A PHASE 2 MULTIPLE DOSE, RANDOMIZED STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF RECIFERCEPT IN CHILDREN WITH ACHONDROPLASIA
Phase: PHASE2
Conditions: Achondroplasia
Sponsor: Pfizer

Recifercept
Protocol C4181005
Final Protocol Amendment 3, 23 March 2022
PFIZER CONFIDENTIAL
Page 1
A PHASE 2 MULTIPLE DOSE, RANDOMIZED STUDY TO ASSESS THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF RECIFERCEPT IN 
CHILDREN WITH ACHONDROPLASIA
Study Intervention Number:
PF-07256472
Study Intervention Name:
Recifercept
US IND Number:
EudraCT Number:
2020-001189-13
Protocol Number:
C4181005
Phase:
2b
Short Title: Phase 2 study of safety, tolerability, PK and efficacy of recifercept in 
achondroplasia
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otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Protocol C4181005
Final Protocol Amendment 3, 23 March 2022
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 3
23 March 2022
The changes in this amendment were made due to 
eDMC recommendations, regulatory requests 
from different countries and addition of a PK 
cohort:
The following changes were made following 
recommendation from the eDMC. 
1.2 Schema
Update to expand recruitment of those aged 2-<6y in 
block C at the high dose (1.5 mg/kg daily) from a 
total of n=3 to n=8 (ie, move all 5 participants from 
block D). 
6.6.1 Rule for Progression to Next Enrollment 
Block
Update to a sentinel dosing approach for recruiting 
those aged 2-<6 years in block C such that n=2 at 
high dose will be dosed followed by a 2-week delay 
before further dosing occurs in that age group.
Rationale: To assess the safety and tolerability 
in all participants aged 2-6yrs old at the highest
dose, prior to dosing 3m-<2yrs old at the 
highest dose.
1.3 Schedule of Activities
Added footnote for blood chemistry that  participants 
are required to fast for >4 hours prior to blood 
sampling.
8.2.5 Clinical Safety Laboratory Assessments
Participants are required to fast for >4 hours prior to 
blood sampling.

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Protocol C4181005
Final Protocol Amendment 3, 23 March 2022
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Summary and Rationale for Changes
Rationale: To aid the interpretation of safety 
blood sample results, specifically Phosphate.
10.2 Appendix 2 – Clinical Laboratory Tests
In addition, the following changes were made due 
to regulatory agency request.
2.2.1 Clinical Overview
Updated clinical safety as of September 2021, to 
include number of participants per Block and AEs.
The following changes were made to add a PK 
assessment cohort. 
1.2 Schema
PK Schema added
Rationale: PK analysis following each dose 
will be conducted to evaluate the two 
formulations of recifercept. Single dose of 
3 mg/kg will be used for the PK study cohort.
1.3 Schedule of Activities
Updated to include PK Cohort SoA table.
4.1 Study Design
Updated to include a PK cohort that will include 
12 participants who will randomly receive 1 dose of 
Phase 2 (process 1c) followed by 1 dose of proposed 
Phase 3 (process 2) recifercept formulation or vice 
versa in a cross-over study, at select sites only. PK 
analysis following each dose will be conducted to 
evaluate the two formulations. Single dose of 
3 mg/kg will be used for the PK study cohort. Dose 
of the cohort could be changed due to emerging 
safety and efficacy data in the study.

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Protocol C4181005
Final Protocol Amendment 3, 23 March 2022
PFIZER CONFIDENTIAL
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4.3 Justification of Dose
Updated to include a PK cohort of 12 participants 
The tentative dose for the PK study cohort is 
3 mg/kg. The dose selected for the PK cohort could 
be changed after evaluating the entirety of the safety, 
PK and efficacy data collected in the program before 
initiating the cohort. The dose selected will not 
exceed the highest dose found to be safe and 
tolerated. 
8.0 Study Assessments and Procedures
Updated to include the PK cohort, as the total blood 
volume collected for individual participants is 
approximately 67 mL in this cohort.
8.5 Pharmacokinetics
Updated to include a PK cohort of 12 participants.
9.2 Sample Size Determination
Updated to include PK cohort sample size 
determination.
9.3 Analysis Sets
Updated to include PK cohort.
9.4 Statistical Analysis 
Update to include endpoints for PK cohort.
The following changes made were corrections of 
errors or minor clarifications to study 
procedures.
1.3 Schedule of Activities
Updated Study drug administration row: Removal of 
arrows from the M12 for the study drug 
administration and dosing diary completion, as the 
first dose will be recorded under the C4181008 
protocol.

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Protocol C4181005
Final Protocol Amendment 3, 23 March 2022
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Summary and Rationale for Changes
Updated Footnote n: Addition of Japan safety 
assessment requirements.
Additional updates:
2.0 Study Introduction
Added that vosoritide is currently the only approved 
treatment to increase linear growth in children with 
achondroplasia.
5.2 Exclusion Criteria 
Revised criteria from Severe <60 ml to ‘Moderate or 
Severe’ per alignment with FDA guidance on renal 
impairment.
Section 4.1 & 6.6 Dose modifications
Updated data review for progression from block C to 
D for once ≥3 months -2y participants (n=4) from 
(n=6).
Rationale: To allow the initiation of Block D 
from 4 participants instead of 6. No new safety 
signals were identified from the 2-11 yrs old 
participants except injection site reactions.
Section 4.1 & Section 9.5 Interim Analysis
Updated: Interim analyses may be performed to 
assess efficacy and safety after at least
approximately 45 participants (up to 15 per dose) for 
clarification.
Amendment 2
14 April 2021
The changes in this amendment were made due to 
eDMC recommendations and additional 
regulatory requests from different countries 
which cumulatively the sponsor classified as 
substantial:

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Protocol C4181005
Final Protocol Amendment 3, 23 March 2022
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Document History
Document
Version Date
Summary and Rationale for Changes
The following changes were made following 
recommendation from the eDMC. 
1.2 Schema
Block B enrollment of high dose participants was
reduced from n=8 to n=3 and enrollment using a 
sentinel approach.
In addition, Block B 2-6yrs old at low & medium 
doses was expanded from n=3 to n=8 per dose with 
enrollment also using a sentinel approach. 
4.1 Overall Design & 6.6 Dose Modification
Block B to Block C progression rules were revised 
in line with the sentinel approach from n=3 per dose 
to n=2 per dose. The number of high dose children 
included in the safety review will stay the same 
(n=3).
Appendix 2
Addition of Phosphate to chemistry panel and 
collection of time since last food intake.
In addition, the following changes was made due 
to regulatory agency request.
1.3 Schedule of Activities
Addition of Hematology & Chemistry Labs at 
Month 9.
2.2.1 Clinical Overview
Final data from study C4181002 added.
Summary safety & PK data from Block A added.

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5.2 Exclusion Criteria 
Criterion No. 6 CrCL GFR formula ‘bedside’ 
Schwartz was added.
6.2.1 Preparation & Dispensing
Clarification of what should be considered adequate 
training for caregivers for home drug administration 
was added.
6.4.1 Participant Compliance & Home 
Administration
Clarified instructions for caregivers regarding 
injection site reactions during home dosing is 
documented in the caregiver dosing diary. 
8.6 Genetics
Confirmation this section is not applicable in 
Denmark.
8.7.2 Banked Biospecimens for Genetics
Confirmation this section is not applicable in 
Denmark.
8.7.7. Banked Biospecimens for Biomarkers
Confirmation this section is not applicable in 
Denmark.
The following changes made were corrections of 
errors or minor clarifications to study 
procedures:
1.3 Schedule of Activities
Minor clarification in the SoA footnotes.
4.3 Justification of Dose
Figure 1 - Erroneously entered multiple times.

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Final Protocol Amendment 3, 23 March 2022
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Document History
Document
Version Date
Summary and Rationale for Changes
8.3.8 Adverse Events of Special Interest
The details of injection site reactions and overall 
grade have been deleted as they are not being 
collected in the eCRF.
8.7.2 Banked Biospecimens for Genetics
Clarification the sample is whole blood.
8.7.3 Blood Samples for Biomarker Analysis
Updated blood volume to collect plasma biomarker 
sample in addition to serum.
Other changes not listed here include general 
correction of errors such as formatting or minor 
typographical changes and updates to Appendix 
where required.
Amendment 1
09 November 
2020
The following changes were made due to 
regulatory requests from different countries 
which the sponsor classified as substantial:
1.3 Schedule of Activities
Additional ECG at close to Cmax (Day 4) and 
additional pharmacokinetic & immunogenicity 
sample at Month 9 were added.
Clarify that monitoring after first 5 doses be done by 
appropriately trained individuals with access to 
facilities necessary to manage hypersensitivity MRI 
at baseline was added and only applicable for those 
without scan in last 12 months.
4.1 Overall Design
Clarify age range to align with inclusion criteria.
4.2 Scientific Rationale for Study Design

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Document History
Document
Version Date
Summary and Rationale for Changes
Clarify language around baseline MRI.
5.1 Inclusion Criteria
 
5.2 Exclusion Criteria
Exclude those with evidence of significant renal or 
hepatic impairment, or with history of 
hypersensitivity to study intervention or excipients.
6.1.1 Administration
To clarify that only parent/caregiver/healthcare 
professional should administer the study medication.
6.6 Dose Modification
Clarify age of those in block A.
6.6.1 Rules for Progression to the Next Enrolment 
Block
There will be a planned eDMC review after block A 
prior to progressing to block B.
Change SUSAR to SAR
Clarify that the primary efficacy analysis will be 
done on treatment naïve participants enrolled to each 
cohort.
7.1 Discontinuation of Study Intervention
To clarify the role of the investigator in stopping 
study intervention as a result of adverse events or 
need for prohibited treatments.
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Final Protocol Amendment 3, 23 March 2022
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8.2.4 Electrocardiograms
Add D4 ECG.
8.3.1. Time Period and Frequency for Collecting 
AE and SAE Information
Confirm that investigator should enquire about both 
AEs and SAEs at follow-up visit.
9.4.2. Primary Endpoint(s)
Clarify the analysis to be performed as ANOVA not 
ANCOVA.
9.4.2 Primary & 9.4.3. Secondary Endpoint(s)
Clarify the analysis to be performed (removal of 
stratification).
9.6 Interim Analysis
Describe control of familywise error rate.
10.4.2 Female Participant Reproductive Inclusion 
Criteria
Confirm that WOCBP cannot enroll in the study 
since participants must be Tanner stage 1 at 
enrolment.
10.5 Liver Safety: Suggested Actions and Follow 
up Assessments Potential Cases of Drug Induced 
Liver Injury
Clarify that LFTs are measured in routine safety 
assessments.
The following changes made were corrections of 
errors or minor clarifications to study 
procedures:
1.1. Synopsis
Update synopsis to align with Section 9.1.1 of the 
main protocol due to typographical error.

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Final Protocol Amendment 3, 23 March 2022
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Document History
Document
Version Date
Summary and Rationale for Changes
5.2 Exclusion Criteria
Move exclusion criteria #5 to correct place.
6.3.2 Other Measures to Minimize Bias & 8.1.1 
Anthropometric measurements
To clarify that blinding to treatment should be 
maintained but that using the same measurer is more 
important in obtaining accurate data than 
maintaining blind.  
8.1.1 Anthropometric Measurements
Removal of reference to blinding manual from this 
section since this is a data blinding manual.
8.1.4.2. Quality of Life in Short Stature Youth 
(QoLISSY) Brief
To provide clearer instructions to the investigator on 
use of the different QoLISSY scale versions.
8.1.6 – Biological Samples 
Section removed as only applicable for vaccine 
studies.
10.8.1. Telehealth Visits
Incorrect section reference was corrected.
Other changes not listed here include general 
correction of errors such as formatting or minor 
typographical changes and updates to Appendix 
where required.
Original 
protocol
22 June 2020
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................17
LIST OF FIGURES .................................................................................................................17
1. PROTOCOL SUMMARY...................................................................................................18
1.1. Synopsis ..................................................................................................................18
1.2. Schema for Blocks A-D ..........................................................................................23
1.3. Schedule of Activities .............................................................................................24
2. INTRODUCTION ...............................................................................................................30
2.1. Study Rationale .......................................................................................................31
2.2. Background .............................................................................................................31
2.2.1. Clinical Overview.......................................................................................31
2.3. Benefit/Risk Assessment.........................................................................................32
2.3.1. Risk Assessment.........................................................................................33
2.3.2. Benefit Assessment.....................................................................................34
2.3.3. Overall Benefit/Risk Conclusion................................................................34
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................34
4. STUDY DESIGN.................................................................................................................36
4.1. Overall Design.........................................................................................................36
4.2. Scientific Rationale for Study Design.....................................................................37
4.2.1. Participant Input Into Design......................................................................38
4.3. Justification for Dose ..............................................................................................39
4.4. End of Study Definition ..........................................................................................41
5. STUDY POPULATION......................................................................................................41
5.1. Inclusion Criteria.....................................................................................................41
5.2. Exclusion Criteria....................................................................................................42
5.3. Lifestyle Considerations..........................................................................................43
5.3.1. Contraception..............................................................................................43
5.4. Screen Failures ........................................................................................................44
6. STUDY INTERVENTION..................................................................................................44
6.1. Study Intervention(s) Administered........................................................................44
6.1.1. Administration............................................................................................45

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6.2. Preparation/Handling/Storage/Accountability ........................................................45
6.2.1. Preparation and Dispensing........................................................................46
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................47
6.3.1. Allocation to Study Intervention ................................................................47
6.3.2. Other Measures to Minimize Bias..............................................................47
6.4. Study Intervention Compliance...............................................................................48
6.4.1. Participant Compliance and Home Administration....................................48
6.5. Concomitant Therapy..............................................................................................49
6.5.1. Prohibited During the Study.......................................................................49
6.5.2. Prohibited Prior Treatments........................................................................49
6.6. Dose Modification...................................................................................................49
6.6.1. Rules for Progression to Next Enrollment Block .......................................50
6.7. Intervention After the End of the Study..................................................................51
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................51
7.1. Discontinuation of Study Intervention ....................................................................51
7.2. Participant Discontinuation/Withdrawal From the Study.......................................52
7.2.1. Withdrawal of Consent...............................................................................53
7.3. Lost to Follow-up....................................................................................................53
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................53
8.1. Efficacy Assessments..............................................................................................55
8.1.1. Anthropometric Measurements ..................................................................55
8.1.2. Polysomnography/Sleep Study...................................................................56
8.1.3. MRI.............................................................................................................56
8.1.4. Patient-Reported (PRO)/Observer-Reported (ObsRO) Outcome 
Assessments.....................................................................................................57
8.1.4.1. Childhood Health Assessment Questionnaire (adapted for 
achondroplasia, [CHAQ])..................................................................58
8.1.4.2. Quality of Life in Short Stature Youth (QoLISSY) Brief.........58
8.1.4.3. Acceptability and Tolerability Questionnaire -
Achondroplasia..................................................................................58
8.1.4.4. EuroQol 5 Dimensions – Youth (EQ-5D-Y) and Youth 
Proxy Version 1 (EQ-5D-Y Proxy Version 1) ..................................59

