
 
X 
X 
X 
Baseline demographics 
 
 
X 
 
 
Physical examination 
 
 
X 
 
 
Participant interview[f] 
 
 
X 
 
 
Pregnancy testing and 
childbearing potential [g] 
 
X[a]* 
 
X 
X 
Linear height and body weight 
[h] 
 
X[a]* 
 
X 
X 
Vital signs [i]  
 
X[a]* 
 
X 
X 
Spinal health assessment [j] 
 
X [a]** 
 
X 
 
Lung function assessments [k] 
 
 
X 
X 
 
Flare-up assessment [l] 
 
 
X 
X 
X [m] 
Additional Extra bone growth 
assessment (without associated 
flare-up) 
 
 
X 
X 
X 
CAJIS [n] 
X* 
 
 
X 
X 
C-SSRS [n] [o] 
 
 
X 
X 
X 
FOP-PFQ assessment[p] [q] 
X* 
 
X [q]*** 
X 
X 
PROMIS Global Health Scale 
[p][q] 
X* 
 
X [q]*** 
X 
X 
FOP assistive devices 
assessment [p] 
 
 
X 
X 
X 
Healthcare Utilization [p] 
 
 
X 
X 
X 
Biochemistry (amylase, lipase, 
AST, ALT) and triglycerides 
X* 
 
 
 
 
Disease and flare-up history 
X 
 
 
 
 
Prior medications 
X 
 
 
 
 
Concomitant medications 
 
X 
 
X 
X 
Concomitant procedures [r] 
 
X 
 
X 
X 
AEs [s] 
 
X 
 
X 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CAJIS=Cumulative Analogue Joint 
Involvement Scale for FOP; COVID-19=coronavirus disease 2019; C-SSRS=Columbia-Suicide Severity Rating Scale; 
DLCO=diffusion capacity of the lung for carbon monoxide; eCRF=electronic case report form; EOS=End of Study; 
EW=Early Withdrawal; FEV1=forced expiratory volume in one second; FVC=forced vital capacity; FOP=fibrodysplasia 
ossificans progressiva; FOP-PFQ=FOP Physical Function Questionnaire; PROMIS=Patient Reported Outcomes 
Measurement Information System. 


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a. 
The Inclusion Visit should be in-clinic and corresponds ideally to the EOS Visit of the parent study (Study PVO-1A-
301 or PVO-1A-202/PVO-1A-204). A maximum of one month is allowed between the two visits. For any assessments 
from the parent EOS Visit performed outside this allowed time window, assessments will need to be performed again 
at the Study CLIN-60120-452 Inclusion Visit (flagged with *). However, to enable continued access to the 
Investigational Product and rollover of participants with impaired mobility [in the case(s) when per investigator’s 
judgement this is considered as beneficial for the participant’s medical conditions], the parent EOS Visit and 
consenting for CLIN-60120-452 and CLIN-60120-452 Inclusion Visit can be conducted remotely. In such case(s) both 
parts of remote consenting used by the site – i.e. Informing/Consenting discussion and ICF signature should be agreed 
with the IRB/EC, and the investigator’s judgement should be sufficiently documented in the patient source notes.  
For the spinal health assessment, a time window of 3 months post parent visit is allowed (flagged with **). 
b. 
Follow-up Visits will be either in-clinic or performed remotely (e.g. at the participant’s home by qualified SP in-home 
services, and/or via video-conference or telephone contact from clinical site personnel).  
c. 
The EOS/EW Visit will be ideally an in-clinic visit (or remotely when permitted by the IRB/IEC) and will occur at the 
time of last study intervention intake. The EOS Visit must take place before the participant transitions to commercial 
treatment. 
d. 
For participants <18 years, assent and legal guardian’s consent will also be required. 
e. 
Palovarotene status (treated or not treated) and regimen (chronic or flare-up treatment) at the time of transition to Study 
CLIN-60120-452 will be collected at the Inclusion Visit. Participants will be supplied with chronic treatment as well 
as the appropriate dose of palovarotene to initiate flare-up treatment when a flare-up or traumatic event is confirmed 
by the investigator. Participants will be instructed to report potential flare-up symptoms to study site personnel, only 
one symptom is required to define a flare-up (see Section Error! Reference source not found. of the protocol). In 
the presence of persistent flare-up symptoms, treatment may be extended in 4-week intervals until the flare-up 
symptoms resolve. If the participant experiences an intercurrent flare-up, or substantial high-risk traumatic event likely 
to lead to a flare-up, at any time during the flare-up treatment, the 12-week flare-up treatment should be restarted. 
f. 
Participant interviews will be conducted in person or by telephone by the PI/qualified site staff and can be carried out 
anytime within 1 year (ideally within 1 month) following the Inclusion Visit. 
g. 
Participants will be assessed for child-bearing status and pregnancy prevention measures (females only). According to 
local practice, medically documented blood or urine pregnancy tests should be carried out prior to starting therapy, 
monthly as long as the participant receives palovarotene and one month after stopping (the results of pregnancy tests 
will be recorded in the eCRF). See Section 8.2.6 and 8.3.5 of the protocol for procedure in case of a positive pregnancy 
test during the study. 
h. 
For linear height, data from the parent EOS Visit will be used for the Study CLIN-60120-452 Inclusion Visit when 
available. Height at 6 to 12 months prior to the Inclusion Visit will be transferred from parent study database. 
i. 
Vital signs to be collected are respiratory rate, blood pressure and heart rate. 
j. 
The spinal health assessment must be performed at the Study CLIN-60120-452 Inclusion Visit ONLY if not already 
performed within the time window allowed (ie,, 3 months post-parent EOS Visit). The spinal health assessment will 
then be performed annually. The spinal health assessment should be performed using radiological imaging (e.g., CT, 
x-ray, scintigraphy, etc). This assessment may be performed locally. 
k. 
Includes spirometry and the DLCO test. Spirometry obtains the lung function parameters of observed and % predicted 
FVC and FEV1 and the absolute and predicted FEV1/FVC ratio. The DLCO test obtains observed and % predicted 
DLCO which provides information on the efficiency of gas transfer from alveolar air into the bloodstream. 
l. 
Includes extra bone growth assessment when associated with a flare-up 
m. 
During remote visit performed at home by the SP in-home services, the participant will be asked if any flare-ups 
occurred since last visit. If yes, the homecare clinician will attempt to facilitate a call between the participant and the 
site to provide details. 
n. 
In case of remote visit, the CAJIS and C-SSRS will be assessed via video-conference if possible or feasible or 
telephone contact from clinical site personnel. The homecare clinician will facilitate the call between the participant 
and Investigator.  
o. 
‘Baseline’ version of C-SSRS will be used at the Study CLIN-60120-452 Inclusion visit. ‘Since Last Visit’ version of 
C-SSRS will be used at Follow-Up Visits. 
p. 
In case of remote visit, the questionnaires will be provided by the SP in-home services and completed by the 
participants. 
q. 
Paper patient-reported questionnaires. Questionnaires completed at the parent EOS Visit will be used for the Study 
CLIN-60120-452 Inclusion Visit. The adult form (developed for participants ≥15 years old) of the FOP-PFQ and 
PROMIS Global Health Scale will be used for all participants. At in-clinic visits when multiple assessments are to be 
performed, the FOP-PFQ and the PROMIS Global Health Scale should be completed first, and in that order, before 
any other assessments are completed. Participants who completed the paediatric versions of the questionnaires at the 
EOS Visit of the parent study are required to complete the adult versions of the questionnaires at the CLIN-60120-452 
Inclusion Visit (flagged with ***). 
r. 
Any vaccinations received during the study (including COVID-19) should be recorded as concomitant procedures. 


