A Pilot Project to Evaluate the Feasibility of Constructing a Concurrent External Control for Recifercept
Conditions: Achondroplasia
Sponsor: Pfizer

Recifercept 
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Study information 
 
Title 
A pilot project to evaluate the feasibility of 
constructing a concurrent external control for 
recifercept 
Protocol number 
C4181010 
Protocol version identifier 
v 1.1 
Date 
November 09, 2023 
EU Post Authorization Study 
(PAS) register number 
N/A 
Active substance 
Recifercept 
Medicinal product 
N/A 
Research question and objectives 
There are two research questions: 
1) Can a concurrent external control for the 
recifercept phase 2 clinical trial be constructed 
using achondroplasia patients from a prospective 
observational natural history study? 
2) What are differences in height growth, 
achondroplasia-related complications, patient 
functional status, and quality of life between 
patients enrolled in the recifercept phase 2 clinical 
trial and those in the concurrent external control? 
Objectives: 
1. To construct a concurrent external control arm 
for recifercept phase 2 clinical trial using 
achondroplasia patients from a prospective 
observational natural history study. 
2. If objective #1 is met, the following will be 
compared to examine differences between 
patients enrolled in the recifercept phase 2 
clinical trial and those in the concurrent external 
control: 

Recifercept 
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• Height growth 
• Selected anthropometric measurements, 
including but not limited to: standing height, 
sitting height, knee height, arm span, length 
of the legs, sitting height/standing height 
ratio, arm span to height/length difference, 
knee height/lower segment ratio 
• Achondroplasia-related orthopaedic 
complications (including lordosis, kyphosis, 
small foramen magnum, and spinal 
stenosis), and other achondroplasia-related 
complications (including apnea, otitis 
media, and hydrocephalus) 
• Differences in functional status and health- 
related quality of life 
Author 
PPD 

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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS ...................................................................................................... 3 
2. LIST OF ABBREVIATIONS ............................................................................................... 5 
3. RESPONSIBLE PARTIES ................................................................................................... 6 
4. ABSTRACT .......................................................................................................................... 7 
5. AMENDMENTS AND UPDATES .................................................................................... 13 
6. MILESTONES .................................................................................................................... 13 
7. RATIONALE AND BACKGROUND ............................................................................... 13 
8. RESEARCH QUESTION AND OBJECTIVES ................................................................. 15 
9. RESEARCH METHODS .................................................................................................... 15 
9.1. Study design ........................................................................................................... 15 
9.2. Setting ..................................................................................................................... 16 
9.2.1. Inclusion criteria ........................................................................................ 17 
9.2.2. Exclusion criteria ....................................................................................... 18 
9.3. Variables ................................................................................................................. 19 
9.4. Study size ................................................................................................................ 21 
9.5. Data management ................................................................................................... 21 
9.6. Data analysis ........................................................................................................... 22 
9.7. Data sources ............................................................................................................ 23 
9.8. Quality control ........................................................................................................ 24 
9.9. Limitations of the research methods ....................................................................... 24 
9.10. Other aspects......................................................................................................... 24 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................ 24 
10.1. Patient information ............................................................................................... 24 
10.2. Patient consent ...................................................................................................... 24 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) ................ 24 
10.4. Ethical conduct of the study ................................................................................. 24 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ...................................................................................................................... 25 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ....... 25 
13. REFERENCES .................................................................................................................. 25 
14. LIST OF TABLES ............................................................................................................ 26 

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15. LIST OF FIGURES ............................................................................................................ 26 
16. ANNEX 1. LIST OF STAND ALONE DOCUMENTS .................................................... 26 
17. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .................................... 26 
18. ANNEX 3. ADDITIONAL INFORMATION ................................................................... 26 

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2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
AOM 
Acute otitis media 
BMI 
Body mass index 
CCI 
CKD 
Chronic kidney disease 
COM 
Chronic otitis media 
CRF 
Case report form 
CSA 
Clinical study agreement 
DCT 
Data collection tool 
EMA 
European Medicines Agency 
FDA 
U.S. Food and Drug Administration 
FGFR3 
Fibroblast growth factor receptor 3 
GPP 
Good Pharmacoepidemiology Practices 
ICH 
International Council for Harmonisation 
IPW 
Inverse probability weight 
MRI 
Magnetic resonance imaging 
NPR-B 
Natriuretic peptide receptor type B 
PK 
Pharmacokinetics 
PS 
Propensity score 
CCI 
SAP 
Statistical analysis plan 