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8.1.4.5. Patient Global Impression of Severity and Patient Global 
Impression of Change Anchor Items.................................................59
8.1.5. Tanner Staging............................................................................................60
8.2. Safety Assessments .................................................................................................60
8.2.1. Physical Examination .................................................................................60
8.2.2. Neurological Examination..........................................................................60
8.2.3. Vital Signs ..................................................................................................60
8.2.4. Electrocardiograms.....................................................................................61
8.2.5. Clinical Safety Laboratory Assessments ....................................................61
8.2.6. Pregnancy Testing ......................................................................................62
8.3. Adverse Events and Serious Adverse Events..........................................................62
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......62
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................63
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................63
8.3.2. Method of Detecting AEs and SAEs ..........................................................63
8.3.3. Follow--up of AEs and SAEs .....................................................................64
8.3.4. Regulatory Reporting Requirements for SAEs...........................................64
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................64
8.3.5.1. Exposure During Pregnancy......................................................64
8.3.5.2. Exposure During Breastfeeding ................................................66
8.3.5.3. Occupational Exposure .............................................................66
8.3.6. Cardiovascular and Death Events...............................................................67
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................67
8.3.8. Adverse Events of Special Interest.............................................................67
8.3.8.1. Lack of Efficacy........................................................................67
8.3.9. Medical Device Deficiencies......................................................................68
8.3.10. Medication Errors.....................................................................................68
8.4. Treatment of Overdose............................................................................................69
8.5. Pharmacokinetics ....................................................................................................69
8.6. Genetics...................................................................................................................70

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8.7. Biomarkers ..............................................................................................................70
8.7.1. Specified Genetics ......................................................................................70
8.7.2. Banked Biospecimens for Genetics............................................................70
8.7.3. Blood Samples for Biomarker Analysis .....................................................71
8.7.4. Specified Gene Expression (RNA) Research .............................................72
8.7.5. Specified Protein Research.........................................................................72
8.7.6. Specified Metabolomic Research ...............................................................72
8.7.7. Banked Biospecimens for Biomarkers .......................................................72
8.8. Immunogenicity Assessments.................................................................................72
8.9. Health Economics ...................................................................................................73
9. STATISTICAL CONSIDERATIONS ................................................................................73
9.1. Estimands and Statistical Hypotheses.....................................................................73
9.1.1. Estimands....................................................................................................73
9.2. Sample Size Determination.....................................................................................74
9.3. Analysis Sets ...........................................................................................................74
9.4. Statistical Analyses .................................................................................................75
9.4.1. General Considerations...............................................................................75
9.4.2. Primary Endpoint(s)....................................................................................75
9.4.3. Secondary Endpoint(s)................................................................................76
9.4.5. Other Safety Analyses ................................................................................77
9.4.6. Other Analyse(s).........................................................................................77
9.4.7. Pharmacokinetic Data.................................................................................77
9.5. Interim Analyses .....................................................................................................77
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............78
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................79
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............79
10.1.1. Regulatory and Ethical Considerations ....................................................79
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10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................79
10.1.2. Financial Disclosure .................................................................................80
10.1.3. Informed Consent Process........................................................................80
10.1.4. Data Protection .........................................................................................81
10.1.5. Dissemination of Clinical Study Data ......................................................82
10.1.6. Data Quality Assurance ............................................................................83
10.1.7. Source Documents....................................................................................84
10.1.8. Study and Site Start and Closure ..............................................................85
10.1.9. Publication Policy.....................................................................................85
10.1.10. Sponsor’s Qualified Medical Personnel .................................................86
10.2. Appendix 2: Clinical Laboratory Tests .................................................................87
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, -Follow-up, and Reporting.....................................................................88
10.3.1. Definition of AE .......................................................................................88
10.3.2. Definition of SAE.....................................................................................89
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................91
10.3.4. Reporting of SAEs....................................................................................94
10.4. Appendix 4: Contraceptive Guidance ...................................................................95
10.4.1. Male Participant Reproductive Inclusion Criteria....................................95
10.4.2. Female Participant Reproductive Inclusion Criteria.................................95
10.4.3. Woman of Childbearing Potential ............................................................95
10.4.4. Contraception Methods.............................................................................96
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........97
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ...................................99
10.7. Appendix 7: Genetics..........................................................................................100
10.8. Appendix 8: Alternative Measures During Public Emergencies ........................101
10.8.1. Telehealth Visits.....................................................................................101
10.8.2. Alternative Facilities for Safety Assessments ........................................101
10.8.2.1. Laboratory Testing ................................................................101
10.8.2.2. Electrocardiograms................................................................102
10.8.3. Study Intervention ..................................................................................102

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10.8.4. Home Health Visits.................................................................................102
10.8.5. Adverse Events and Serious Adverse Events.........................................103
10.8.6. Efficacy Assessments .............................................................................103
10.8.7. Independent Oversight Committees .......................................................103
10.9. Appendix 9: Abbreviations .................................................................................104
10.10. Appendix 10: Subcutaneous Dosing Instructions .............................................108
11. REFERENCES ................................................................................................................111
LIST OF TABLES
Table 1.
Treatment Sequence..................................................................................37
Table 2.
Monkey Exposure Margins Based on Steady State Serum 
Recifercept Concentrations Compared to the NOAELs...........................40
Table 3.
Protocol--Required Safety Laboratory Assessments................................87
LIST OF FIGURES
Figure 1.
Predicted Concentration vs Time Profile for a 20kg Child at Low, 
Medium and High Doses Using the PopPK Model from the 
C4181002 Phase 1 Study..........................................................................39
Figure 2.
Injection Site Rotation............................................................................109
Figure 3.
Technique for Holding Skin Prior to Injection.......................................109
Figure 4.
Injection Angle .......................................................................................110
Figure 5.
Technique for Injecting Study Intervention............................................110

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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: Phase 2 study of safety, tolerability, PK and efficacy of recifercept in 
achondroplasia
Rationale
The purpose of the study is to investigate the safety, tolerability, pharmacokinetics (PK) and 
efficacy of recifercept in children with achondroplasia.  Safety has been demonstrated in 
preclinical studies and in healthy adult volunteers in single and multiple ascending doses.
Recifercept is under development to address the unmet need in children with achondroplasia 
including the treatment of short stature and cranial, axial and appendicular skeletal 
complications.  Recifercept is a novel class of compound (decoy receptor) that has not been 
studied before in achondroplasia.
Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

Evaluate the safety and 
tolerability of recifercept doses 
and dosing regimes in 
participants aged ≥2 to 
<11 years with achondroplasia.
N/A.
Safety and tolerability of recifercept as 
assessed through frequency and severity 
of AEs/SAEs.

To assess efficacy of 
recifercept to increase height 
growth in children with 
achondroplasia.

The primary efficacy estimand is 
intended to provide a population 
level estimate of the effect of the 
IP on a continuous endpoint.
Population-level summary: ratio 
between participants in the trial 
and a reference population 
[Merker et al, 2018]30 in growth of 
height at 12 month; ratio between 
treated and reference population is 
observed change-from-baseline of 
treated participants standardized 
by reference participant given age 
and gender.

Increase in height growth above 
expected in reference population 
[Merker et al, 2018].30
Secondary: 
Secondary:
Secondary: 

To evaluate the 
pharmacokinetics (PK) of 
recifercept in children aged 
≥2 to <11 years old with 
achondroplasia.
Population PK characterization in 
children aged ≥2 to <11 years old with 
achondroplasia.  Clearance (CL/F) and 
other PK parameters of recifercept to 
assess exposures in different age group.

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Objectives
Estimands
Endpoints

To assess efficacy of 
recifercept to improve 
achondroplasia-related 
complications.

Sitting height/standing height ratio.

Arm span to height/length 
difference.

Knee height:lower segment ratio.

Occipito-frontal circumference.

Ratio of occipito-frontal distance to 
occipito-mid-face measurements.

z-score of the above proportionality 
and skull morphology where 
achondroplasia reference datasets 
exist (occipito-frontal 
circumference, arm span, sitting 
height).

Fixed flexion angles at elbow.

Polysomnography parameters in 
those with pre-existing sleep-
disordered breathing at the time of 
enrollment.

Body mass index (BMI).

Waist:chest circumference ratio.

Change from baseline in CHAQ 
(adapted for achondroplasia)
component and index scores, 
QoLISSY Brief total score.

Assess change in individual 
safety parameters.

Change from baseline in safety labs, 
vital signs, physical examination.

Rate of anti-drug antibodies.
 
 
 
 
 
PK Study Cohort:
Multiple changes have been made in the manufacturing process of the drug product 
(process 2) which will be used in Phase 3. These changes include, but are not limited to, host 
cell line change, manufacturing process optimization, scale up and manufacturing site 
changes. Therefore, an additional PK cohort (at selected sites only) has been added, to 
evaluate the PK of Phase 2 formulation (process 1c) and Phase 3 formulation (process 2).
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Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To evaluate the PK of single 
subcutaneous doses of 
2 formulations (process 1c and 
process 2) of recifercept in 
children aged ≥2 to <11 years 
old with achondroplasia.
N/A
PK endpoints after single dose 
recifercept: Cmax, Tmax, AUC168,
AUC360,  AUCinf and t½.
Secondary: 
Secondary:
Secondary: 

To assess the safety and 
tolerability of single SC doses 
of 2 formulations (process 1c 
and process 2) of recifercept in 
children aged ≥2 to <11 years 
old with achondroplasia.
Adverse event monitoring, 
injection/infusion site assessment.
Overall Design
The study is a phase 2, randomized, dose-finding study of safety, tolerability, 
pharmacokinetics, and efficacy.  Approximately 63 participants will be randomized to one of 
three doses (1mg/kg once weekly, 2 mg/kg twice-weekly, 1.5 mg/kg once-daily) for 
12 months.  Participants will be children diagnosed with achondroplasia aged ≥3 months to 
<11 years; enrollment will progress in an age and dose staggered manner (descending age 
and ascending dose).  Progression to the next enrollment block will be after review of safety 
and PK data, including review by an external data monitoring committee (eDMC) if safety 
signals are identified.  In order to minimize bias in measurement of the primary efficacy 
endpoint (height), the anthropometrist will be blinded to dose assignment. There will be no 
additional blinding.
An interim analysis will be performed when approximately 45 participants (up to
15 participants per dose) aged ≥2 to <11 years have received 6 months of treatment with 
recifercept.
All participants who complete the study and in the opinion of the investigator, continue to 
have a positive risk: benefit profile, will be offered to enroll into an open-label extension 
(OLE) study.  Participants will continue to receive recifercept at the dose previously received 
in this phase 2 study or at the therapeutic dose once this is identified.
PK Study Cohort: 
At selected sites only, an additional PK cohort has been added to evaluate the PK of two 
recifercept formulations (process 1c and process 2). A total of 12 children with 
achondroplasia aged 2- <11 years will be enrolled in the PK cohort (6 in each treatment 
sequence). Each participant will receive 2 treatments (3 mg/kg Phase 2 formulation 
[process 1c] and 3 mg/kg Phase 3 formulation [process 2]) in a randomized manner 
according to one of two sequences.

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Number of Participants
Approximately 54 participants aged 2-10 inclusive at the time of informed consent will be 
randomly assigned to study intervention enrolled such that approximately 45 evaluable 
participants complete the study. In addition, 9 participants aged ≥3 months - 2y at the time 
of informed consent will be enrolled in 
 cohort.
PK Study Cohort: 
A PK cohort will include 12 participants who will randomly receive a single dose of 3 mg/kg 
of Phase 2 study (process 1c) formulation and a single dose of 3 mg/kg of the proposed 
Phase 3 (process 2) study formulation in a cross over study. Dose of the cohort could be 
changed due to emerging safety and efficacy data in the study.
Note: “Enrolled” means a participant's legally authorized representative’s, agreement to 
participate in a clinical study following completion of the informed consent process.  
Potential participants who are screened for the purpose of determining eligibility for the 
study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Intervention Groups and Duration
63 participants will receive recifercept for 12 months and will be randomized to one of the 
following three doses of recifercept: 1 mg/kg once-weekly, 2 mg/kg twice-weekly or 
1.5 mg/kg once-daily.  All doses are given by subcutaneous injection.  There are no 
prospectively planned dose changes, however the dose may be changed based on review of 
safety and PK data. Dose will be adjusted according to weight every 3 months.
PK Study Cohort:
In PK study cohort only, participants will randomly receive a single dose of Phase 2
(process 1c) followed by a single dose of Phase 3 (process 2) recifercept formulation or vice 
versa in a cross over study. A single dose of 3 mg/kg will be used for the PK study cohort.
Dose of the cohort could be changed due to emerging safety and efficacy data in the study.
Data Monitoring Committee or Other Independent Oversight Committee: 
An external data monitoring committee will assess the safety and, where relevant, PK data on 
a regular basis and additionally, if certain pre-defined criteria are met, at enrollment block 
progression review.  A patient advocate will also be included on the eDMC if an 
appropriately qualified individual can be identified as agreed upon by the eDMC chairperson.
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Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
The primary efficacy estimand will be the population treatment effect of the mean 
change-from-baseline of a continuous response (ie, height growth) at month 12 irrespective 
of IP compliance. Increase in height growth above expected growth in reference population, 
a co-primary endpoint, is defined as the height growth in the achondroplasia reference 
population +50%. Intercurrent event for the efficacy estimand: withdrawal and all events 
leading missing data will be excluded from efficacy analysis and will not have their data 
imputed. The population-based treatment effect will be the mean change-from-baseline at 
month 12.
Sample size determination is based on the co-primary endpoint of height growth, defined as 
change from baseline of height at 12 months for participants on drug versus change from 
baseline of height at 12 months for a reference achondroplasia population. A total of 
18 participants each randomized to three doses in order to obtain 15 participants per dose, 
assuming a one-sided family-wise error rate of 0.05 with a Bonferroni correction (0.017 after 
Bonferroni adjustment for 3 comparisons), and inter-participant variability. of .15 (estimated 
from C4181001), there is over 90% power to detect at least one dose providing 50% height 
growth above reference. No statistical comparison will be made between recifercept doses. 
PK Study Cohort: 
No formal sample size calculation was performed and 12 participants were selected 
empirically to characterize PK, safety, and tolerability after single 3 mg/kg dose 
administration of two formulations. 