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s. 
AEs first occurring during participation in the parent study and ongoing at the time of the Study CLIN-60120-452 
Inclusion Visit will be entered again in the Study CLIN-60120-452 eCRF. 
 


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2.6 
Change from Statistical Section of the Protocol 
As per section 9.4.1 of the protocol it stated that all analyses will be performed by parent study 
(PVO-1A-301 or PVO-1A-202/PVO-1A-204), by palovarotene status at the time of transition 
to Study CLIN-60120-452 (treated, not treated) and treatment regimen (chronic treatment only, 
flare-up treatment only, chronic & flare-up treatment) and overall.  
However, all analyses will only be performed overall and by treatment regimen (chronic 
treatment only, flare-up treatment only, chronic & flare-up treatment).  
3 
PLANNED ANALYSES 
3.1 
Data Monitoring  
Participant safety will be regularly monitored by an external Independent Data Monitoring 
Committee (IDMC), which includes safety signal detection at any time during the study. Three 
IDMC meetings are planned to take place over the maximum three-year duration of the study. 
Details related to IDMC membership, responsibilities, procedures and roles are described in the 
IDMC charter and the statistical analysis is described in the IDMC SAP.  
3.2 
Interim Analysis  
No formal interim analysis will be performed. A stand-alone final report for the qualitative 
participant interviews will be made available once enrolment and all interviews have been 
completed within 1 year following the Inclusion Visit. 
3.3 
Final Analysis 
The final analysis will be completed after database lock when all participants have completed 
the study.  
4 
ANALYSIS SETS 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Screened Set 
All participants who signed the ICF 
Enrolled Set 
The Enrolled Set will contain all participants who were assigned to receive 
palovarotene in Study CLIN-60120-452. Participants will be included 
based upon the “Is participant included in the study?” question within the 
eCRF.  
Full Analysis Set (FAS)/Safety 
Analysis Set (SAS) 
The FAS/SAS will contain all participants who received at least one dose 
of palovarotene during Study CLIN-60120-452.  
Per Protocol (PP) Set 
The PP set will contain all participants from the FAS who did not 
experience any major protocol deviations that may interfere with 
safety/efficacy evaluations. Please refer to section 5.3 for details regarding 
the management of deviations. 
 
5 
STATISTICAL METHODS/ANALYSES 
The statistical analyses will be performed in accordance with ICH E9 guidelines. 
5.1 
General Considerations 
No formal statistical testing will be performed. All the analyses will be primarily descriptive in 
nature. If p-values are presented, they will be for exploratory purposes only. Confidence 
intervals will be 95%, unless otherwise specified in the description of the analyses. 


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With the exception of the QoL questionnaires, where missing data will be handled based upon 
the calculation of the derived scores, missing data will not be replaced but will be displayed in 
all relevant tables. 
All analyses will be performed overall and by treatment regimen (chronic treatment only, flare-
up treatment only, chronic & flare-up treatment). 
All listings will be presented on the screened set. 
All statistical analyses will be performed using the Statistical Analysis System® software 
version 9.4. 
5.1.1 
Outputs Presentation 
5.1.1.1 
Tables Header 
All summary tables will be presented overall and by treatment regimen.  
5.1.1.2 
Presentation of Groups 
Tables, Figures and Listings (TFLs) will be displayed using the following group labels, in the 
order presented:  
Overall 
• 
Overall 
Overall includes all participants. 
Treatment Regimen  
• 
Chronic Treatment Only 
• 
Flare-up Treatment Only 
• 
Chronic and Flare-up Treatment 
• 
Not Treated (Only required on outputs not using FAS/SAS) 
The treatment regimen will be derived from the dosing form collected in CLIN-60120-452 
study. All dosing records will be used. Cases where the treatment regimen is not available from 
the CRF will be discussed with the IPSEN team on a case-by-case basis.  
5.1.1.3 
Presentation of Visits / Timepoints 
Summaries by visit will be presented using the derived window visits (See Section 6.1). Visits 
in the TFLs will be presented as follows and in the following order: 
Visit Name  
Baseline 
Month 6 
Month 12 
Month 18 
Month 24 
Month 30 
Month 36 
5.1.1.4 
Subgroups 
As per section 5.1.1.1 all summaries will be performed by treatment regimen (chronic treatment 
only, flare-up treatment only, chronic & flare-up treatment). 
5.1.2 
Descriptive Statistics 
All raw and derived variables will be listed and described using summary statistics.  
For descriptive analyses, summary statistics will be presented at each scheduled visit and will 
include sample size, number of available observations (n), number of missing observations 