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3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
 
Name, degree(s) 
Job Title 
Affiliation 
Address 
PPD 

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PPD 
4. ABSTRACT 
Title: A pilot project to evaluate the feasibility of constructing a concurrent external control 
for recifercept 
Version and Date: v1.1, November 09, 2023 
Author: 
 
Rationale and background 
Achondroplasia is a heritable autosomal dominant disorder and is the most common form of 
skeletal dysplasia in humans, with a global birth prevalence of 1 in 25,000-30,000 or 
approximately 250,000 individuals worldwide (1–3). Achondroplasia is caused by a single- 
point gain-of-function mutation in the gene encoding the fibroblast growth factor receptor 3 
(FGFR3) (2,4). FGFR is a key inhibitory regulator of endochondrial ossification and its over- 
activiation interferes with normal chondrocyte maturation and causes shorter long bones and 
changes in flat bones such as the occipital bone and vertebrae. 
Achondroplasia results in short stature and a range of severe complications due to abnormal 
ossification centers in the cranial base, facial bones, vertebrae, rib cage, and joints. Lordosis, 
kyphosis, small foramen magnum, and spinal stenosis are the most common achondroplasia- 
related orthopaedic complications. Other achondroplasia related complications include sleep- 
disordered breathing, otitis media, and hydrocephalus. Medical complications associated with 
achondroplasia greatly impact physical and psychosocial functioning, self-esteem, and 
patient quality of life (3,5). 
Currently, vosoritide is the only treatment approved by European Medicines Agency (EMA) 
(for achondroplasia patients aged 2 years and older with open growth plates) and U.S. Food 
and Drug Administration (FDA) (for achondroplasia patients aged 5 years and older with 
open growth plates) to increase linear growth. It is an analog of C-type natriuretic peptide 
and works by binding to a receptor called natriuretic peptide receptor type B (NPR-B), which 
reduces the activity of FGFR3. Other available treatments are either aimed at limb 
lengthening with surgery or are interventions to treat the complications associated with 
achondroplasia. Recifercept is a modified soluble recombinant human FSFR3 under 
development 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. 
A recifercept phase 2 clinical study (Study C4181005) is ongoing to investigate the safety, 
tolerability, pharmacokinetics (PK) and efficacy of recifercept in children aged 3 months to 
10 years with achondroplasia. Fifty-four eligible participants aged 2-10 years and 9 patients 
aged 3 months to 2 years will be enrolled and randomized to receive one of three doses of 

Recifercept 
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recifercept subcutaneously (1mg/kg once-weekly, 2mg/kg twice weekly, or 1.5mg/kg once- 
daily, n=21 per dose). Once participants complete the phase 2 trial, they will be offered 
enrollment into an open-label extension study at the dose previously received in the phase 2 
trial or at the therapeutic dose once it is identified. A separate multi-country prospective 
observational natural history study (Study C4181001) is ongoing to examine the 
anthropometric characteristics, achondroplasia-related symptoms, tests, and treatments 
among children with achondroplasia. A total of 300 achondroplasia patients aged 0 to 15 
years of age will be recruited and followed up for a duration of 5 years. All patients 
participating in Study C4181005 were or will be recruited from Study C4181001. 
Objectives of this project are to evaluate the feasibility of constructing a concurrent external 
control for the recifercept phase 2 clinical trial (Study C4181005) using achondroplasia 
patients from the ongoing prospective natural history study (Study C4181001) and to 
compare selected outcomes of interest such as height growth, achondroplasia-related 
complications, patient functional status, and quality of life between achondroplasia patients 
in Study C4181005 and those in the concurrent external control. Ultimately, this project will 
assess the feasibility of leveraging the ongoing Study 4181001 to construct a concurrent 
external control for the recifercept pivotal trial. 
Research question and objectives 
There are two research questions: 
1) Can a concurrent external control for the recifercept phase 2 clinical trial be constructed 
using achondroplasia patients from a prospective observational natural history study? 
2) What are differences in height growth, achondroplasia-related complications, patient 
functional status, and quality of life between patients enrolled in the recifercept phase 2 
clinical trial and those in the concurrent external control? 
Objectives of this pilot project will be: 
1. Construct a concurrent external control arm for recifercept phase 2 clincial trial using 
achondroplasia patients from a prospective observal natural history study 
2. If objective #1 is met, the following will be compared to examine differences between 
patients enrolled in the recifercept phase 2 clincial trial and those in the concurrent 
external control: 
• Height growth 
• Selected anthropometric measurements, including but not limited to: standing height, 
sitting height, knee height, arm span, length of the legs, sitting height/standing height 
ratio, arm span to height/length difference, knee height/lower segment ratio 