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1.2. Schema for Blocks A-D
Study schema for PK Study cohort
* Dose of the cohort could be changed due to emerging safety and efficacy data in the study.

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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the wellbeing of the participant. 
Abbreviations used in this table may be found in Appendix 9.
Screening
M1
M2
M3
M4a
M5a
M6
M7n
M8n
M9
M10n M11n M12
Early 
Termination/ 
Discontinua
tion
Follow-upb
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Days Relative to Day 1c
Day 
-14 to -1
D1 D4 D8 D15 D29 D61
D91
D121 D152 D183 D213 D243 D273 D303 D333 D365
D396
Visit Window (Days)
0
0
0
0
+1
±3
±5
±7
±7
±7
±7
±7
±7
±7
±7
14
±7
Informed consent/assent
X
Demographyd
X
Medical history
X
Physical examinatione
X
X X X
X
X
X
X
X
X
X
X
Neurological 
examination
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Vital signs
X
X X X
X
X
X
X
X
X
X
X
Laboratory
Hematology
X
X
X
X
X
X
X
X
X
X
Blood chemistryp
X
X
X
X
X
X
X
X
X
X
Pregnancy testf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception checkf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG 
X
X

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Screening
M1
M2
M3
M4a
M5a
M6
M7n
M8n
M9
M10n M11n M12
Early 
Termination/ 
Discontinua
tion
Follow-upb
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Days Relative to Day 1c
Day 
-14 to -1
D1 D4 D8 D15 D29 D61
D91
D121 D152 D183 D213 D243 D273 D303 D333 D365
D396
Visit Window (Days)
0
0
0
0
+1
±3
±5
±7
±7
±7
±7
±7
±7
±7
±7
14
±7
Study intervention
Randomizationc
X
Study Intervention 
Dispensing 
X
X
X
X
X
X
X
X
X
X
X
X
Study intervention 
administrationg













X
Dosing diary













X
Assessments
Anthropometry
X
X
X
X
X
X
Polysomnographyh
X
X
X
Tanner staging
X
X
X
X
X
X
Cranial MRIi
X
X
Clinical Outcome Assessments
CHAQ (adapted for 
achondroplasia)
X
X
X
X
X
X
QoLISSY Brief
X
X
X
X
X
X
Acceptability and 
Tolerability 
Questionnaire
X
X
X
X
X
X
X
X
X
X
X
EuroQol 5D
X
X
X
X
X
X
PGIS anchor items
X
X
X
X
X
X
PGIC anchor items
X
X
X
X
X
Additional blood sampling
PK samplingj
X X
X
X
Xk
Xl
X
X
X
X
Xo
Immunogenicity 
samplingj
X
X
X
X
X
X
X
X
X
Xo
Biomarker blood 
samplingj
X
X X
X
X
X
X
X
X
X

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Screening
M1
M2
M3
M4a
M5a
M6
M7n
M8n
M9
M10n M11n M12
Early 
Termination/ 
Discontinua
tion
Follow-upb
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Days Relative to Day 1c
Day 
-14 to -1
D1 D4 D8 D15 D29 D61
D91
D121 D152 D183 D213 D243 D273 D303 D333 D365
D396
Visit Window (Days)
0
0
0
0
+1
±3
±5
±7
±7
±7
±7
±7
±7
±7
±7
14
±7
Biobanked blood 
samplesm
X
X
X
Concomitant treatment(s)
X
















Serious and non-serious 
adverse event monitoring
X
















a.
M4 and M5: Telephone contact only, drug dispensing through IRT.
b.
Follow-up visit only applicable to those participants not continuing in the open label extension study. Follow-up contact may occur via telephone contact 
and must occur 28 to 35 days from administration of the final dose of study intervention.
c.
Day relative to start of study intervention (Day 1). If required, dose assignment may be allocated in the Interactive Response Technology (IRT) system prior 
to Day 1
d.
Data collected to reflect local regulatory requirements on date of birth, race and ethnicity.
e.
Examination of cardiovascular, respiratory, gastrointestinal systems and skin.
f.
Pregnancy testing is Only for WOCBP, urine pregnancy test with sensitivity of at least 25 mIU/ml acceptable. Contraception check is applicable to both 
WOCBP and sexually active male participants.
g.
Participants must have dosing performed at site with clinical observation for a minimum of 4 hours post-dose for first 5 doses (Once daily dosing; Days 1-5, 
Twice-weekly dosing; Days 1, 4, 8, 11, 15, Once-weekly dosing; Days 1, 8, 15, 22, 29). Staff administering the dose should be trained in management of 
acute hypersensitivity with access to appropriate facilities to treat such events. Following appropriate training, dosing will then be performed at home.  First 
dose at home to be observed by home nursing.  Dosing may be performed in the clinic at any time if investigator determines that home dosing is not feasible 
or appropriate.
h.
Sleep study to be performed only in participants with a documented diagnosis of sleep-disordered breathing prior to enrollment.  Baseline PSG data can be 
within 6 months prior to enrollment.  Final PSG to be ±1 months of M12 visit.
j.
Samples to be drawn pre-dose unless otherwise specified.
k.
Day 61 sample to be taken pre-dose and between 20 – 28 h post-dose for participants receiving once- or twice-weekly dosing (2 samples in total).  
Once-daily dosing participants will have only the pre-dose sample (1 sample in total).
l.
Day 91 sample to be taken pre-dose and between 40-56h post-dose for participants receiving once- or twice-weekly dosing (2 samples in total).  Once-daily 
dosing participants will have only the pre-dose sample (1 sample in total).
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m. Prep-D1.5 can be collected at any blood draw during the study, prep B1.5 to be collected at specified time points.
n.
M4 & M5 are telephone contact only and for dispensing medication using the Interactive Response Technology (IRT) system, except Japan safety 
assessment (at least but not limited to: AE/SAE, concomitant treatment) should be confirmed via physical site visit or telehealth before dispensing.  M7, M8, 
M10 & M11 are for dispensing medication using the IRT system.  No on-site visit is scheduled for M7, M8, M10 & M11, except Japan safety assessment (at 
least but not limited to: AE/SAE, concomitant treatment) should be confirmed via physical site visit or telehealth before dispensing.  Drug may be shipped to 
the participants home after dispensing. Site personnel can register the visits anywhere in the SoA window and schedule pick up and delivery. Site personnel 
should not register multiple visits at once, except under special circumstances, eg, the patient is traveling out of the country for a long duration.
o.
Participants attend site for PK/ADA sampling at follow up visit only if ADA positive at M12.
p.
Participants are required to fast for >4 hours prior to blood sampling.

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PK Study Cohort – Period 1
Screening
Visit Identifier
1
2
2
2
2
3
4
5
6
7
8
11
Days Relative to Day 1a
Day 
-14 to -1
D1
0h
D1
2h
D1
6h
D1
12h
D2
24h
D3
48h
D4
72h
D6
120h
D8
168h
D12
264h
D18
408h
Visit Window (Hours)
0
0
0
0
±2
±6
±6
±12
±12
±24
±48
Informed consent/assent
X
Demographyb
X
Medical history
X
Physical examinationc
X
X
X
Weight
X
Vital signs
X
X
X
Hematology
X
X
Blood chemistryd
X
X
Pregnancy teste
X
Contraception checke
X
X
12-Lead ECG 
X
X
Randomization
X
Study intervention administrationf
X
PK samplingg
Xg
Xh
Xh
Xh
X
X
X
X
X
X
X
Immunogenicity samplingg
Xg
Concomitant treatment(s)
X











Serious and non-serious adverse event 
monitoring
X











a.
Day relative to start of study intervention (Day 1). 
b.
Data collected to reflect local regulatory requirements on date of birth, race, and ethnicity.
c.
Examination of cardiovascular, respiratory, gastrointestinal systems, and skin.
d.
Participants are required to fast for >4 hours prior to blood sampling.
e.
Urine pregnancy test with sensitivity of at least 25 mIU/ml acceptable.  Contraception check is applicable to both WOCBP and sexually active male 
participants.
f.
Participants will receive 1 dose of the recifercept Phase 2 (process 1c) formulation on D1 and 1 dose of the proposed Phase 3 (process 2) recifercept 
formulation on Day 29 or vice versa.
g.
Samples to be drawn pre-dose unless otherwise specified.
h.
For PK collection window, see Section 8.5.

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PK Study Cohort – Period 2
Visit Identifier
12
12
12
12
13
14
15
16
17
18
19
20
Days Relative to Day 1a
D29
0h
D29
2h
D29
6h
D29
12h
D30
24h
D31
48h
D32
72h
D34
120h
D36
168h
D40
264h
D46
408h
D57/EOSb
672h
Visit Window (Hours)
0
0
0
±2
±6
±6
±12
±12
±24
±48
±24
Physical examinationc
X
X
X
Weight
X
Vital signs
X
X
X
Hematology
X
X
X
Blood chemistryd
X
X
X
Pregnancy teste
X
Contraception checke
X
X
X
Study intervention administrationf
X
PK samplingg
Xg
Xh
Xh
Xh
X
X
X
X
X
X
X
X
Immunogenicity samplingg
Xg
X
Concomitant treatment(s)












Serious and non-serious adverse 
event monitoring












a.
Day relative to start of study intervention (Day 29 for Period 2). 
b.
End of Study visit with option to enroll in the open label study C4181008.
c.
Data collected to reflect local regulatory requirements on date of birth, race and ethnicity.
d.
Participants are required to fast for >4 hours prior to blood sampling.
e.
Urine pregnancy test with sensitivity of at least 25 mIU/ml acceptable.  Contraception check is applicable to both WOCBP and sexually active male 
participants.
f.
Participants will receive 1 dose of the recifercept Phase 2 formulation (process 1c) on D1 and 1 dose of the proposed Phase 3 (process 2) recifercept 
formulation on Day 29 or vice versa.
g.
Samples to be drawn pre-dose unless otherwise specified.
h.
For PK collection window, see Section 8.5.

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2. INTRODUCTION
Achondroplasia is the commonest skeletal dysplasia in humans with a prevalence of around 
4 per 100,000 (Waller et al., 2008)2 and results from mutations in the gene for the FGFR3 
receptor.  Almost all cases of achondroplasia result from p.Gly380Arg mutations that are 
gain-of-function.  Whilst achondroplasia is inherited in an autosomal dominant fashion, 
approximately 80% of cases are due to de novo mutations.
Achondroplasia results in short stature and a range of severe complications due to abnormal 
ossification centres in the cranial base, facial bones, vertebrae, rib cage, and joints. There is 
shortening of the limbs, with the proximal segments disproportionately affected (rhizomelia), 
as well as large head with frontal bossing, midface hypoplasia, narrowed skull base foramina, 
spinal stenosis, kyphosis/lordosis, tibial bowing and respiratory tract complications. Short 
stature impacts quality of life, social functioning and self-esteem (Gollust et al., 2003).13
Significant morbidity and functional impairment arise from abnormal proportionality, tibial 
bowing, joint hypermobility, excessive lumbar lordosis, fixed hip contractures and flexion 
deformities of knees/elbows (Kopits, 1988; Kitoh et al., 2002; Ireland et al., 2011; Ireland, 
Donaghey, et al., 2012).17,18,4,19  There is associated neurodevelopment and psychosocial 
morbidity [Ireland et al, 2011;4 Wigg et al, 2016],5 with increased mortality throughout life 
that is most pronounced in early childhood [Hecht et al, 1987; Hecht et al, 1988; Horton et al, 
2007; Simmons et al, 2014; Hashmi et al, 2018].6-10
Thoracolumbar kyphosis is observed soon after birth and remains at least until the child is 
able to stand independently, when lumbar hyper-lordosis begins to develop.  Kyphosis may 
require bracing if severe/persistent and severe kyphosis associated with vertebral wedging at 
age 5 requires surgical intervention (Misra and Morgan, 2003; Ireland et al., 2014).24,12  
There is also associated overall developmental motor delay and inter-vertebral disc 
abnormality can be present even very early in life (Karikari et al., 2012).25
Vosoritide is currently the only approved treatment to increase linear growth in children with 
achondroplasia. Other available treatments are either aimed at limb lengthening with surgery 
or are interventions to treat the complications of achondroplasia. Limb length can be 
significantly increased (an average of 20 cm) by limb lengthening surgery, however, 
complications, including fractures, early consolidation, failed union, malalignment, joint 
stiffness, paralysis, equinus, and severe infections [Shirley and Ain, 2009; Aldegheri and 
Dall’Orca, 2001]27,26 occur in up to 70% of patients [Donaldson et al, 2015].28
Recifercept is a modified soluble recombinant human FGFR3 for the treatment of 
achondroplasia.  Recifercept is designed to be a decoy protein, competing for ligands of the 
FGFR3-G380R receptor responsible for achondroplasia and by forming inactive 
heterodimers with FGFR3 monomers.  By binding free FGFR3-activating ligands and 
forming inactive dimers, recifercept reduces activation of the receptor, allowing chondrocyte 
proliferation and differentiation to proceed.