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(missing), mean, 95% CIs of the mean/median, standard deviation (SD), median and range for 
continuous variables. For categorical or discrete variables, the absolute and relative 
(percentage) numbers based on the non-missing number of observations for each category will 
be presented, including 95% CIs. 
5.1.3 
Baseline value 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
on the day of first Investigational Medicinal Product (IMP) administration in study CLIN-
60120-452. This includes data collected at the Inclusion Visit and data transferred from the final 
parent study databases (either programmatically or entered by site). See the schedule of 
assessments in section 2.5 for the method of collection of data for the Inclusion Visit. 
5.1.4 
Reference Start Date and Study Day 
Reference start date is defined as the day of the first IMP administration of palovarotene (Day 
1) in Study CLIN-60120-452. Study day will be calculated as: 
- The difference between the event date and the reference date plus one day, if the event is on 
or after the reference date. 
- The difference between the event date and the reference date, if the date of event is prior to 
the reference date.  
Study day will appear in any listings where an assessment date or event date appears. 
In case of partial or missing event date, study day will appear missing while any associated 
durations will be presented based on the imputations described in appendix A3.  
5.2 
Disposition and Analysis Sets 
The following disposition summaries and listings will be provided: 
- 
Summary table with the number and percentages of enrolled participants per country, 
site on the screened set 
- 
Summary table with the number and percentage of participants screened, enrolled, 
treated, completed, withdrawn and reason for withdrawal on the screened set  
- 
Summary table with the number and percentage of participants per visit on the enrolled 
set  
- 
Summary table on duration of participant participation in the study on the enrolled set. 
The definition of the duration of participant participation is from date of consent to the 
last study visit or date of completion/discontinuation, whichever comes later. 
- 
Listing of dates of visit including duration of participant participation 
- 
Listing of withdrawal participants 
In addition, the below summaries and listings will be provided: 
- 
Summary of the number of participants within each treatment regimen subgroup 
- 
Summary of the number and percentages of participants included in each analysis set 
with reasons for exclusion from each analysis set 
- 
Listing including flag for each analysis set and reason for exclusion from each set 
5.3 
Protocol Deviations 
An exhaustive list of major/important protocol deviations that may occur during the course of 
the study and any action to be taken regarding exclusion of participants from the PP set is 
defined in Protocol Deviation Plan. Major protocol deviations will be determined and finalised 
during the data review for the final analysis and documented. 


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The following protocol deviation summary and listing will be provided on the enrolled set: 
- 
Number and percentage of participants with major protocol deviations by deviation 
category  
- 
A listing of major protocol deviations.  
- 
A listing of all protocol deviations  
5.4 
Demography and Other baseline characteristics 
All demographic and baseline characteristics summaries and listings will be provided for the 
FAS/SAS. The summary will be repeated on the PP set if ≥10% of participants are excluded 
from the FAS/SAS. [Note: Demographic variables of age and sex will be collected in Study 
CLIN-60120-452, all other variables will be transferred from the parent study database]   
Following descriptive summaries will be provided: 
- 
Demographic variables (age, age categories [<15, 15-25 & >25] and EudraCT age 
categories, sex, race, ethnicity, height (cm), weight (kg) and BMI (kg/m^2)). See 
appendix A6 for defined EudraCT age categories 
- 
Disease history (time since date of diagnosis by a physician (years), method of diagnosis 
and type of FOP genetic mutation) 
- 
Flare-up history over the past 12 months prior to the Inclusion Visit (number of flare-
ups, start and stop date of flare-ups, location of flare-ups, symptoms of flare-up, cause of 
flare-up and time since last flare-up (months)). 
- 
Extra bone growth history over the past 6 months prior to the Inclusion visit (number of 
extra bone growths, locations, preceded by and symptoms) 
- 
Bone maturity history, for participants aged <18 years at study inclusion, (bone age, 
difference between chronological age and bone age (months), hand/wrist and knee 
epiphyseal assessment and skeletally mature assessments) 
Time since date of diagnosis is defined as (Date of the first IMP administration of palovarotene 
in Study CLIN-60120-452 - date of diagnosis). 
Date of diagnosis is collected directly for study PVO-1A-301. For PVO-1A-202/PVO-1A-204, 
age at first confirmation of heterotopic ossification (years) will be considered equivalent to the 
age of diagnosis and as such in combination with the birth date used to derive the year of the 
equivalent date of diagnosis.  
[Note: 1 year = 365.25 days and 1 month = 30.4375 days]. 
Difference between chronological age and bone age is defined as (bone age – estimated age at 
time of bone maturity assessment [age captured at the inclusion visit will be used to calculate 
the year of birth, from which age at time of bone maturity assessment will be estimated by 
imputing the day and month as 30th June]. 
Listings will also be provided for all the summaries listed above.  
5.5 
Non-drug therapies, medications and surgical procedures 
Non-drug therapies and surgical procedures will be coded using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) in effect within IPSEN at the time of database 
lock. Medications will be coded using the latest version of World Health Organization-Drug 
dictionary at the time of database lock. [Note: Prior medications will not be collected in Study 
CLIN-60120-452 but transferred from the final parent study database] 


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Medication, non-drug therapies and surgical procedures start and stop dates will be compared 
to the date of the first IMP administration of palovarotene in Study CLIN-60120-452 to allow 
classification as either Prior only, Prior and Concomitant, or Concomitant only: 
 
Prior (P) 
Start and stop dates prior to the date of the first IMP 
administration of palovarotene in Study CLIN-60120-452. 
Prior and 
Concomitant (PC) 
Start date before the date of the first IMP administration and 
stop date on or after the date of the first IMP administration 
of palovarotene in Study CLIN-60120-452. 
Concomitant (C) 
Start date on or after the date of first IMP administration of 
palovarotene in Study CLIN-60120-452. 
 
Summary tables on prior medications/will include “P” only, summary tables on concomitant 
medications/non-drug therapies/surgical procedures will include “C” and “PC”. See detailed 
rules in appendix A3 for classification of prior and concomitant medication/non-drug therapies, 
surgical procedures in case of partial/missing date. 
Following summaries, presenting count and percentages of participants will be provided on the 
enrolled set: 
- 
Prior medications (P) by ATC class level 2 and Preferred Name, 
- 
Concomitant medications (PC, C) by ATC class level 2 and Preferred Name 
- 
Concomitant procedures (PC, C) by primary SOC and Preferred Term, 
Listings will be provided for all the summaries listed above. These listings should include a 
flag indicating the category (P, PC and C) as described in the table above.  
5.6 
Compliance 
Compliance is defined as (total actual doses taken/total expected doses taken) x 100.  
The total actual dose taken will be calculated as (total [capsules dispensed to the participant x 
respective dosage] – total [capsules returned x respective dosage]) by the participant across all 
medication kits dispensed. 
If the number of returned capsules is missing from any kit, the number of returned capsules for 
that kit will be imputed by multiplying the number of capsules dispensed by the mean 
compliance observed in the MOVE study. For chronic kits (or weight-adjusted/de-escalate 
equivalent) <=5mg, a compliance of 80% will be used estimate the number of capsules returned. 
For flare-up kits (or weight-adjusted/de-escalate equivalent) >5mg, a compliance of 87% will 
be used to estimate the number of capsules taken for that kit. These imputed values will then be 
used to determine the overall dose taken across the duration of the study.   
The total expected dose taken will be calculated by multiplying the duration of treatment in 
days for each treatment regimen, across all cycles of that regimen, (see derivation under section 
5.6.6) by the planned dose for each regimen and finally totalling the expected dose across all 
regimens.   
The expected duration of treatment is calculated as following for each treatment regimen: 
Total of expected regimen cycle dosing periods across all regimen cycles. Each expected 
regimen cycle dosing period is defined as (last regimen cycle dose date – first regimen cycle 
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Compliance will be summarised for the FAS/SAS set with descriptive statistics. Compliance in 
each category (<80%, ≥80% - ≤120%, >120%) will also be summarised for counts and 
percentages of participants. 
A listing of treatment compliance, including all derived parameters will be provided. 
5.7 
Primary and Secondary Analysis  
5.7.1 
General Considerations 
The FAS/SAS will be used for the analysis of the primary and secondary endpoints. Analyses 
of the secondary endpoints will be repeated on the Per Protocol (PP) Set if ≥10% of participants 
are excluded from the FAS/SAS Set. 
All analyses will be performed overall and by treatment regimen (chronic treatment only, flare-
up treatment only, chronic and flare-up treatment). 
5.7.1.1 
Significance Testing and Estimations 
The statistical analysis is only descriptive therefore no formal statistical significance testing 
will be performed. 
5.7.1.2 
Handling of Dropouts and missing data  
Diligent attempts will be made to limit the amount of missing data and to follow-up all enrolled 
participants to collect the primary and secondary efficacy endpoints for the statistical analysis. 
With the exception of the QoL questionnaires, where missing data will be handled based upon 
the calculation of the derived scores, missing data will not be replaced but will be displayed in 
all relevant tables. 
5.7.1.3 
Statistical/analytical issues  
Given all analysis is descriptive, adjustment for multiplicity is not applicable to this study. 
5.7.2 
Analysis of Primary Endpoint 
5.7.2.1 
Endpoints 
The primary endpoints of the study are: 
- 
Incidence and description of all treatment emergent adverse events (TEAEs) whether or 
not they are considered as related to the study intervention; 
- 
Incidence and description of all serious and nonserious treatment-related TEAEs; 
- 
Incidence and description of all serious TEAEs, whether or not they are considered as 
related to the study intervention; 
- 
Incidence and description of all nonserious TEAEs whether or not they are considered as 
related to the study intervention. 
5.7.2.2 
Primary Analysis – Adverse Events 
All adverse events (AEs) recorded in the eCRF will be coded using the latest version of 
MedDRA dictionary at the time of the database lock and will be classified by System Organ 
Class (SOC) and Preferred Term (PT). [Note: All ongoing AEs at the time of participant 
transition will be transferred from the parent study database]    
AEs will be classified as Treatment-Emergent AEs (TEAEs) according to the rules below: 
- 
Events with start date on or after the date of first IMP administration and up to 30 days 
after date of last dose of treatment of palovarotene in Study CLIN-60120-452 (or date of 
last contact if not available).  


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- 
Ongoing AEs from the parent study with a worsening in intensity or relationship (see 
relationship and intensity order below) to the study intervention following transition to 
Study CLIN-60120-452. New AEs during Study CLIN-60120-452 will be compared by 
SOC and PT to all previous study ongoing AEs for comparison of the intensity and 
relationship. 
Ongoing AEs from the parent study with no change in intensity or relationship to the study 
intervention following transition to Study CLIN-60120-452 will therefore be an AE (non-
TEAE). 
In the case where it is not possible to define an AE as treatment emergent or not, the AE will 
be classified by the most conservative case; i.e. treatment emergent.  
The below summaries will be provided: 
• 
An overview table summarising the: 
- 
number and percentage of participants with at least one of the following AEs: any 
AE; any TEAE; maximum intensity of TEAEs; causality of TEAEs, worst 
causality and intensity of TEAEs (worst case); TEAE leading to a dose change; 
TEAE leading to withdrawal; TEAE leading to death; Serious Adverse Events 
(SAEs); Serious TEAE; 
- 
corresponding number of events for each of the AE categories listed above 
• 
A summary of the number and percentage of participants reporting an AE by SOC and 
PT 
• 
A summary of the number and percentage of participants reporting a TEAE by SOC and 
PT 
• 
A summary of the number and percentage of participants reporting a TEAE by maximum 
intensity, SOC and PT 
• 
A summary of the number and percentage of participants reporting a TEAE by worst 
causality, SOC and PT 
• 
A summary of the number and percentage of participants reporting a related TEAE by 
SOC and PT 
• 
A summary of the number and percentage of participants reporting a TEAE by intensity, 
causality, SOC and PT 
• 
A summary of the number and percentage of participants reporting a non-Serious TEAE 
by SOC and PT 
• 
A summary of the number and percentage of participants reporting a non-Serious 
related TEAE by SOC and PT 
• 
A summary of the number and percentage of participants reporting a TEAE leading to 
treatment discontinuation by SOC and PT 
• 
A summary of the number and percentage of participants reporting a TEAE leading to 
dose change (increase or decrease) by SOC and PT 
The below summaries will also be provided by treatment dose at time of AE onset (5mg, 
10/20mg and all palovarotene): 
• 
Overall summary of Adverse events 
• 
A summary of the number and percentage of participants reporting a TEAE by SOC 
and PT 


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• 
A summary of the number and percentage of participants reporting a TEAE by 
maximum intensity, SOC and PT 
• 
A summary of the number and percentage of participants reporting a TEAE by worst 
causality, SOC and PT 
• 
A summary of the number and percentage of participants reporting a TEAE leading to 
treatment discontinuation by SOC and PT 
• 
A summary of the number and percentage of participants reporting a TEAE leading to 
dose change (increase or decrease) by SOC and PT 
To calculate the treatment regimen at time of AE onset, the start date of each AE will be merged 
with each participant dosing log. Given dosing end dates are not captured the latest dosing 
record prior to the AE start date will be identified. If the dosing record is either 0 mg or after 
treatment discontinuation the regimen will be set to “off treatment”.    
 