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2.1. Study Rationale 
The purpose of the study is to investigate the safety, tolerability, pharmacokinetics (PK) and 
efficacy of recifercept in children with achondroplasia.  In addition, one PK study cohort of 
12 participants has been added in the study to evaluate the PK of single subcutaneous doses 
of 2 formulations (Phase 2 [process 1c] and proposed Phase 3 [process 2]) of recifercept
before initiating Phase 3 study. Safety has been demonstrated in preclinical studies and in
healthy adult volunteers in single and multiple ascending doses – more details can be found 
in the IB.
2.2. Background 
Recifercept is under development to address the unmet need in children with achondroplasia 
including the treatment of short stature and cranial, axial and appendicular skeletal
complications.  Recifercept is a novel class of compound (decoy receptor) that has not been 
studied before in achondroplasia.
In preclinical studies, recifercept was active in restoring growth to long bones and 
normalising cranial anatomy and skull morphology with maintenance and restauration of 
patency of synchondroses in the cranial base in Fgfr3ach/+ mice, as well as significantly 
reducing the complications that lead to mortality in these mice.  Based on these studies, the 
minimally effective SC dose in the mouse is approximately 3 mg/kg twice weekly, and the 
optimally effective dose is 10 mg/kg twice weekly.  These in vivo studies strongly support 
further development of recifercept as a treatment for achondroplasia.  Further details of the 
preclinical safety studies can be found in the IB.
2.2.1. Clinical Overview
As of September 2021, a total of 32 participants were enrolled from 2 to 10 years old. 
14 participants were randomized to 1 mg/kg once weekly (QW) arm and 15 participants were 
randomized to 2 mg/kg twice weekly (BIW) dosing arm and 3 participants were randomized 
to 1.5 mg/kg daily (QD). A total of 36 treatment related AEs were reported from 13 out of 
32 participants; 3 at low dose, 8 at medium dose and 2 at high dose. The most frequently 
reported AEs were ISRs such as redness/rash/erythema/pruritis at the injection site. All AEs 
were mild or moderate in severity and there were no serious adverse events. There were no 
other clinically significant laboratory abnormalities or physical examination/vital sign 
changes. Following, administration of study drug, observed serum recifercept concentrations 
at all three doses were in the range of the predicted exposures in 2 to <10 year old children 
with achondroplasia using the population PK (PopPK) model.
In the recifercept Phase 1 study (C4181002), healthy participants were administered single 
(n=30) and multiple (n=24) SC doses of recifercept. In addition, 18 participants received 
placebo in the study. The dose-range studied in single ascending dose (SAD) part of the 
study was 0.3 – 20 mg/kg and in the multiple ascending dose (MAD) part was 1 mg/kg and 
3 mg/kg twice weekly and 3 and 10 mg/kg once weekly for four weeks. Signs and symptoms 
of an injection site/infusion site reaction, including erythema, swelling, pain, inflammation, 
and pruritis, were the most frequently reported adverse events in the SAD and MAD part of 

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the study. There were no clinically significant changes in laboratory tests, vital signs or 
ECG. No systemic allergic reactions or serious adverse events occurred during the study.  
In the SAD portion of the study, all participants were ADA negative (ADA-) prior to 
treatment with recifercept. A confirmed ADA positive (ADA+) response was observed in 
8 participants receiving recifercept and 1 placebo participant at the end of the study (Day 29).
In the MAD portion of the study, 2 participants were ADA+ prior to treatment with 
recifercept. The majority of the participants who received multiple doses of recifercept were 
ADA+ (21/24) and 2 placebo participants during the observation period. 
Results from C4181002 suggest that the PK of recifercept after single SC administration is 
approximately dose proportional in the dose range 0.3-3 mg/kg and more than proportional in 
the range 3-20 mg/kg. Median time of maximum concentration (Tmax) increases with 
increasing dose. The mean terminal half-life (t1/2) ranged from about 47.8 hours to 
92.1 hours across a dose range from 1 to 20 mg/kg recifercept dose groups, respectively. 
In the MAD portion; following multiple SC dose of recifercept BIW at 1 mg/kg and 
3 mg/kg, median Tmax was 30.0 and 60.0 hours post dose, respectively, after administration 
on Day 1, and 12.0 and 18.0 hours post dose, respectively, after administration on Day 25. 
The mean t1/2 was 96.1 and 71.3 hours after administration of 1 mg/kg and 3 mg/kg, 
respectively, on Day 25. After both 1 mg/kg and 3 mg/kg BIW administration, mean trough 
concentrations on Day 11, Day 15 and beyond suggest that steady state was achieved after 
the third dose for both the doses. The geometric mean accumulation ratio (Rac) for TA-46 
was 4.90 for the 1 mg/kg treatment and 3.51 for the 3 mg/kg treatment.
Following multiple SC dose administration of recifercept once weekly at 3 mg/kg and
10 mg/kg, median Tmax was 72.0 and 36.04 hours post dose, respectively, after administration 
on Day 1, and 60.01 and 48.0 hours post dose, respectively, after administration on Day 22. 
The mean t1/2 was 93.5 and 97.4 hours after administration of 3 mg/kg and 10 mg/kg, 
respectively, on Day 22. After 3 mg/kg and 10 mg/kg QW administration, mean trough 
concentrations on Day 15 and Day 22 suggest that steady state was achieved after the third 
dose for both the doses. The Rac for TA-46 was 1.47 for the 3 mg/kg treatment and 1.16 for 
the 10 mg/kg treatment. More than proportional increase in exposures were observed 
between 3 mg/kg and 10 mg/kg QW dosing regimen on Day 1 and Day 22.
Further details of the phase 1 study can be found in the IB.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of recifercept may be found in the IB which is the SRSD for this study. 

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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) [Recifercept]
Risk of injection site reactions (ISR).
ISRs seen in the phase 1 study in healthy 
volunteers.
Monitoring of ISRs as AESI.
Hypersensitivity to study intervention.
Risk of hypersensitivity to early doses of study 
intervention.  No cases seen in phase 1 study.
At a minimum, the first 5 doses must be 
administered at site with post-dose monitoring.  
Caregivers will be trained to administer the study 
intervention during these dose administrations.
Study Procedures
Blood sampling.
Younger children may require multiple/large 
volumes of blood to be taken.
Limits on sampling volumes and prioritization of 
samples (see Section 8).
General anaesthetic administered to perform MRI 
scanning.
Children undergoing MRI scans may require a 
general anaesthetic to undertake scanning.
Allowing collection of data at baseline from a 
“standard of care” MRI scan to reduce the number 
of scans within the trial to a single scan at the end 
of the trial.
MRIs will only be performed at centres 
experienced in the procedure in young children.

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2.3.2. Benefit Assessment
Potential benefits of participating in the trial include:

Potential benefit of recifercept on growth and associated complications of 
achondroplasia;

Contribution to the development of medicines for the treatment of achondroplasia and 
its complications.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with recifercept are justified by the 
anticipated benefits that may be afforded to participants with achondroplasia.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

Evaluate the safety and 
tolerability of recifercept doses 
and dosing regimes in 
participants aged ≥2 to 
<11 years with achondroplasia.
N/A.
Safety and tolerability of recifercept
as assessed through frequency and 
severity of AEs/SAEs.

To assess efficacy of 
recifercept to increase height 
growth in children with 
achondroplasia.

The primary efficacy estimand is 
intended to provide a population level 
estimate of the effect of the IP on a 
continuous endpoint.
Population-level summary: ratio 
between participants in the trial and a 
reference population [Merker et al, 
2018]30 in growth of height at 
12 month; ratio between treated and 
reference population is observed 
change-from-baseline of treated 
participants standardized by reference 
participant given age and gender.

Increase in height growth 
above expected in reference 
population [Merker et al, 
2018].30
Secondary: 
Secondary:
Secondary: 

To evaluate the 
pharmacokinetics (PK) of 
recifercept in children aged ≥2 
to <11 years old with 
achondroplasia.
Population PK characterization in 
children aged ≥2 to <11 years old 
with achondroplasia. Clearance 
(CL/F) and other PK parameters of 
recifercept to assess exposures in 
different age group.

To assess efficacy of 
recifercept to improve 
achondroplasia-related 
complications.

Sitting height/standing height 
ratio.

Arm span to height/length 
difference.

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Objectives
Estimands
Endpoints

Knee height:lower segment 
ratio.

Occipito-frontal circumference.

Ratio of occipito-frontal 
distance to occipito-mid-face 
measurements.

z-score of the above 
proportionality and skull 
morphology where 
achondroplasia reference 
datasets exist (occipito-frontal 
circumference, arm span, 
sitting height).

Fixed flexion angles at elbow.

Polysomnography parameters 
in those with pre-existing 
sleep-disordered breathing at 
the time of enrollment.

Body mass index (BMI).

Waist:chest circumference 
ratio.

Change from baseline in 
CHAQ (adapted for 
achondroplasia) component 
and index scores, QoLISSY 
Brief total score.

Assess change in individual 
safety parameters.

Change from baseline in safety 
labs, vital signs, physical 
examination.

Rate of anti-drug antibodies.
 
 
 
 
 
 
 
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PK Study Cohort
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To evaluate the PK of single 
subcutaneous doses of 
2 formulations (process 1c and 
process 2) of recifercept in 
children aged ≥2 to <11 years 
old with achondroplasia.
N/A
PK endpoints after single dose 
recifercept: Cmax, Tmax, AUC168,
AUC360,  AUCinf and t½.
Secondary: 
Secondary:
Secondary: 

To assess the safety and 
tolerability of single SC doses 
of 2 formulations (process 1c 
and process 2) of recifercept in 
children aged ≥2 to <11 years 
old with achondroplasia.
Adverse event monitoring, 
injection/infusion site assessment.
4. STUDY DESIGN
4.1. Overall Design
This is a phase 2 randomized, 3 arm (3 active doses of Recifercept), parallel group
dose- finding study of safety, tolerability, PK and efficacy.
The study will enroll approximately 54 children with achondroplasia aged 2-10 years 
(inclusive) who will be enrolled and randomized to receive one of three doses of recifercept 
(1 mg/kg once-weekly, 2 mg/kg twice-weekly or 1.5 mg/kg once-daily, n=18 per dose) such 
that approximately 45 paticpants are evaluable (up to 15 participants per dose).  Additionally, 
 cohort of approximately 9 children with achondroplasia, ages 3 months to 
2 years, will be enrolled later in the study (n=3 per dose).  All 63 participants in this part of 
the study will receive recifercept for 12 months.
PK Study Cohort:
At selected sites only, an additional PK cohort has been added to evaluate the PK of two 
recifercept formulations. A total of 12 children with achondroplasia aged 2- <11 years will 
be enrolled in the PK cohort (6 in each treatment sequence). Each participant will receive 
2 treatments (3 mg/kg Phase 2 formulation [process 1c] and 3 mg/kg Phase 3 formulation
[process 2]) in a randomized manner according to one of two sequences as outlined in 
Table 1 below. Dose of the cohort could be changed due to emerging safety and efficacy 
data in the study.
PK samples collected following each dose will be analyzed to evaluate the exposures of two 
formulations. 
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Table 1.
Treatment Sequence
Sequence
Period 1
Period 2
1 (n = 6)
Phase 2 study (process 1c)
Formulation 
Phase 3 study (process 2)
Formulation
2 (n = 6)
Phase 3 study (process 2)
Formulation
Phase 2 study (process 1c)
Formulation
All participants who complete the study and in the opinion of the investigator, continue to 
have a positive risk: benefit profile, will be offered to enroll into an open-label extension 
(OLE) study.  Participants will continue to receive recifercept at the dose previously received 
in this phase 2 study or at the therapeutic dose once this is identified.
Enrollment will follow an age and dose-staggered approach (descending age and ascending 
dose) with review of safety and PK data by the study team before progression to the next 
enrollment block (see Section 1.2).  If certain pre-defined safety signals occur (see 
Section 6.6.1) then a meeting of the eDMC will be convened to make a decision on 
progression of enrollment. The PK data collected in block A will be used in the PopPK 
model (developed using healthy adult data) to confirm the dosing for younger children 
(ie, ≥2 to <6 years and ≥3 months to <2 years).
An interim analysis is planned when approximately 45 participants (up to 15 participants) per 
dose aged ≥2 to <11 years have received 6 months of treatment with recifercept.  eDMC will 
review safety, PK and efficacy data to confirm ongoing positive benefit:risk in participants.
Progression to the next enrollment block will be controlled by study team review of safety 
and PK data in the following manner:
Block A to B
Review after all block A participants (n=6, all aged 6-10y) have 
completed D29
Block B to C
Review once 2-6y participants (n=4) and 3 high dose 6-10y participants 
have completed D29
Block C to D
Review once all ≥3m-2y participants (n=4) and 3 high dose 2-6y 
participants have completed D29
4.2. Scientific Rationale for Study Design
Achondroplasia is a disease of abnormal endochondral ossification at growth plates, therefore 
the ability to affect this process only exists whilst these growth plates are open.  Fusion of 
growth plates varies across anatomical sites occurring very early in life for some cranial and 
spinal ossification centres (Dimeglio and Canavese, 2012, Calandrelli et al., 2017),40,41 but 
persisting until adolescence in the long bones (Hoover-Fong, Del Pino, Merker).11,16,30  

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Treatment with recifercept is only of potential benefit to those with open growth plates, thus 
this trial will only include children that are still growing in height.  The effect of pubertal 
growth spurt is not clear in achondroplasia, therefore this phase 2 study will only enroll those 
aged ≥3months to <11y and Tanner stage 1.
Enrollment will progress in an age- and dose-staggered fashion to confirm the safety profile
of recifercept before increasing exposure or progressing to younger participants.  This 
approach also allows confirmation of the predicted exposures using PopPK modelling in 
older (heavier) participants before progression to younger (lighter) participants.
Human reproductive safety data are not available for recifercept, but there is no suspicion of 
human teratogenicity based on the intended pharmacology of the compound. Therefore, the 
use of a highly effective method of contraception is required (see Appendix 4).  Given the 
age of the participants in the study, abstinence is the only acceptable form on contraception.
Banked Biospecimens will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
 
  Complications at the craniocervical 
junction are amongst the most serious complications seen in achondroplasia and are 
particularly prevalent in those under 2 years.  MRI scanning in very young children with 
achondroplasia is being widely adopted and standard of care [Kubota et al, Clin Pediatr 
Endocrinol. 2020; 29(1): 25–42.].45 In order to minimize risk from general anaesthetic, data 
can be collected at baseline from a prior “standard of care” MRI scan and an additional scan 
taken at the end of this study.
PK Study Cohort:
Multiple changes have been made in the manufacturing process of the drug product 
(process 2) which will be used in Phase 3. These changes include, but are not limited to, host 
cell line change, manufacturing process optimization, scale up and manufacturing site 
changes. Therefore, an additional PK cohort (at selected sites only) has been added, to 
evaluate the PK of Phase 2 formulation (process 1c) and Phase 3 formulation (process 2).
Serum & Plasma biomarker samples will be taken during the study as indicated in the SoA.  
Further details can be found in Section 8.7.
4.2.1. Participant Input Into Design
Patient advocacy groups and patient experts assisted with review of the protocol, including 
attending the final medical advisory board meeting on phase 2 design.
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4.3. Justification for Dose
PK data from the FIH study is discussed in Section 2.2.1.  The proposed doses for this study 
are 1 mg/kg once-weekly, 2 mg/kg twice-weekly and 1.5 mg/kg once-daily in achondroplasia 
participants aged ≥2 to <11 years old. The 3 doses and dosing regimen selected in this study 
are widest feasible dose range with minimal exposure overlap (Figure 1) to evaluate 
dose/exposure response relationship for clinically relevant efficacy, biomarker and safety 
event in children with achondroplasia.
Figure 1.
Predicted Concentration vs Time Profile for a 20kg Child at Low, Medium 
and High Doses Using the PopPK Model from the C4181002 Phase 1 Study
Based upon the proposed mechanism, it is presumed that efficacy of recifercept will be 
related to the degree of ligand trapping and the prevention of native FGFR3 receptor 
dimerization. Recifercept has demonstrated efficacy in restoring normal growth in a mouse 
model of achondroplasia. However, the relationship between exposure and 
biomarker/efficacy cannot be established in adults (due to closed growth plates) and, 
therefore, high uncertainty remains around target exposure in children with achondroplasia
which could be efficacious.  
Exposure ratios at the NOAEL in monkey ranged from ~8.5-20 fold higher than that 
predicted by the PopPK modelling of steady-state recifercept concentrations (AUC0-168) at 
1.5 mg/kg once daily dosing (10.5 mg/kg weekly dose) in children with achondroplasia age 
6–10 year old (Table 2).  This along with the safety data from the FIH study provides an 
acceptable safety and tolerability profile to study the proposed three doses in children with 
achondroplasia.