AEs will be counted as follows: 
• 
AEs summaries will be ordered in terms of decreasing frequency for SOC and PT within 
the overall column of each output. 
• 
Participants with more than one AE within a particular SOC are counted only once for 
that SOC. Similarly, participants with more than one AE within a particular PT are 
counted only once for that PT. 
• 
Participants reporting a TEAE more than once within that SOC/ PT, the TEAE with the 
worst-case intensity (intensity order: severe > missing > moderate > mild) will be used 
in the corresponding intensity summaries. 
• 
Participants reporting a TEAE more than once within that SOC/ PT, the TEAE with the 
worst-case causality to study medication (order: related > missing > not related) will be 
used in the corresponding relationship summaries; 
• 
If the intensity/relationship is missing for a TEAE, it will be considered as missing in the 
summary tables; Summaries by intensity/relationship will be presented (in the same order 
as above). 
• 
The non-serious TEAEs table should include a specific row “any non-serious TEAE 
above x%” 
A listing with all AEs data will be listed including non-TEAEs, Treatment-emergence status 
will be flagged in the listing. In addition listings for participants with a pregnancy or overdose 
will be presented (a table will be provided if more than 3 cases are observed in either category).    
Deaths and SAEs 
The below summaries will be provided:  
• 
A summary of the number and percentage of participants reporting a serious TEAE  
• 
A summary of the number and percentage of participants reporting a serious related 
TEAE 
• 
A summary of the number and percentage of participants reporting a TEAE leading to 
death 
• 
A summary of the number and percentage of participants reporting a serious TEAE by 
treatment dose at AE onset (5mg, 10/20mg and all palovarotene) 
The below listings will be also provided: 
• 
All SAEs 


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All TEAEs leading to treatment discontinuation 
• 
All Deaths 
5.7.3 
Analysis of Secondary Endpoints 
All secondary endpoints (including derived parameters) will be listed.   
5.7.3.1 
FOP Physical Function Questionnaire (FOP-PFQ)  
The FOP-PFQ is a disease-specific patient-reported outcome measure of physical impairment 
which includes questions related to ADL and physical performance. The adult form (developed 
for participants ≥15 years old) will be used for all participants. 
The adult FOP-PFQ consists of 28 questions which are scored on a scale of 1 to 5, with lower 
scores indicating that the participant has more difficulty completing those tasks. A total score, 
upper extremities subscore and a mobility subscore will be calculated.  
• 
The total score: the sum of the scores from each question which will range from 28 × 1 
= 28 to 28 × 5 = 140 
• 
Upper extremities subscore: the sum of the scores from 15 questions (Questions 1-12, 
14, 25 and 26) which will range from 15 × 1 = 15 to 15 × 5 = 75 
• 
Mobility subscore: the sum of the scores from 13 questions (Questions 13, 15-24, 27 and 
28) which will range from 13 × 1 = 13 to 13 × 5 = 65 
Missing scores for individual questions will not be imputed, but they will be taken into account 
according to the rules described below: 
(1) 
If more than 20% of the questions contributing to the total score, upper extremities 
subscore or mobility subscore are missing, the corresponding total score will not be 
calculated. It will be considered as missing 
(2) 
If less than 20% of the questions contributing to the total score, upper extremities 
subscore or mobility subscore are missing, the score will be calculated by summing all 
observed question scores, divided by the number of questions that were answered and by 
multiplying this average score by the total number of questions that were meant to be 
answered (i.e. × 28 for the total score). 
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. The table below illustrates some sample derivations of 
the percentage of worst scores for upper extremities: 
Sample 
Participant 
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%  
The percentage of worst scores (for total score, upper extremities subscore and mobility 
subscore) and changes from the inclusion visit of each subscore will be summarised at each 
scheduled visit with descriptive statistic on the FAS/SAS. 


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5.7.3.2 
PROMIS Global Health Scale 
The PROMIS Global Health Scale is a patient-reported outcome measure of physical and 
mental function. The adult form (developed for participants ≥15 years old) will be used for all 
participants. The PROMIS Global Health Scale consists of 10 questions from which two scores 
are calculated: the global physical health score and the global mental health score, both ranging 
from 4 (worse health) to 20 (better health) and are calculated as follows: 
• 
Global physical health score: the sum of scores from Questions 3, 6, 7 and 8 
• 
Global mental health score: the sum of scores from Questions 2, 4, 5 and 10 
In the calculation of the Global Physical Health and Global Mental Health scores, the following 
questions will be rescaled as shown in the table below: 
Questions 
Raw 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 
PROMIS=Patient Reported Outcomes Measurement Information System. 
If a participant is missing any of the contributing raw scores, the corresponding score (global 
physical health or global mental health score) will not be calculated for that participant. 
Global Physical Health scores and Global Mental Health scores will also be converted to T-
scores as described in detail in Section 7.1. T-score distributions are standardised such that a 
value of 50 represents the average (mean) for the general population and increments of ±10 
points represent ±1 SD away from the norm. Higher T-scores indicate better physical/mental 
health. A T-score <50 indicates worse health than the general population, while a T-score >50 
indicates better health. 
PROMIS Global Physical Health and Global Mental Health T-scores and changes from the 
inclusion visit will be summarised at each scheduled visit with descriptive statistics on the 
FAS/SAS. 
In additional the raw scores and changes from the inclusion visit for questions 1 and 9 will be 
summarised separately at each scheduled visit with descriptive statistics on the FAS/SAS. 
5.7.3.3 
Cumulative Analogue Joint Involvement Scale (CAJIS) 
Range of motion across the whole body will also be assessed using the CAJIS. This scale, 
assesses functional disability by categorising range of motion across 12 joints (both right and 
left shoulder, elbow, wrist, hip, knee and ankle joints) and three body regions (neck, 
thoracic/lumbar spine and jaw), with each joint/region assessed as: 0=normal (<10% deficit); 
1=partially impaired (10% to 90% deficit); 2=functionally ankylosed (>90% deficit). 
The CAJIS total score is calculated as the sum of the scores of all joints/regions and ranges 
from 0 (no involvement) to 30 (maximally involved). 
The CAJIS total score, each locations score and associated changes from the inclusion visit will 
be summarised at each scheduled visit with descriptive statistics on the FAS/SAS. 
Ambulation will be summarised at each scheduled visit with descriptive statistics for each 
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• 
Walks only 
• 
Walks/Wheelchair [defined as both “Walks” and “Wheelchair” marked]  
• 
Wheelchair only 
Use of assistive devices/adaptions will also be summarised at each scheduled visit with 
descriptive statistics for each category as below: 
• 
Independent [defined as neither “Needs some help” or “Needs complete help” are 
marked] 
• 
Needs some help 
• 
Needs complete help 
In addition a shift table of each category from the inclusion visit to each post-inclusion visit 
will be presented. 
5.7.3.4 
FOP Assistive Devices 
The use of assistive devices and adaptations for daily living will be collected using the FOP 
assistive devices assessment at each visit. 
The number of assistive devices in each category (mobility aids, eating tools, personal care 
tools, bathroom aids and devices, bedroom aids and devices, home adaptions, work 
environment adaptions, technology adaptions, sports and recreation adaptions, school adaptions 
and medical therapies for daily living) and the total number of assistive devices and adaptations 
for daily living being used will be summarised at each scheduled visit with descriptive statistics.  
In addition the change in the number of assistive devices of each category and the total number 
of assistive device and adaptations for daily living from the inclusion visit to each post-inclusion 
visit will be presented. 
5.7.3.5 
Healthcare Utilisation 
The use of health care services (yes/no) and their frequency in the past 6 months will be 
summarised at each scheduled visit with descriptive statistics. The below health services will 
be assessed: 
• 
General Practitioner 
• 
Homeopathic/Naturopathic provider 
• 
Podiatrist 
• 
Dentist – Orthodontist 
• 
Occupational therapist 
• 
Physiotherapist  
• 
Speech therapist 
• 
Ear, nose and throat doctor 
• 
Psychologist/psychiatrist/counsellor 
• 
Orthopaedic specialist 
• 
Gastroenterologist 
• 
Obstetrician-Gynecologist 
• 
Dermatologist 
• 
Pulmonologist  
• 
Pain specialist 
• 
Cardiologist  