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Table 2.
Monkey Exposure Margins Based on Steady State Serum Recifercept 
Concentrations Compared to the NOAELs
Study
Dose (mg/kg)
AUC 
(µg·h/mL)
Exposure 
Margins at 
NOAEL
Monkey 4-week GLP 
toxicity 
100
12600
-
Monkey 26-week GLP 
toxicity 
100
5350
-
C4181002 phase 1 study
10
1118.5
4.8 – 11.3
Population PK model
1.5 once-daily
(10.5 total weekly)
629.9
8.5 - 20
PopPK modelling was developed using the data from C4181002 single and multiple 
ascending dose cohorts. For prediction of recifercept exposures in the pediatric patient 
population it was assumed that the PK parameters scale with body weight with the theoretical 
allometric exponents (Figure 1).  For this age group no maturation effects on PK were 
assumed since recifercept is a protein therapeutic.  The theoretical values of allometric 
exponents (0.75 for clearance and 1.0 for volume of distribution) are considered to have 
physiological basis and often provide adequate explanation for body weight relationships in 
paediatric patients thus exposures were likely to decrease for lower bodyweights, this
increases the exposure margins and supports the proposed phase 2 design.  The PopPK model 
will be updated in the step-wise cohort enrollment approach.  However, even if exposures lie 
at the upper limits of the prediction model, exposure remains within safe margins.  
The PK and safety data from the phase 1 study, as described in the IB and above, support 
once-weekly, twice-weekly and daily dosing.
PK will be assessed on an ongoing basis using sparse sampling approach to inform and 
update the PopPK model. The PopPK model could be used to predict exposure in the 
younger children and before progression to the next enrollment block (≥2 to <6 years and 
≥3 months to <2 years).  Dose may be amended based on this PK assessment.
PK Study Cohort: 
The tentative dose for the PK study cohort is 3 mg/kg. The dose selected for the PK cohort 
could be changed after evaluating the entirety of the safety, PK, and efficacy data collected in 
the program before initiating the cohort. The dose selected will not exceed the highest dose 
found to be safe and tolerated. Weight limits for this study (Section 5.2) are based on 
technical feasibility of dosing with the current study intervention formulation such that 
injection volumes will be between 0.2 ml and 1 ml. 

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4.4. End of Study Definition
A participant is considered to have completed the study if they have completed all phases of 
the study, including the last visit or the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the trial globally.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and non-medical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex
1. Main cohort: Aged ≥2 years to <11 years (up to the day before 11th birthday 
inclusive) at time of enrollment;
 
 
Type of Participant and Disease Characteristics
2. Documented, confirmed genetic diagnosis of achondroplasia from historical medical 
records prior to entry into this trial (test must have been performed at a laboratory 
fully accredited for genetic testing under local regulations).
3. Completed the C4181001 natural history study with at least 2 valid height/length
measurements (at least 3 months apart) prior to enrollment in this study. One of these 
measurement timepoints must be within the 3 months prior to enrollment in 
C4181005.
4. Tanner stage 1 based on investigator assessment during physical examination (must 
include assessment of breast development for females, testicular stage for males).
5. Able to stand independently for height measurements (if ≥2 years of age at 
enrollment).
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6. If aged <2 years at enrollment, has a documented historical MRI brain/cervical spine 
performed in the previous 12 months.
Informed Consent:
7. Capable of giving signed informed consent/assent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
8. Following receipt of oral and written information about the trial, the child (depending 
on local institutional review board/independent ethics committee requirements) must 
provide assent, and one or both (according to local regulations) parents or guardians 
of the child must provide signed informed consent before any trial-related activity is 
carried out.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Presence of co-morbid conditions or circumstances that, in the opinion of the 
investigator, would affect interpretation of growth data or ability to complete the trial 
procedures.
2. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
3. Presence of severe obesity (BMI >95th percentile on Hoover-Fong BMI charts) 
[Hoover-Fong et al, 2008].14
4. Known closure of long bone growth plates (cessation of height growth).
5. Body weight <7 kg or >30 kg.
6. Moderate or severe renal impairment CrCL GFR <60 mL/min/1.73m2 (Calculated 
GFR based on updated “bedside” Schwartz formula for pediatric patients 
(CrCL (mL/min/1.73 m2) = 0.413 * Height (cms)/ Serum cr (mg/dL) or hepatic 
impairment (AST/ALT >1.5 ULN).
7. History of hypersensitivity to study intervention or any excipients.
Prior/Concomitant Therapy:
8. History of any prior treatment with human growth hormone or related products 
(including insulin-like growth factor 1 [IGF-1]).

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9. History of receipt of any treatment that are known to potentially affect growth 
(including oral steroids >5 days in the last 6 months, high dose inhaled corticosteroids 
(>800 mcg/day beclametasone equivalent) and medication for attention deficit 
hyperactivity disorder).
10. History of limb lengthening surgery (defined as distraction 
osteogenesis/Ilizarov/callostasis technique following submetaphyseal osteotomy to 
extend bone length).
11. Any limb lengthening/corrective orthopaedic surgery planned at any point during the 
trial period.
12. Less than 6 months since fracture or surgical procedure of any bone determined from 
the screening visit date.
13. Presence of any internal guided growth plates/devices.
14. History of removal of internal guided growth plates/devices within less than 
6 months.
15. History of receipt of any investigational product for achondroplasia or that may affect 
growth/interpretation of growth parameters.
16. History of receipt of an investigational product (not for achondroplasia/growth 
affecting) within the last 30 days or 5 half-lives (whichever is longer).
Other Exclusions
17. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 
5.3. Lifestyle Considerations
5.3.1. Contraception
Should a participant become a WOCBP (defined as reaching menarche) during the course of 
the study then the investigator or his or her designee, in consultation with the participant and 
their guardian, will confirm that the participant has been informed of the potential risks of 
pregnancy whilst receiving study intervention and advised of the need for continuing total 
abstinence from sexual activity. At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use continue total abstinence from sexual 
activity and document the conversation and the participants affirmation in the participants'
chart. This also applies to males should they become sexually active.  In addition, the 
investigator or designee will instruct the participant or guardian to call immediately if total 
abstinence from sexual activity is discontinued or if pregnancy is known or suspected in the 
participant or partner.

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5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to recifercept (PF-07256472) 
provided as lyophilized powder for solution for injection/infusion, 50 mg/vial.
Further details for the sections below can be found in the Investigational Product Manual (IP 
Manual) and/or dosing diary.
6.1. Study Intervention(s) Administered
Intervention Name
PF07256472 (Recifercept).
ARM Name
(group of patients receiving 
a specific treatment (or no 
treatment)
Refer to the study schema provided in the STUDY DESIGN section.
Type
Biologic.
Dose Formulation
Lyophilized powder for solution for injection.
Unit Dose Strength(s)
50 mg/vial.
Dosage Level(s)
Refer to the study schema provided in the STUDY DESIGN section.
Route of Administration
Subcutaneous injection.
Use
Experimental.
IMP or NIMP
IMP.
Sourcing
Provided centrally by the sponsor.
Refer to the IP Manual for further information.
Packaging and Labeling
Study intervention will be provided in vials.  Each vial will be 
labeled as required per country requirement.  The IP will be 
provided as open label, as the only personnel required to be blinded 
are anthropometrists.
Vials are single-use only.
Current/Former Name(s) or 
Alias(es)
TA-46.

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6.1.1. Administration
Administer study intervention according to the Subcutaneous Dosing Instructions (see 
Appendix 10).  Study intervention should not be self-administered by the participant.  
6.2. Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions 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 
authorized site staff may supply study intervention.  Authorized site staff and 
caregivers, who have demonstrated their proficiency, may prepare and administer 
study intervention.

All study interventions stored at the clinical site must be stored in a secure, 
environmentally controlled, and monitored (manual or automated recording) area in 
accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff.  At a minimum, daily minimum and maximum temperatures 
for all site storage locations must be documented and available upon request. Data 
for nonworking days must indicate the minimum and maximum temperatures since 
previously documented for all site storage locations upon return to business.

Site staff will instruct caregivers on the proper storage requirements for take home 
study intervention.

All study interventions stored at participants’ homes must be stored according to the 
labeled storage conditions.

Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.

The site should actively pursue options for returning the study intervention to the 
storage conditions described in the labeling, as soon as possible.  Once an 
excursion is identified, the study intervention must be quarantined and not used 
until Pfizer provides permission to use the study intervention.  Specific details 
regarding the definition of an excursion and information the site should report for 
each excursion will be provided to the site in the IP Manual.

Pfizer cannot analyze the acceptability of any excursion that occurs once the study 
intervention leaves the clinical site.  If an excursion occurs at the participants’
homes, the caregivers must quarantine the study intervention until it can be 
returned to the clinical site for accountability.  Further instructions are provided in 
the dosing diary.

Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.

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
Study interventions should be stored in their original containers.

See the IP manual for storage conditions of the study intervention once reconstituted.

Details of the transport to and storage of study intervention at the participants’ homes
can be found in the dosing diary.

Used and unused vials stored at the participants’ homes must be returned to site.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent and dosing diary. All study interventions will 
be accounted for using a study intervention accountability form/record.

Further guidance and information for the final disposition of unused study 
interventions are provided in the IP Manual. All destruction must be adequately 
documented.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery, as described in the IP Manual.
6.2.1. Preparation and Dispensing
Study intervention should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, pharmacy assistant/technician, or pharmacist) as allowed by local, state, and 
institutional guidance.  Site staff will reference the IP Manual for instructions on how to 
prepare the study intervention for administration.  A second staff member will verify the 
preparation of the dose. All persons who are responsible for dose preparation and dispensing 
of IP must be listed on the Delegation of Authority log.
Caregivers will reference the Dosing Instructions Diary for instructions on how to prepare 
and administer the study intervention at home, following demonstration of their proficiency 
at the site.
Adequate caregiver competency for home-dosing may include, but not be limited to the
following criterion: 

Caregivers demonstrate adequate adherence to storage & preparation routine 
including sterile technique.

Caregivers understand which sites can be used for injection and the need to rotate 
these sites.

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
Caregivers demonstrate correct techniques to reconstitute & draw up solution into 
syringe for administration.

Caregivers demonstrate correct injection technique including preparation of skin prior 
to injection.

Caregivers show knowledge of adequate disposal of used medication supplies and 
completion of dosing diary.
The caregiver should be instructed to maintain the study intervention in the vials and cartons 
provided, throughout the course of dosing, and return the vials, in the cartons provided, to the 
site at the next study visit.
6.3. Measures to Minimize Bias: Randomization and Blinding
In order to minimize bias in measurement of the primary efficacy endpoint (height), the 
anthropometrist will be blinded to dose assignment. There will be no additional blinding.
6.3.1. Allocation to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system.  
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including, but not limited, to the user’s ID and password, the protocol number 
and the participant number.  The site personnel will then be provided with a treatment 
assignment, randomization number and Dispensable Unit (DU) or container number when 
study intervention is being supplied via the IRT system.  The IRT system will provide a 
confirmation report containing the participant number, randomization number and DU or 
container number assigned.  The confirmation report must be stored in the site’s files. 
This is a partially blinded study with open-label supplies.  Potential bias will be reduced by 
the following: central randomization, and an otherwise uninvolved third party will be 
responsible for conducting assessments related to primary efficacy endpoint and 
anthropometric secondary endpoints. Study intervention will be dispensed at the study visits 
summarized in the SoA. 
The study -specific IRT reference manual and IP Manual will provide the contact 
information and further details on the use of the IRT system.
6.3.2. Other Measures to Minimize Bias
Anthropometric data will only be collected by appropriately trained individuals at the trial 
site and in accordance with the anthropometric measurement manual.  All sites will follow a 
consistent, structured and documented training program.  This will occur prior to trial start, 
through regular refresher training and at targeted retraining based on analysis of 
measurement data consistency at the site.  Training and assessment of competency will be 
performed by dedicated anthropometric training staff contracted by the sponsor.

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Sites will be required to make all efforts to have the same anthropometrist at each visit for 
each participant (longitudinal consistency) and between participants (cross-sectional 
consistency).  As well as following the specific procedures for measurement laid out in the 
measurement manual, sites will be provided with the same (or exactly equivalent) equipment 
across all sites and will follow the specific calibration procedures.  The anthropometrist 
should remain blinded to dose assignment.
If the anthropometrist becomes unintentionally unblinded then they should continue to act as 
the anthropometrist for that participant since a change in anthropometrist is known to be a 
significant source of variability in measurement data.  If any measures are taken following 
unblinding of the anthropometrists, this will be recorded in the eCRF.  All blinded & 
unblinded measurements collected will be analysed, with further details available in the SAP.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator, a designee (under medical supervision) or from the caregiver under supervision 
of site staff.  The date, time, injection site and volume of each dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF.  The same data will be 
collected in the dosing diary when administered at home.  The dose of study intervention and 
study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study intervention. 
The site will complete the required dosage Preparation Record located in the IP Manual.  The 
use of the Preparation Record is preferred, but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after 
approval from the sponsor and/or designee.
When participants are dosed at home, compliance will be monitored by completion of a 
dosing diary by the caregiver which will record date, time, injection site and volume of dose 
administration.  This diary will be reviewed by the site staff.  Where home nursing have 
supported home dosing then this will be recorded.
If poor compliance is identified by site staff then additional training and support will be 
provided to the caregivers.
6.4.1. Participant Compliance and Home Administration
Caregivers will be permitted to administer recifercept once they have demonstrated an 
understanding of the preparation and administration process at the site. Confirmation of a 
caregiver’s ability to perform preparation and administration must be documented in the site 
file.  For administration of recifercept at home, compliance and any injection site reactions 
will be captured and completed by the caregiver by completing the dosing diary. Caregivers 
should contact the site immediately in the event of any potential injection site reactions.