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• 
Urologist 
• 
Rheumatologist 
• 
Neurologist 
• 
Wound care specialist 
In addition, the overall annualized rate for each healthcare service (and total healthcare services) 
will be summarised with descriptive statistics. The overall annualized rate will be calculated as 
(number of utilization during the study / duration of participant participation in the study in 
days) * 365.25. 
5.7.3.6 
Lung Function Parameters 
Lung function parameters (observed and % predicted FVC, observed and % predicted FEV1, 
absolute and predicted FEV1/FVC ratio and observed and % predicted DLCO) and changes 
from the inclusion visit will be presented for all scheduled visit with descriptive statistics. 
The DLCO value will be reported in either traditional units (mL/min/mmHg) or SI units 
(mmol/min/kPa). Values in SI units can be multiplied by 2.987 to obtain values in traditional 
units (Graham et al., 2017).  
5.7.3.7 
Flare-ups 
The number of flare-ups since the last visit (for post-inclusion visits) as well as the number of 
participants with investigator-reported flare-ups, number of intercurrent flare-ups, location of 
flare-ups, flare-up causes, flare-up symptoms, flare-up outcomes (restricted movement and 
bone formation) and flare-up duration will be presented for each scheduled visit by body 
location and overall with descriptive statistics. For the summary of flare-ups, percentages will 
be calculated using the number of participants with at least a flare-up at each visit as the 
denominator. The following body locations will be presented: 
• 
Shoulder (Includes left and right shoulder) 
• 
Elbow (Includes left and right shoulder) 
• 
Wrist or Hand (Includes left wrist or hand and right wrist or hand) 
• 
Hip (Includes left hip and right hip) 
• 
Knee (Includes left hips and right hip) 
• 
Ankle or Foot (Includes left ankle or foot and right ankle or foot) 
• 
Back (Includes upper back and lower back) 
• 
Chest 
• 
Abdomen 
• 
Head and Anterior neck 
• 
Jaw and Submandibular Area 
• 
Spine (Includes Cervical Spine, Thoracic Spine and Lumbar Spine) 
• 
Other (Includes all other locations) 
The number of flare-ups since the last visit will be calculated by totalling the number of distinct 
flare-ups (based upon the flare-up start dates, not including intercurrent flare-ups) using the 
visit windows as defined in section 6.1. 
Duration of flare-up will be defined as (date of end of flare-up – date of start of flare-up + 1) 
and will be calculated for each distinct flare-up before summing across each participant. 
An intercurrent flare-up is defined as a new flare-up or marked worsening of the original flare-
up at any time during a flare-up based treatment cycle.  


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In addition, the total number of flare-ups across the study, the duration of study participation, 
the individual flare-up rate per month and the global flare-up rate (including the 95% confidence 
interval derived using a poisson model offset by the duration of study participation) across all 
participants per month will be summarised.  
The individual flare-up rate per month will be defined as [(Number of flare-ups during study 
follow-up) / duration in the study (in months)]. This duration will be calculated as (end of study 
date – informed consent date +1) / 30.4375. 
The global flare-up rate will be calculated as the sum of flare-ups across all participants / sum 
of durations in the study(months).  
5.7.3.8 
Extra Bone Growth 
The percentage of participants with any extra bone growth (associated or not with a flare-up) 
since the previous visit will be presented for each visit with descriptive statistics. The number 
of extra bone growths since the previous visit will be calculated by totalling the number of 
distinct records (based upon the start date) within each of the visit windows as defined in section 
6.1.  
The location (and associated restricted movement if collected), the cause/proceed by, the 
number preceded by symptoms and the duration of bone growth will be presented in a listings 
The duration of the bone growth will be defined as (date of end of bone growth – date of start 
of bone growth + 1). 
5.7.4 
Analysis of Exploratory Endpoints 
No exploratory endpoints are defined for this study. 
5.8 
Safety 
5.8.1 
General Consideration 
All safety summaries and analyses will be based upon the FAS/SAS.  
All analyses will be performed overall and by treatment regimen (chronic treatment only, flare-
up treatment only, chronic and flare-up treatment). 
All safety data will be included in participant data listings (see listing detail conventions in 
Appendix A5).  
5.8.2 
Extent of exposure  
Duration of total treatment, duration of flare-up treatment, mean duration of flare-up treatment 
and duration of chronic treatment will be summarised for the FAS/SAS with descriptive 
statistics. In the eCRF Dosing Form, for each treatment period, only the start date if completed 
(no end date). So, for each period, the end date will be considered as the start date of the 
following period (periods have to be sorted by start date) – 1. For the last record, it will be the 
date of last dose if collected, or if not the date of last contact. The date of last contact will be 
the latest date available across all assessments. 
5.8.2.1 
Total Duration of Treatment 
Total duration of treatment is defined as (last dose date of IMP administration of palovarotene 
in Study CLIN-60120-452 - first dose date of IMP administration of palovarotene in Study 
CLIN-60120-452 + 1). The first dose date will be the start date of the first record in eCRF 
Dosing Form and the last dose date will be the date of last contact. 