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Caregivers will administer treatment from the point of which they have demonstrated the 
capability to do so (as stated above) until the end of dosing. Prior to administration at home, 
sites must ensure caregivers are trained on IP administration and storage per the dosing diary. 
Dosing between planned clinic visits may be administered by investigational site staff until 
the respective caregiver has been properly trained in administration. Sites should follow -up 
(eg, via phone call) to ensure compliance with administration instructions, where necessary.
Clinic administration of study intervention can be readministered at any time where home 
dosing is deemed not feasible or inappropriate.  Caregivers will be supported to reinstitute 
home dosing where appropriate.
6.5. Concomitant Therapy
6.5.1. Prohibited During the Study
Participants may not receive any medication or procedure that may affect the growth of the 
long bones.  This includes human growth hormone (or related medicines such as IGF-1) and 
surgical/interventional procedures such as limb lengthening.
Participants cannot undergo surgical procedures of the bone during the course of the trial.  
This includes limb lengthening, guided growth (eg, 8 plates), tibial osteotomies, spinal 
surgery, neurosurgical procedures or ear, nose, and throat (ENT) bone procedures.
6.5.2. Prohibited Prior Treatments
Participants who have received prior human growth hormone or related products will not be 
eligible to participate.
Any participant that has previously received an investigational medicinal product for the 
treatment of achondroplasia is not eligible to participate.
Past receipt of any investigational medicinal product that could affect growth may not 
participate.
Receipt of any other investigational medicinal product (not covered above) in the last 30 days 
or 5 half-lives (whichever is longer) is prohibited.
Participants may not have previously undergone any limb-lengthening surgery.
6.6. Dose Modification
The decision to proceed to the next enrollment block of recifercept will be made by the study 
team based on safety, tolerability, and preliminary PK data obtained in at least 3 participants
at each new dose and age bracket. The PK data from Block A participants aged ≥6 to 
<11 years will be integrated into the PopPK model developed using healthy adult PK data, to 
then confirm the dosing recommendations in younger age sub-cohorts (≥2 to <6 years and 
≥3 months to <2 years). It is anticipated that the relationship between body weight and PK 
will be well characterized at this stage and no further dosing adjustment may be required for 
the youngest age group (≥3 months to <2 years). However, to minimize the uncertainty in 

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children aged ≥3 months to <2 years, PK data collected in the ≥2 to <6 -years cohort will be 
used to evaluate consistency with the predicted dose-concentration relationship. This review 
will be performed at the following times:
Block A to B
Review after all block A participants (n=6, all aged 6-10y) have 
completed D29
Block B to C
Review once 2-6y participants (n=4) and 3 high dose 6-10y participants 
have completed D29
Block C to D
Review once all ≥3 months -2y participants (n=4) and 3 high dose 
2-6y participants have completed D29
6.6.1. Rules for Progression to Next Enrollment Block
The eDMC will meet after block A participants have received 4 weeks of study intervention 
(completed D29) to review safety and PK data.  They will make recommendations on dose 
levels and progression to block B.  
Progression to blocks C and D, will occur without eDMC review if NONE of the following 
criteria are met:

Serious Adverse Reaction (IMP-related SAR);

≥2 participants affected by the same moderate/severe study intervention-related AE;

≥2 participants affected by an AE of hypersensitivity to study intervention;

≥2 participants with severe ISRs;

≥2 participants with ISR leading to withdrawal of study intervention.
If any of these criteria are met then the eDMC must be convened to make a decision on 
progression to the next enrollment block.  In addition, no further participants will be enrolled 
at that dose (or higher) until eDMC recommendation has been issued.  
A sentinel approach will be used in recruiting those aged 2-<6 years in block C such that 
n=2 at high dose will be dosed followed by a 2-week delay before further dosing occurs in 
that age group.
The dosing schedule may also be adjusted by the eDMC to expand a dosing cohort to further 
evaluate safety and/or PK findings at a given dose level or to amend the doses to be studied 
in each enrollment block.  The study procedures for these additional participant(s)/cohort(s) 
will be the same as that described for other study participants/cohorts.

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In addition, following evaluation of the overall benefit:risk assessment at the interim 
analysis, the dose levels may be adjusted.  If a new dose level is introduced then this will 
form a new cohort (minimum n=15) of treatment naïve participants. Previously treated 
subjects at a discontinued dose will be moved to the next lowest continuing dose.  
Any dose modifications will not exceed the current maximum dose (1.5mg/kg once-daily)
without submission and approval of a protocol amendment.  
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study, however 
participants will be offered to roll over into an open-label extension study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following:

Non-compliance with study intervention;

Pregnancy;

Withdrawal of consent by parent/guardian;

Investigator decision to withdraw;

Death.
The decision to withdraw the participant from the study ultimately lies with the investigator.
For example occurrence of any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal.  Additionally if a subject experiences 
a serious or intolerable AE that prevents them from continuing with study participation such 
as severe injection site reaction or hypersensitivity, this would be expected to lead to 
withdrawal.  
Study intervention will be discontinued if the investigator considers that it is in the 
participants best interest to initiate any of the prohibited treatments described in 
Section 6.5.1.  
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.

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ECG Changes
ECG will be collected at baseline and at Day 4, then only repeated if, in the opinion of the 
investigator, they are clinically indicated.  If a clinically significant finding is identified 
(including, but not limited to, changes from baseline in QTcF after enrollment), the 
investigator or qualified designee will determine if the participant can continue in the study 
and if any change in participant management is needed. This review of the ECG printed at 
the time of collection must be documented. Any new clinically relevant finding should be 
reported as an AE.  Further details of potentially significant ECG changes can be found in
Appendix 6.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor.
At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted. See the SoA for assessments to be collected at the time of early termination and 
follow-up and for any further evaluations that need to be completed. 
The early termination visit applies only to participants who are enrolled/randomized and then 
are prematurely withdrawn from the study.  Participants and/or their parent/guardian should
be questioned regarding their reason for withdrawal.  
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.

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7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled 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 for a required 
study visit or refuses attendance of the home nurse:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not 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, 3 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. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any -study specific procedures including assent as per local 
regulations.
The date of birth will be collected to critically evaluate the effect on growth by age.  At a 
minimum the recorded date of birth must include the participant’s month and year of birth.

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Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or within 
24 hours following awareness to determine whether 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.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol -specified criteria and were performed 
within the time frame defined in the SoA.
Every effort should be made to ensure that protocol -required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test specified in this protocol.  In these cases, the investigator must take all steps 
necessary to ensure the safety and well-being of the participant.  When a protocol -required 
test cannot be performed, the investigator will document the reason for the missed test and 
any corrective and preventive actions that he or she has taken to ensure that required 
processes are adhered to as soon as possible.  The study team must be informed of these 
incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
130 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer.  For the PK cohort, 
the total blood sampling value for individual participants is approximately 67 mL.
Sampling volumes will not exceed 1% of total blood volume in any single blood draw or 
3% blood volume within a 28 day period. [Ethical considerations for clinical trials on 
medicinal products conducted with minors. Recommendations of the expert group on 
clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on 
medicinal products for human use. Revision 1. 18 September 2017.].

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If sampling will exceed these limits then the samples should be prioritized as follows:
1. Clinical Safety Laboratory Samples.
2. PK.
3. Immunogenicity.
4. Biomarker samples.
5. Biobanked samples.
Further details, such as minimum volumes required for each type of sample, can be found in 
the laboratory manual.
8.1. Efficacy Assessments
8.1.1. Anthropometric Measurements
Anthropometric measurements for height and proportionality will be performed and reported 
in the eCRF. Anthropometric measurements will be performed according to a trial-specific 
Anthropometric Measurement Manual, which will be provided to the investigational sites. 
This manual will contain a detailed description on the following:
1. Which measurements to perform.
2. The tools/instruments to be used.
3. Standard procedure for performing these measurements.
The measurements to be taken on a 3-monthly basis are:

Standing height (length for participants <2y);

Sitting height (crown-rump length for participants <2y);

Knee height;

Head circumference;

Arm span;

Body weight;

Elbow extension angle;

Cranial dimensions (occipito-frontal, occipito-nasal distances).

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Waist and chest circumference will be measured at baseline and at final visit.
Anthropometric data will only be collected by appropriately trained individuals at the trial 
site and in accordance with the anthropometric measurement manual.  All sites will follow a 
consistent, structured and documented training programme.  This will occur prior to trial 
start, through regular refresher training and at targeted retraining based on analysis of 
measurement data consistency at the site.  
Sites will be required to make all efforts to have the same anthropometrist at each visit for 
each participant (longitudinal consistency) and between participants (cross-sectional 
consistency).  As well as following the specific procedures for measurement laid out in the 
measurement manual, sites will be provided with the same (or exactly equivalent) equipment 
across all sites and will follow the specific calibration procedures.
Anthropomotrists should remain blinded to dose assignment in order to minimize bias.  
8.1.2. Polysomnography/Sleep Study
In participants with a documented current diagnosis of sleep disordered breathing at 
enrollment, baseline sleep study data will be collected.  This sleep study should be within 
6 months of enrollment (this can be at site or a home study).  The following data will be 
collected where available:

Clinical summary of findings (including reported diagnosis);

Whether study was performed in room air/oxygen/on continuous positive airway 
pressure;

Apnea-hypopnea index (obstructive and total);

Desaturation index (number of desaturations per hour >3% from baseline);

Percentage time spent <90% oxygen saturation (SaO2);

Percentage time spent with end-tidal carbon dioxide >50 mmHg;

SaO2 nadir.
The sleep study will be repeated at the end of the study.
8.1.3. MRI
MRI scans of the brain will be assessed in the 
 cohort of those aged under 2 years
at enrollment.  A historical scan collected within the 12 months prior to enrollment can be 
used as baseline data.  The scan will be repeated at the end of this study.  The scan will be 
read and reported locally with the following data entered into the eCRF.
CCI

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
Whether the participant has had prior foramen magnum surgery.

History of other cranial surgery.

CSF signal loss.

Presence of posterior effacement ± associated anterior effacement.

Whether there is increased intramedullary signal on T2-weighted sequences.

Were any other intracranial abnormalities identified?

Reduced cisterna magna;

Enlarged ventricles;

Increased CSF spaces (non-ventricular);

Increased tentorial angle;

Other (specified).

Does the participant have document central apnoea (this should also be recorded 
under the polysomnography)?

Are the scan findings associated with any abnormalities on neurological examination?

Did this scan prompt foramen magnum decompression surgery to take place?
8.1.4. Patient-Reported (PRO)/Observer-Reported (ObsRO) Outcome Assessments
COAs implemented in this study are the Childhood Health Assessment Questionnaire 
(adapted for achondroplasia, [CHAQ]), Quality of Life in Short Stature Youth (QoLISSY) 
Brief, and Acceptability and Tolerability Questionnaire-Achondroplasia. These measures 
were chosen to be included in the phase 2 study based on: 1) concept mapping to the 
conceptual model, and 2) guidance provided to the team based on regulatory feedback 
provided to date. 
The COA measures are completed in accordance with the SoA during the scheduled site 
visits. At each relevant visit, the measures are administered before dosing, treatment, or 
conversation between health care team and participants about their health condition.

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8.1.4.1. Childhood Health Assessment Questionnaire (adapted for achondroplasia,
[CHAQ])
The Childhood Health Assessment Questionnaire (adapted for achondroplasia, [CHAQ]) is a 
36-item measure of health status and physical function. Participants aged 1 year of age and 
older at enrollment will have the CHAQ (adapted for achondroplasia) completed at 
designated study visits. The parent-report version will be completed for all participants.
Participants will start on the age appropriate version and continue with that version 
throughout the study.  
Participants or their caregivers will be asked to provide responses to questions designed to 
assess function in 8 components/domains in addition to: 2 scales (pain and well-being), 
2 questions that ask about the use of aids and devices, and 2 questions that ask about the 
requirement for help with the functional areas. The 8 functional components are: Dressing 
and Grooming (4 items); Getting Up (2 items); Eating (3 items); Walking (2 items); Hygiene 
(5 items); Reach (4 items); Grip (5 items); and Activities (5 items). Both a disability and 
discomfort index can be calculated. The CHAQ (adapted for achondroplasia) has a recall 
period of ‘over the past week’. A 5-point Likert Scale is utilized ranging from ‘without any 
difficulty' to ‘unable to do’ and a ‘not applicable option’. Lower component and index 
scores indicate better health status/functioning.
8.1.4.2. Quality of Life in Short Stature Youth (QoLISSY) Brief
For participants aged 4 years of age and above at enrollment, the parent will complete the 
Quality of Life Short Stature Youth Brief (QoLISSY Brief) tool.  QoLISSY Brief measures 
health-related quality of life (HRQoL) in children 4-18 years old from the participant and 
caregiver perspectives. The assessment assignments will start with the age appropriate 
version at baseline and continue with that the same version assignment throughout the study.  
The 9 items on the QoLISSY Brief were selected from the full QoLISSY physical, social and 
emotional HRQoL dimensions. The QoLISSY Brief questions ask the participant or 
caregiver about their status currently. Intended for children or caregivers of children, the 
instrument uses a 5-point Likert Scale ranging from 'not at all/never' to 'extremely/always’.
The QoLISSY Brief total score is the 0-100 transformed sum of the 9 item scores, with 
higher scores representing better quality of life.
The assessment version assignments will start with the age appropriate version at baseline 
and continue with the same version throughout the study.
8.1.4.3. Acceptability and Tolerability Questionnaire - Achondroplasia
The Acceptability and Tolerability Questionnaire – Achondroplasia will be used to measure 
the acceptability and tolerability of the subcutaneous injection being received as part of the 
achondroplasia treatment. There are 10 items with a recall period of ‘past 7 days’ that ask 
about pain, satisfaction with treatment, acceptability and tolerability of the injection. The 
caregiver completes the questionnaire throughout the study.

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8.1.4.4. EuroQol 5 Dimensions – Youth (EQ-5D-Y) and Youth Proxy Version 
1 (EQ-5D-Y Proxy Version 1)
The EQ-5D-Y is a newly developed generic instrument measuring health-related quality of 
life in children and adolescents 8 years and older. The EQ-5D-Y Proxy measures the health 
status of children 4 to 7 years of age. EQ-5D-Y was adapted from the EQ-5D original 
questionnaire (http://www.euroqol.org/about-eq-5d.html). It consists of a descriptive system 
(EQ-5D) of health-related quality of life states, consisting of five dimensions including 
mobility (walking about), self-care (looking after myself), usual activities (doing usual 
activities), pain/discomfort (having pain or discomfort), and anxiety/depression (feeling 
worried, sad or unhappy) each of which can take one of three responses. The responses 
record three levels of severity (no problems, some problems, or a lot of problems) within a 
particular ED-5D dimension. Additionally, the EQ-5D consists of a standard vertical 20 cm 
visual analogue scale (EQ VAS) for recording an individual’s rating of their current 
health-related quality of life state on a scale from 0 to 100 with 0 representing the worst and 
100 the best health state he or she can imagine. All items refer to the health state 
“today”. For younger ages, the caregiver completes the EQ-5D-Y Proxy Version 1 and 
continues to complete throughout the study; the children can also complete the EQ-5D-Y 
self-report version when they are old enough.
8.1.4.5. Patient Global Impression of Severity and Patient Global Impression of Change 
Anchor Items
Additionally, 4 anchor items have been developed to assess change over time on the CHAQ 
(adapted for achondroplasia) and QoLISSY Brief: two global impression of severity items 
(PGIS) and 2 global impression of change items (PGIC); all four anchor items are completed 
by the caregiver. The 2 PGIS single item assessments will be completed at each clinic visit 
when the CHAQ (adapted for achondroplasia) and QoLISSY Brief are assessed. The 2 PGIC 
single item assessments will be also completed at each clinic visit when the CHAQ (adapted 
for achondroplasia) and QoLISSY Brief are assessed, but not at the baseline visit.
The PGIS-Physical Activities-Caregiver is a single item assessment completed by the 
caregiver rating the impact of achondroplasia on their child’s ability to do physical activities
over the past 7 days. The response scale is a 4-point categorical rating scale ranging from 
“none” to “severe”.
The PGIS-Emotional and Social Well-Being-Caregiver is a single item assessment completed 
by the caregiver rating the impact of achondroplasia on their child’s overall emotional and 
social well-being over the past 7 days. The response scale is a 4-point categorical rating
scale ranging from “none” to “severe”.
The PGIC-Physical Activities-Caregiver is a single item assessment completed by the 
caregiver rating the change in their child’s ability to do physical activities since they started 
taking the study medication. The response scale is a 5-point categorical rating centered 
around “no change” with 2 grades of improvement and 2 grades of worsening.

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The PGIC-Emotional and Social Well-Being-Caregiver is a single item assessment 
completed by the caregiver rating the change in their child’s overall emotional and social 
well-being since they started taking the study medication. The response scale is a 5-point
categorical rating centered around “no change” with 2 grades of improvement and 2 grades
of worsening.
8.1.5. Tanner Staging
In order to evaluate the effects of early puberty on growth trajectory, Tanner stage of puberty 
will be assessed. For children 7 years and older, at the timing indicated in the SoA, the 
Tanner Stage of puberty will be recorded in the eCRF as stage I-V. Children under 7 years 
of age do not require this assessment, providing the investigator confirms there is no 
suspicion of a diagnosis of precocious puberty.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examination
A physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal systems and skin. Height and weight will also be measured and 
recorded as per the anthropometric measurements manual.
Investigators should pay special attention to clinical signs related to medical history.
8.2.2. Neurological Examination
Neurological examination will be performed at visits indicated in the SoA.  This will include 
examination of cranial nerves (excluding fundoscopy) and examination of upper and lower 
limbs to include tone, power, reflexes and sensation.  This should be performed by an 
investigator, or designee, experienced in such examinations in children who can suitably 
adapt to the age range in this study.
8.2.3. Vital Signs
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
Blood pressure and pulse rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.  Blood 
pressure measurement must use an appropriate size cuff for the age and weight of the 
participant.
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones) where 
possible (with consideration of the age of the child).

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Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse
rate and 1 blood pressure measurement.  If the BP reading is abnormal then this should be 
repeated after 1 minute. The blood pressure reading will be recorded on the eCRF.
8.2.4. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at screening and at Day 4 using an ECG machine that automatically calculates the 
heart rate and measures PR, QT, and QTc intervals and QRS complex. Alternative lead 
placement methodology using torso leads (eg, Mason-Likar) is not recommended given the 
potential risk of discrepancies with ECGs acquired using standard limb lead placement.  All 
scheduled ECGs should be performed after the participant has rested quietly for at least 
10 minutes in a supine position (where possible). 
ECGs in this study are conducted at screening to document baseline ECG characteristics 
prior to dosing.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 6.  However, these should be 
considered in light of age-specific norms.
8.2.5. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Participants are required to fast for >4hr prior to blood sampling. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 1 week after the last dose of study intervention should be 
repeated according to the judgement of the investigator until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or medical 
monitor.

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If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention.  Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations.  If a urine test cannot 
be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required.  In 
such cases, the participant must be excluded if the serum pregnancy result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
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 to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
Each participant/parent/legal guardian/legally authorized representative will be questioned 
about the occurrence of AEs in a non-leading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant/parent(s)/legal 
guardian/legally authorized representative provides informed consent, which is obtained 
before the participant’s participation in the study (ie, before undergoing any study-related 
procedure and/or receiving study intervention), through and including the follow up visit.  At 
the final follow up (final contact), the participant/parent(s)/legal guardian/legally authorized 
representative will be contacted by telephone to inquire about AEs and SAEs, including 
hospitalizations and NDCMCs, since visit Month 12.

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Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the parent(s)/legal guardian/legally authorized representative withdraws from the study and 
also withdraws consent for the collection of future information, the active collection period 
ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in Appendix.
The investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. The investigator will submit any updated SAE data to the sponsor within 24 hours 
of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
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.

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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. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to -follow-up (as defined in Section 7.3).
In general, -follow-up information will include a description of the event in sufficient detail 
to allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on -follow-up procedures is given in Appendix 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, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: A female participant is found to be pregnant while receiving or after 
discontinuing study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

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
A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation or skin contact then exposes his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 4 weeks after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

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
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further follow-
up of birth outcomes will be handled on a case by case basis (eg, follow-up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner.  The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.

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The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease Related Events and/or Disease Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Injection site reactions will be considered an adverse event of special interest (AESI).  
Injection site reactions may include but are not limited to erythema, induration, ecchymosis, 
pain and pruritis.  The size and severity of these symptoms or reactions will be assessed and 
documented.  The following details will be collected:

Date of onset and resolution of the ISR;

Presence of the following features on a mild/moderate/severe grading scale:

Erythema;

Induration;

Pain;

Swelling;

Pruritis.

Did the ISR lead to any missed or delayed doses?

Did the ISR lead to withdrawal of the participant from the study?
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.3.1 through Section 8.3.4. An AESI is to be recorded as an AE or SAE on the 
CRF. In addition, an AESI that is also an SAE must be reported using the CT SAE Report 
Form.
8.3.8.1. Lack of Efficacy
Not applicable.

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8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant;

The administration of expired study intervention;

The administration of an incorrect dosage;

The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.

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8.4. Treatment of Overdose
For this study, any dose of recifercept equivalent to greater than 5mg/kg within a 48-hour 
time period or greater than 20mg/kg within a 7 day period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of recifercept (whichever is 
longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Blood samples of approximately 2 mL, to provide approximately 1 mL serum, will be 
collected for measurement of serum concentrations of recifercept as specified in the SoA.  
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. Collection of samples up to and including 12 hours 
after dose administration that are obtained within 10% of the nominal time relative to dosing 
(eg, within 6 minutes of a 60-minute sample) will not be captured as a protocol deviation, as 
long as the exact time of the collection is noted. The actual date and time (24-hour clock 
time) of each sample will be recorded.
Serum samples for population pharmacokinetic (PK) and non-compartmental (for PK study 
cohort only) analysis of recifercept will be collected as per the time points specified in SoA. 
In general, every effort should be made to collect blood samples for PK analysis within 
specified time windows. At all times, it is essential to accurately record the date and time 
study treatment is administered and PK samples are collected. Samples will be used to 
evaluate the Population PK of recifercept. Each serum sample will be divided into 2
aliquot(s) (1 each for Intact recifercept and Total [intact + clipped] recifercept analysis). 
Samples collected for analyses of recifercept serum concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study, for 
metabolite identification and/or evaluation of the bioanalytical method, or for other internal 
 purposes.
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Genetic analyses will not be performed on these serum samples.  Participant confidentiality 
will be maintained.
Samples collected for measurement of serum concentrations of recifercept will be analyzed 
using a validated analytical method in compliance with applicable SOPs.  The PK samples 
must be processed and shipped as indicated in the instructions provided to the investigator 
site to maintain sample integrity. Any deviations from the PK sample handling procedure 
(eg, sample collection and processing steps, interim storage or shipping conditions), 
including any actions taken, must be documented and reported to the sponsor.  On a 
case-by-case basis, the sponsor may make a determination as to whether sample integrity has 
been compromised.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.6. Genetics
Genetics (specified analyses) are not evaluated in this study.  
 
This section is not applicable in Denmark.
8.7. Biomarkers
Collection of samples for biomarker research is also part of this study. 
The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA.
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
 
 
 
 
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8.7.3. Blood Samples for Biomarker Analysis
A 6 mL sample will be collected at timepoints outlined in the Schedule of assessments and 
described in the laboratory manual.  However, should the blood volumes to be taken exceed 
maximum guidelines then the clinical safety laboratory assessments, PK sampling and 
immunogenicity samples will be prioritized.

Detailed collection, processing, storage, and shipment instructions will be provided in 
the central laboratory manual.

Samples will be analyzed using analytical methods in compliance with Pfizer 
standard operating procedures.
The following biomarkers may be analysed using immunoassays: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.7.4. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.7.5. Specified Protein Research 
Specified protein research is not included in this study.
8.7.6. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
 
 
 
 
8.8. Immunogenicity Assessments
Blood samples of approximately 2 mL, to provide a minimum of 1 mL serum volume, will be 
collected for determination of ADA and NAb as specified in the SoA. Instructions for the 
collection and handling of biological samples will be provided in the laboratory manual or by 
the sponsor.  The actual date and time (24-hour clock time) of each sample will be recorded.
 
 
Genetic analyses will not be performed on these serum samples.  Participant confidentiality 
will be maintained.
Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs. Samples determined to be positive for ADA may be further characterized for NAb.
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The immunogenicity samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity. Any deviations from the 
immunogenicity sample handling procedure (eg, sample collection and processing steps, 
interim storage, or shipping conditions), including any actions taken, must be documented 
and reported to the sponsor. On a case-by-case basis, the sponsor may make a determination 
as to whether sample integrity has been compromised.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment.  The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Estimands and Statistical Hypotheses
Height Growth Endpoint
Null hypothesis for height growth in this study is that height 12 months post-baseline for 
children on recifercept is equal to the expected height growth for the achondroplasia 
reference population based on Merker (2018).30 The alternative hypothesis is that height 
growth for recifercept-treated participant is greater than the expected growth for 
achondroplasia reference population based on Merker (2018).30
9.1.1. Estimands
The primary efficacy estimand will be the population treatment effect of the mean 
change-from-baseline of a continuous response (ie, height growth) at month 12 irrespective 
of IP compliance. Increase in height growth above expected growth in reference population, 
a co-primary endpoint, is defined as the height growth in the achondroplasia reference 
population +50%. Intercurrent event for the efficacy estimand: withdrawal and all events 
leading missing data will be excluded from efficacy analysis and will not have their data 
imputed. The population-based treatment effect will be the mean change-from-baseline at 
12 months.

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The secondary estimand will be the population treatment effect of the mean change from
baseline of a continuous response, defined as the decline in the difference of arm span to 
standing height. Intercurrent event for the efficacy estimand: withdrawal and all events 
leading missing data will be excluded from efficacy analysis and will not have their data 
imputed.
9.2. Sample Size Determination
Sample size determination is based on the co-primary endpoint of height growth, defined as 
change from baseline of height at 12 months for participants on drug versus change from 
baseline of height at 12 months for a reference achondroplasia population. A total of 
54 participants randomized to three dose levels in order to obtain 15 participants per dose, 
assuming a one-sided family-wise error rate of 0.05 with a Bonferroni correction (0.017 after 
Bonferroni adjustment for 3 comparisons), and inter-participant variability of .15 (estimated 
from C4181001), there is over 90% power to detect at least one dose providing 50% height 
growth above reference. No statistical comparison will be made between recifercept doses. 
PK Study Cohort: 
No formal sample size calculation was performed and 12 participants will be selected 
empirically to characterize PK, safety and tolerability after single 3 mg/kg dose 
administration of two formulations.  
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Full Analysis Set 
(FAS)/Safety
All participants receiving at least one dose of recifercept. 
Participants will be analyzed according to the dose they 
actually received.
Per-protocol analysis set 
(PPAS)
All participants receiving at least one dose of recifercept and 
have complete data at baseline through month 12 and without 
protocol deviations that were thought to impact the efficacy 
evaluation during the treatment period.
Participants will be analyzed according to their randomized 
dose.
PK Concentration set
All participants who received at least one dose of recifercept 
and have at least one evaluable concentration result.
PK Study Cohort
All participants who received a dose of the recifercept Phase 2
formulation and a dose of the Phase 3 formulation with at least 
one evaluable concentration result.
PK Study Cohort 
Parameter (PKCP)
All participants in the PK cohort who have at least one PK 
parameter of interest.

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9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the analyses 
and procedures for accounting for missing, unused, and spurious data.  This section is a 
summary of the planned statistical analyses of the primary and secondary endpoints.
9.4.1. General Considerations
Data presented in tables will be summarized by recifercept dose (defined in Section 4.1) and 
total. If needed summary presentations may also be grouped by gender. In addition, separate 
summaries will be completed for participants aged 3 months to<2 years (by dose, though not 
stratified by gender). 
9.4.2. Primary Endpoint(s)
Efficacy
The primary efficacy endpoint of change from baseline of height at 12 months will be 
analyzed using an analysis of variance (ANOVA) model comprising terms for recifercept 
dose groups. Change from baseline estimates for height and their corresponding 
95% confidence intervals will be provided via least-square means. A Bonferroni adjustment 
will be applied to the 95% confidence intervals. The population for the primary analysis will 
be based on the FAS, while the PPAS is the population that will be used for sensitivity 
analysis. 
Safety
The safety data will be summarized in accordance with Pfizer Data Standards. All 
participants who receive IP (safety population) will be included in the safety analyses. All 
safety data will be summarized descriptively through appropriate data tabulations, descriptive 
statistics, categorical summaries, and graphical presentations. Safety endpoints for the study 
include: 

TEAEs and SAEs; 

Withdrawals from treatment due to AEs. 
Change from baseline in laboratory data and vital signs will be additionally summarized. 
Participant listings will also be produced for these safety endpoints. 
PK Study Cohort: 
The pharmacokinetic parameters following single dose administration in the PK cohort will 
be derived from the concentration-time profile as follows:

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Parameter
Definition
Method of Determination
AUCinf
Area under the serum concentration 
time profile from time 0 extrapolated to 
infinite time.
AUClast+(Clast*/kel),
Where Clast* is the predicted serum 
concentration at the last quantifiable time point 
estimated from the loglinear regression 
analysis.
AUC168
Area under the serum 
concentration-time profile from 0 to 
168 hours.
Linear/Log trapezoidal method.
AUC360
Area under the serum 
concentration-time profile from 0 to 
360 hours.
Linear/Log trapezoidal method.
Cmax
Maximum serum concentration.
Observed directly from data.
Tmax
Time for Cmax.
Observed directly from data as time of first 
occurrence.
t½
Terminal elimination half-life.
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the 
loglinear concentration time curve.  Only those 
data points judged to describe the terminal 
loglinear decline will be used in the regression.
Actual PK sampling times will be used in the derivation of PK parameters.
The serum PK parameters for recifercept will be summarized descriptively by formulation. 
Serum concentrations will be listed and summarized descriptively by formulation and 
nominal PK sampling time. Individual participant summary profiles (mean and median 
plots) of the serum-concentration time data will be plotted by formulation and PK sampling 
time. For summary statistics and summary plots, the nominal PK sampling time will be used. 
For individual participant plots, the actual PK sampling time will be used, whilst the pre-dose 
will be set to zero. Summary plots will be presented on both linear-linear and log-linear 
scales.
9.4.3. Secondary Endpoint(s)
The secondary efficacy endpoint of change from baseline of the difference of arm span to 
height difference at 12 months will be analyzed using an analysis of variance (ANOVA) 
model comprising terms for recifercept dose groups. Change from baseline estimates for 
height and their corresponding 80% confidence intervals will be provided via least-square 
means. The population for the primary analysis will be based on the FAS, while the PPAS is 
the population that will be used for sensitivity analysis.
Additional safety endpoints (laboratory values, physical examination, vital signs and 
immunogenicity) will be analyzed as change from baseline by dose group.