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5.8.2.2 
Duration of Flare-up Treatment 
For participants 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. This includes any days for 
which the participant is receiving persistent flare-up symptom or intercurrent flare-up treatment.  
For a flare-up cycle, the flare-up cycle dosing period (days) is defined as days that participants 
received flare-up-based treatment and is calculated as (last dose date of the flare-up cycle – first 
date of the flare-up cycle – days where flare-up medications were not taken/interrupted during 
the flare-up cycle + 1). 
The mean duration of flare up treatment is defined as the total duration of flare-up treatment 
(across all cycles) divided by the number of flare-up treatment cycles for each individual.  
The duration of persistent flare-up symptom and intercurrent flare-up treatment will be 
calculated in a similar manner. 
5.8.2.3 
Duration of Chronic Treatment 
Based on the study design, participants are assumed to be on non-flare-up-based treatment from 
the date they received the first non-flare-up treatment unless they receive flare-up-based 
treatment. Thus, duration of non-flare-up treatment (days) will be calculated as (last non-flare-
up treatment date - first non-flare-up treatment date – duration of flare-up treatment (days) - 
days where non-flare-up medications were not taken/interrupted + 1). 
5.8.3 
Laboratory Data 
Amylase, lipase, AST, ALT and fasting triglyceride levels from the EOS of parent studies and 
centrally measured (or locally measured of the inclusion visit is >1 month than the end of the 
parent study visit) will be used at the Inclusion Visit for screening purposes only. [Note: 
Amylase, lipase, AST, ALT and fasting triglyceride levels at the EOS of parent studies will be 
transferred from the parent study database.]    
All laboratory data will be presented in the units of International System of Units (SI), 
summarised descriptively for the inclusion visit and listed.  
5.8.4 
C-SSRS 
A summary of the number and percentage of participants with any type of suicidal ideation or 
behaviour (yes/no) will be presented at each visit. The number of questionnaires completed and 
the CSSRS suicidal ideation score will be also presented at each visit. Suicidal ideation includes 
the categories: 
• 
Wish to be dead 
• 
Non-specific active suicidal thoughts 
• 
Active suicidal ideation with any methods (not plan) without intent to act 
• 
Active suicidal ideation with some intent to act, without specific plan 
• 
Active suicidal ideation with specific plan and intent 
Whereas suicidal behaviour includes: 
• 
Preparatory acts or behaviour 
• 
Aborted attempt 
• 
Interrupted attempt 
• 
Non-fatal suicide attempt 
• 
Completed suicide 


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In addition, a shift table from the inclusion visit to each post-inclusion visit of no suicidal 
ideation or behaviour, any suicidal ideation and any suicidal behaviour will be presented. 
Participants with both suicidal ideation and suicidal behaviour are included in the suicidal 
behaviour category.  
Similarly, a shift table of maximum suicidal ideation assessments from the inclusion visit to 
each post-inclusion visit will be presented. Maximum refers to the maximum C-SSRS suicidal 
ideation score during treatment (0 = least severe, 5 = most severe) where 0=No Suicidal 
Ideation, 1=Wish to be Dead, 2=Non-specific Active Suicidal Thoughts, 3=Active Suicidal 
Ideation with Any Methods (Not Plan) without Intent to Act, 4=Active Suicidal Ideation with 
Some Intent to Act, without Specific Plan, and 5=Active Suicidal Ideation with Specific Plan 
and Intent. 
All participants who report any type of suicidal ideations in the C-SSRS or any suicidal 
behaviour during the study will be presented in listings. 
5.8.5 
Linear Height and Body Weight 
Actual values and mean changes from baseline in height/linear height (cm) and body weight 
(kg) will be presented descriptively at each visit for the FAS/SAS. For participants under the 
age of 18 years, the mean of triplicate height measurements will be used. 
In addition, for participants aged <18 years at study inclusion, height velocity [cm/year] and 
linear height z-score actual values and changes from inclusion visit will be summarised 
descriptively at each visit for the FAS/SAS. 
The calculation of height velocity will be performed as follows: ((Current Height – Previous 
Height)/(duration (days)=(current date – previous date))) * 365.25 = Annualized height velocity 
(cm/year). In addition to providing the calculated height velocities per time period for each 
participant at each visit, the data will also be categorized according to the following three 
categories: <4 cm/year; 4 to 5 cm/year; and >5 cm/year.  
The linear height z-scores will be calculated using the reference population from the Centers 
for Disease Control and Prevention (CDC). See Appendix 7.2 for further details.  
A listing of all linear height and body weight parameters will be presented. 
5.8.6 
Vital Signs 
Vital signs include systolic blood pressure [mmHg], diastolic blood pressure [mmHg], heart 
rate [beats/min] and respiratory rate [breathes/min]. 
A summary of all vital sign variables (vital sign raw values and changes from inclusion visit) 
will be calculated for each visit for the FAS/SAS with descriptive statistics. 
Potentially clinically significant (PCS) values are predefined criteria/thresholds presented in 
Appendix A2. 
New-onset PCS values are defined as values that were not PCS at baseline and were PCS post-
baseline. New-onset PCS values post-baseline will be summarised with counts and percentages. 
In addition a shift table from inclusion visit to each post-inclusion visit will be presented by 
abnormality (low, normal, high) as defined by the below criteria: 
In addition a shift table from inclusion visit to each post-inclusion visit will be presented by 
abnormality (low, normal, high) as defined by the below criteria: 
 
Low 
Normal 
High 
Systolic blood 
pressure 
<86 mmHg 
86 – 180 mmHg 
>180 mmHg 


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Low 
Normal 
High 
Diastolic blood 
pressure 
<48 mmHg 
48 – 110 mmHg 
>110 mmHg 
Heart rate 
<45 bpm 
45 – 125 bpm 
>125 bpm 
mmHg = millimeters of mercury, bpm = beats per minute. 
A listing of all vital sign data and PCS values will be presented. 
5.8.7 
Physical Examination 
A summary of physical examination results (Normal, Abnormal non-clinically significant and 
abnormal clinically significant) will be provided by body system at the inclusion visit for the 
FAS/SAS with descriptive statistics.  
A listing of physical examination data will be provided. 
5.8.8 
Spinal Health Assessment 
A listing of Spinal health assessment data will be provided using the FAS/Safety Set. 
6 
DATA HANDLING 
6.1 
Visit window 
The below time windows for visit/timepoints will be used for analyses: 
 Analysis Visit 
Scheduled Day 
Visit Window 
Baseline 
Up to Day 1 
≤ Day 1 
Last non-missing 
measurement taken prior to 
first Investigational 
Medicinal Product (IMP) 
administration in study 
CLIN-60120-452 
Month 6 
182 
Day 2-274 
Month 12 
365 
Day 275-456 
Month 18 
547 
Day 457-639 
Month 24 
730 
Day 640-821 
Month 30 
912 
Day 822-1003 
Month 36 
1095 
≥Day 1004 
For post-baseline visit windows, the following applies when there are multiple assessments in 
a particular visit window, the closest to the scheduled day is chosen (if two assessments have 
the same distance, then the later one will be chosen). 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit  
All listings will include retests and unscheduled visits, while for the description by visit in the 
tables, only the scheduled visits according to the protocol will be described.  
Unscheduled visit and retest measurements will be used to provide a measurement for a baseline 
data or endpoint value (e.g. worst value), if appropriate according to their definition. These 
measurements will also be used to determine PCS vital signs values. 
If a value requires a retest (for vital signs) or there is an unscheduled visit the closest non-
missing reliable value to the scheduled visit will be used in the summary tables. 
7 
DERIVED DATA  
7.1 
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 