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PK Study Cohort: 
The safety data will be summarized in accordance with Pfizer Data Standards. All 
participants who receive IP (safety population) will be included in the safety analyses. All 
safety data will be summarized descriptively through appropriate data tabulations.
 
9.4.5. Other Safety Analyses
All safety analyses will be performed on the safety population.
9.4.6. Other Analyse(s)
Patient-reported/observer-reported outcome assessments will be summarized by dose.
Additional analysis of these assessments will be detailed in the SAP or in a separate analysis 
plan.
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned to 
be included in the CSR. 
9.4.7. Pharmacokinetic Data
Nonlinear mixed effect modeling will be performed to evaluate pharmacokinetic parameters 
including clearance, area under the curve at steady state over the dosing interval for 
recifercept. PK will be assessed on an ongoing basis using a sparse sampling approach to 
inform and update the PopPK model. The PK data from Block A participants aged ≥6 to 
<11 years will be integrated into the PopPK model developed using healthy adult PK data, to 
confirm the dosing recommendations in younger age sub-cohorts (≥2 to <6 years and 
≥3 months -<2 years).
PK Study Cohort: 
Non-compartmental analysis will be conducted to evaluate the PK of the two formulations 
administered in the PK study cohort. 
9.5. Interim Analyses
Interim analyses may be performed to assess efficacy and safety after approximately 
45 participants (up to15 per dose), complete their study participation through 50% of the 
study (completion of 6 months treatment). Before any interim analysis is instigated, the 
details of the objectives, decision criteria, dissemination plan, and method of maintaining the 
study blind as per Pfizer’s SOPs will be documented and approved in a charter.  In addition,
the analysis details must be documented and approved in an interim analysis SAP or final 
SAP.
CCI

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The Bonferroni correction method is used to control the overall familywise error rate of 
0.05 for multiple comparisons. The post-baseline estimate will be considered statistically 
significant at the 1-sided 0.017 level. No statistical comparisons will be performed between 
treatment arms.  
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an eDMC.  The eDMC is independent of the study team and includes 
only external members.  The eDMC charter describes the role of the eDMC in more detail.
The eDMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charters.  The recommendations made by the eDMC to alter the 
conduct of the study will be forwarded to the appropriate Pfizer personnel for final decision.  
Pfizer will forward such decisions, which may include summaries of aggregate analyses of 
safety data to regulatory authorities, as appropriate. 
The study team will meet to assess progression to the next enrollment block (Section 1.2) 
based on the available safety and PK data.  If safety signals are identified at this review (see 
Section 6.1) then a meeting of the eDMC will be convened to decide next steps.
The eDMC will meet regularly to assess all available safety and PK data to ensure ongoing 
safety of all trial participants.  The eDMC will review unblinded safety data in order to fully 
assess the impact of dose/exposure on safety signals.  A patient advocate will also be 
included on the eDMC if an appropriately qualified individual can be identified as agreed 
upon by the eDMC chairperson.

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
CCI

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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.  The participant or his/her legally authorized representative should be given sufficient 
time and opportunity to ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative defined as parent or legal guardian will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study -related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.  Additionally, 
assent of the participant must be obtained as per local regulations.

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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to each participant the objectives of the additional
research. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a participant's agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional 
additional research will not provide this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant -specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant -specific code. The study site will
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.

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10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for -Pfizer sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  These 
results are submitted for posting in accordance with the format and timelines set forth by US 
law.
EudraCT
Pfizer posts clinical trial results on EudraCT for -Pfizer sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for -Pfizer
sponsored interventional studies at the same time the corresponding study results are posted 
to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods.  Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.

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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, -risk based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical -risk based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.

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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the clinical monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.

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10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.

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For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site staff cannot be reached to 
provide advice on a medical question or problem originating from another healthcare 
professional not involved in the participant’s participation in the study.  The contact number 
can also be used by investigator staff if they are seeking advice on medical questions or 
problems; however, it should be used only in the event that the established communication 
pathways between the investigator site and the study team are not available.  It is therefore 
intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study.  The contact number is not intended for use by the participant directly, 
and if a participant calls that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues.
Table 3.
Protocol--Required Safety Laboratory Assessments
Hematology
Chemistry (>4 h fast)b
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and creatinine
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Phosphate 
Pregnancy test (β-hCG)a
a.
Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/EC.  Serum or urine -hCG for female participants of childbearing potential.
b.
Time since last food intake should be entered on the laboratory requisition form.
Investigators must document their review of each laboratory safety report.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, -Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.  Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/-self
harming intent. Such overdoses should be reported regardless of sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.

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Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately -life threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.

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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  These 
requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse events 
(AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure.
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding.
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP).  
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

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
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities.  An AE that is assessed 
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

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
The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor.  In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this causal 
relationship in the source documents and CRF, and report such an assessment in the 
dedicated section of the CT SAE Report Form and in accordance with the SAE 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.

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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.

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10.4. Appendix 4: Contraceptive Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 21 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s) plus an additional 90 days (a spermatogenesis cycle): 

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
10.4.2. Female Participant Reproductive Inclusion Criteria
The requirement for participants to be Tanner stage 1 at enrolment will preclude WOCBP 
from enrolling, however it is possible participants may become WOCBP later in the study.  
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and agrees to total abstinence until 21 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s). The investigator, or his or her designee, in 
consultation with the participant and the participant’s legally authorized 
representative, will confirm that the participant has been informed of the potential 
risks of pregnancy whilst receiving study intervention and advised of the need for 
continuing total abstinence from sexual activity.  
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.  
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

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
Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview.  The method of documentation should be recorded in the participant’s medical 
record for the study.
10.4.4. Contraception Methods
Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks.  The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample).  In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.

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10.6. Appendix 6: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.
ECG Findings That May Qualify as Serious Adverse Events

QTcF prolongation >500 msec.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter. 

At the discretion of the Investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.

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10.7. Appendix 7: Genetics
Use/Analysis of DNA collected as part of the banked biospecimens

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease.  Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to recifercept or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for banking will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Banked 
Biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.

Banked Biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.

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10.8. Appendix 8: Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic locally and will become effective for other public emergencies only 
upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
10.8.1. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the Schedule of Activities
or unscheduled visits. Telehealth visits may be used to continue to assess participant safety 
and collect data points. Telehealth includes the exchange of healthcare information and 
services via telecommunication technologies (eg, audio, video, video-conferencing software) 
remotely, allowing the participant and the investigator to communicate on aspects of clinical 
care, including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit 

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4 and Section 10.8.2.1 of this appendix regarding 
pregnancy tests.

If PRO/ObsROs can be administered by telehealth then these should be performed.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.8.2. Alternative Facilities for Safety Assessments
10.8.2.1. Laboratory Testing
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital. The 
following safety laboratory evaluations may be performed at a local laboratory: 

See table of safety labs in Appendix 2.

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If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and 
certifications/accreditations for filing at the site. Laboratory test results are to be provided to 
the site staff as soon as possible.   The local laboratory reports should be filed in the 
participant’s source documents/medical records. Relevant data from the local laboratory 
report should be recorded on the CRF. 
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol. 
10.8.2.2. Electrocardiograms
If the participant is unable to visit the study site for ECGs, the participant may visit an 
alternative facility to have the ECGs performed. Qualified study site personnel must order, 
receive, and review results. 
10.8.3. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
Recifercept may be shipped by an appropriate third-party courier to study participants if 
permitted by local regulations and in accordance with storage and transportation
requirements for recifercept.  Pfizer does not permit the shipment of recifercept by mail. The 
tracking record of shipments and the chain of custody of recifercept must be kept in the 
participant’s source documents/medical records. 
Study intervention can continue to be administered at home in accordance with the protocol.
10.8.4. Home Health Visits
A home health care service will be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the participant’s location, rather than an in-person study visit at the site. The 
following may be performed during a home health visit:

Support of home dosing in accordance with the protocol;

Blood draws.

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10.8.5. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided. Study 
treatment should continue unless the investigator/treating physician is concerned about the 
safety of the participant, in which case temporary or permanent discontinuation may be 
required.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
10.8.6. Efficacy Assessments
Anthropometric measurements cannot be undertaken in the participant’s home.  
Administration of PRO/ObsRO and blood draws may be undertaken by home health teams.
10.8.7. Independent Oversight Committees
The eDMC will continue to meet via teleconference in accordance with the eDMC charter.

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10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ADA
anti-drug antibodies
ADE
adverse device effect
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC0-168
area under the concentration-time curve from time 0 to 168 hours
AUClast
area under the concentration-time curve from 0 to time of last 
measurable concentration
AUCinf
area under the concentration-time curve from time 0 to infinity
AUCtau
area under the concentration-time curve at steady state over the 
dosing interval t
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BIW
twice weekly
BMI
body mass index
BP
lood pressure
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CHAQ
Childhood Health Assessment Questionnaire
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL/F
apparent clearance of drug from eg, plasma
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
COA
Clinical Outcome Assessment
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CCI
CCI
CCI

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Abbreviation
Term
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
DRE
disease-related event
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
eDMC
external data monitoring committee
EDP
exposure during pregnancy
EMA
European Medicines Agency
ENT
Ear nose and throat
EQ-5D
EuroQol- 5 dimensions
EQ-VAS
EuroQoL- visual analogue score
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
Food and Drug Administration
FGF
Fibroblast growth factor
FGFR3
Fibroblast growth factor receptor 3
FIH
first-in-huma
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good laboratory practice
HIPAA
Health Insurance Portability and Accountability Act
HRQL
health-related quality of life
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IGF-1
Insulin-like growth factor 1
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IPM
investigationalp manual
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISR
injection site reaction
LFT
liver function test
MAD
multiple ascending dose

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Abbreviation
Term
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
NDCMC
newly diagnosed chronic medical condition
Msec
millisecond
N/A
not applicable
Nab
neutralizing antibodies
NDCMC
Newly diagnosed chronic medical condition
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
NPRB
Natriuretic peptide receptor B
ObsRo
Observer report outcome
OLE
Open-label extension
PBMC
peripheral blood mononuclear cell
PCRU
Pfizer clinical research unit
PD
pharmacodynamic(s)
PFS
prefilled syringe
PGIC
Patient global impression of change
PGIS
Patient global impression of severity
PI
principal investigator
PK
pharmacokinetic(s)
PKCP
PK study cohort parameter
PopPK
Population pharmacokinetics
PRO
Patient-Reported Outcome
PSG
polysomnography
PT
prothrombin time
QoLISSY Brief
Quality of Life in Short Stature Youth Brief
QTc
corrected QT
QTcF
QTc corrected using Fridericia’s formula
QW
Once Weekly
RAC
accumulation ratio based on AUC (observed)
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAD
single ascending dose
SaO2
oxygen saturation
SAP
statistical analysis plan
SAR
Serious Adverse Reaction
SC
subcutaneous
CCI
CCI
CCI

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Abbreviation
Term
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
T1/2
terminal phase half-life
TA-46
Previous name for recifercept
TBili
total bilirubin
TEAE
treatment-emergent adverse event
Tmax
time to reach Cmax
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman/women of childbearing potential

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10.10. Appendix 10: Subcutaneous Dosing Instructions
SUBCUTANEOUS DOSING INSTRUCTIONS
GENERAL INSTRUCTIONS

Allow prepared syringes with the medication to reach room temperature for 
15 minutes prior to administration (they should not be cold to touch);

Never reuse needles or syringes;

Dispose of all used materials in the appropriate sharps container and return used vials 
into the cartons to be checked by a study monitor.
Gather your supplies: 

Alcohol pads;

Prepared syringe with medication;

Puncture resistant sharps container.
Choose one of the recommended injection sites described below:
The injection(s) should be given when participant is sitting or lying down into the abdomen 
or outer thighs. The back of the arms may be used as an alternative injection site
(Figure 2).
Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid areas 
with scars, moles and avoid the area 1 inch from the naval.

Injections should start in either the abdomen or outer thighs at number one and 
proceed in a clockwise manner from site number 1 through to number 4.

If injections are given in the back of the arms, alternate between the left and right 
arms. 

For each injection given (including if two injections are needed for one dose), a new 
injection site must be chosen. Inject at least 2 inches from the previous site.

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Figure 2.
Injection Site Rotation
Preparing the subcutaneous injection site and injecting Recifercept
1. Wash hands thoroughly with soap and water prior to any injections.
2. Choose the site from Figure 2 and clean the site where Recifercept is to be injected 
with a new alcohol swab, using a circular motion, starting from the inside and 
working to the outside of the chosen injection site. Allow the area to dry thoroughly, 
do not blow the area dry. DO NOT touch this area again before giving the injection.
3. Using the thumb and forefinger, lift up a fold of skin with one hand (Figure 3).  
Figure 3.
Technique for Holding Skin Prior to Injection

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1. With the other hand, hold the syringe like a pencil with the bevel up. With a quick, 
short motion, push the needle into the skin at an angle of 45° (Figure 4).
Figure 4.
Injection Angle
1. Once the needle has been pushed into the skin, release the pinched skin while still 
holding the needle in place. With your free hand, push the plunger all the way down 
at a slow, steady rate to deliver the entire contents of the syringe Figure 5).
Figure 5.
Technique for Injecting Study Intervention
1. When the syringe is empty, remove the needle from the skin; be careful to keep it at 
the same angle it was when it was inserted into the skin. Place the syringe/needle in 
the sharps container provided. 
2. Repeat steps 1 through 5 if a second syringe is required for the total dose.  
3. Slight bleeding may occur. Cover with a sterile gauze pad if needed. DO NOT rub 
the injection site. You may place a band aid over the injection site.

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