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that mean is 10 points. A high score always represents more of the concept being measured. 
Thus, a participant who has a T-score of 60 is one standard deviation better (healthier) than the 
general population. 
 
Global Physical Health 
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 
PROMIS=Patient Reported Outcomes Measurement Information System. 
7.2 
Linear Height Z-scores 
The linear height z-scores will be calculated using the reference population from the Centers 
for Disease Control and Prevention (CDC): 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. 
The Z-scores will be derived by following the below steps: 
(1) 
Download the reference file and SAS code from the above link 
(2) 
Create a temporary dataset that contains the height (cm), sex (1 for males and 2 for 
females) and age (months) of each participant. 
(3) 
The SAS code should be executed to generate the Z-score based upon the reference 
population.  
 
8 
REFERENCES 
1. 
https://www.healthmeasures.net/explore-measurement-systems/promis/obtain-
administer-measures 
2. 
Graham BL, Brusasco V, Burgos F et al. 2017 ERS/ATS standards for single-breath 
carbonmonoxide uptake in the lung. Eur Respir J 2017;49(1):1600016. 
 


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9 
APPENDICES 
 
A1. SAS code 
No predefined SAS code is required. 
 
A2. List of PCSA criteria 
 
PCSA for Vital Signs parameters: 
 
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. 


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A3. Partial/Missing Date Convention 
In all listings, missing or incomplete dates should be left as they have been recorded. However, 
for calculation / sorting / assignation based on dates, the following methods will be used: 
- 
The most conservative approach will be systematically considered (i.e. if the onset date 
of an AE/concomitant medication is missing / partial, it is assumed to have occurred 
during the study treatment phase (i.e. a TEAE for AEs) except if the partial onset date or 
the stop date indicates differently. 
- 
Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the first IMP administration 
performed on 31JAN2004, the days since last dose will be “≥2”, similarly the duration 
of ongoing AEs or medication will be “≥xx” according to the start and last visit dates). 
 
Algorithm for Prior/ Concomitant  
In case of partial start and/or stop medication/ non-drug therapies/surgical procedures dates, 
imputation will be done to determine the classification: 
- 
If a partial start date, the first day of the month will be imputed for missing day and 
January for missing month, 
- 
If a partial stop date, the last day of the month will be imputed for missing days and 
December will be imputed for missing month. 
In case incomplete start or stop date does not allow the classification, it will be classified as 
concomitant. 
 
Algorithm for TEAE 
The date imputation algorithm for incomplete adverse event start dates is described in the table 
below. Classification of adverse event according to its treatment-emergent status is then done 
using the imputed date. 
In the following table, all dates are presented using an YYYY-MM-DD format. As an example, 
suppose First IMP administration = 2002-08-11 and several AEs have incomplete start dates. 
 
Description of incomplete date 
Imputed numeric 
date 
Example 
Character date Imputed date 
Day is missing 
YYYY-MM < YYYY-MM of 
[First IMP admin.] 
YYYY-MM-01 
2002-07-XX 
2002-07-01 
YYYY-MM = YYYY-MM of 
[First IMP admin.] 
Min ([First IMP 
admin.], AE end 
date) 
2002-08-XX 
Min (2002-08-
11, AE end 
date) 
YYYY-MM > YYYY-MM of 
[First IMP admin.] 
YYYY-MM-01 
2002-09-XX 
2002-09-01 
Day and month are missing 
YYYY < YYYY OF [First IMP 
admin.] 
YYYY-01-01 
2001-XX-XX 
2001-01-01 
YYYY = YYYY OF [First IMP 
admin.] 
Min ([First IMP 
admin.], AE end 
date) 
2002-XX-XX 
Min (2002-08-
11, AE end 
date) 


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YYYY > YYYY OF [First IMP 
admin.] 
YYYY-01-01 
2003-XX-XX 
2003-01-01 
Day, month, and year are missing 
XXXX-XX-XX 
Min ([First IMP 
admin.], AE end 
date) 
 
Min (2002-08-
11, AE end 
date) 
YYYY = non-missing year, MM = non-missing month, DD = non-missing day, XX = missing 
field. 
 


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A4. Programming Convention for Outputs 
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
not done, unknown, <4.5, …) must be decimal justified. 
The mean, median, lower quartile, upper quartile, SD and standard errors (SE) of the 
mean/median 95% confidence interval values will be reported to one decimal place greater than 
the raw data recorded in the database.   
The minimum and maximum values will be reported with the same number of decimal places 
as the raw data recorded in the database. 
In general, the maximum number of decimal places reported should be four for any summary 
statistic. 
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentage will be calculated using n as denominator. The denominator n will be 
specified in a footnote for clarification if necessary. If sample sizes are small, the data displays 
will show the percentages, but in the CSR only frequency counts should be described.  
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as such.   
Dates will be presented in the format [ddmmmyyyy] and times in the format [hh:mm]. 
A5. Listings conventions 
All listings will contain at least the following data: participant identifier, age and gender. When 
dates are presented, the associated study days should be included. All listing will be sorted by 
treatment regimen and participant identifier.  


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A6. EudraCT categories for age 
For EudraCT results summaries, in addition to quantitative descriptive statistics of age, 
demographic tables should include presentation of age using the following EudraCT categories 
(as applicable): 
 
In utero 
Preterm newborn - gestational age < 37 weeks 
Newborns (0-27 days) 
Infants and toddlers (28 days-23 months) 
Children (2-11 years) 
Adolescents (12-17 years) 
Adults:18-64 years 
            65 - 84 years 
            85 years and over