Recifercept 
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• Achondroplasia-related orthopaedic complications (including lordosis, kyphosis, 
small foramen magnum, spinal stenosis), and other achondroplasia-related 
complications (including apnea, AOM, and hydrocephalus) 
• Differences in functional status and health-related quality of life 
Study design 
This is a retrospective cohort study using existing data from two ongoing studies: C4181001 
and C4181005. Study C4181005 includes 63 achondroplasia patients in total, approximately 
54 patients aged 2 to 10 years (inclusive) and 9 patients aged 3 months to 2 years, who are 
enrolled and randomized to receive one of three doses of recifercept (1mg/kg once-weekly, 
2mg/kg twice-weekly, or 1.5mg/kg once-daily, n=21 per dose) subcutaneously for 12 
months. Study C4181001 includes approximately 300 children with achondroplasia aged 0- 
15 years who are recruited from global sites. Patient data will be collected at baseline and at 
every 3-month interval visit, for a maximum of 5 years. 
Study population 
Inclusion Criteria: 
All patients from Study C4181005 who have completed Visits 1 through 11 (at D183) will be 
included in this project. 
To construct a concurrent external control from Study C4181001, patients from Study 
C4181001 will need to meet the following eligibility criteria from Study C4181005: 
• Documented, confirmed genetic diagnosis of achondroplasia from historical medical 
records (test must have been performed at a laboratory fully accredited for genetic testing 
under local regulations) 
 
• Aged ≥ 3 months to <11 years (up to the day before 11th birthday inclusive) at time of 
enrollment into Study C4181001 
• Have completed at least 2 valid height/length measurements (at least 3 months apart) 
• Assessed for Tanner stage 1 during physical examination before or at enrollment into 
Study C4181001 (must include assessment of breast development for females, or 
testicular stage for males) 
 
• Able to stand independently for height measurements (if ≥ 2 years of age at enrollment); 
If aged <2 years at enrollment, has a documented historical MRI brain/cervical spine 
performed in the previous 12 months. 
• Have at least 6 months of available follow-up data after enrollment into Study C4181001 

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Exclusion criteria: 
• Presence of severe obesity (BMI > 95% percentile on Hoover-Fong BMI charts) 
• Body weight <7kg or >30kg 
• History of chronic kidney disease (CKD) or renal impairment 
• History of receipt of any treatment that are known to potentially affect growth (including 
oral steroids > 5 days in the last 6 months before enrollment, high dose inhaled 
corticosteroids (>800 mcg/day beclametasone equivalent) and medication for attention 
deficient hyperactivity disorder) 
• Less than 6 months since fracture or surgical procedure of any bone determined from the 
baseline visit date. 
• Presence of any internal guided growth plates/devices 
History of removal of internal guided growth plates/devices within 6 months prior to 
enrollment 
Data sources 
This retrospective cohort study will include achondroplasia patients from Study C4181005 
and those from Study C4181001 who meet the inclusion and exclusion criteria of Study 
C4181005. Study C4181005 is a single-arm trial to evaluate the safety and tolerability of 
recifercept doses and dosing regimen, and efficacy to increase height growth in 
achondroplasia patients. Study C4181005 will include approximately 63 children with 
achondroplasia aged 3 months to 10 years (inclusive) with Tanner Stage 1, who are enrolled 
and randomized to receive one of three doses of recifercept (1mg/kg once-weekly, 2mg/kg 
twice-weekly, or 1.5mg/kg once-daily) subcutaneously for 12 months. Demographics, 
medical history, anthropometric measurements, and patient-reported outcomes in functional 
status and quality of life are collected approximately every 3 months. Study C4181001 is a 
prospective natural history study to collect longitudinal anthropometric and disease-related 
complication data in children with achondroplasia. It will include approximately 300 
achondroplasia patients aged 0-15 years with Tanner Stage 1 recruited from global sites. 
Patient data will be collected at baseline and at every 3-month interval visits, for a maximum 
of 5 years. Further details on data sources are presented in Table3. 
Study size 
The determination of study size of this protocol is exclusively limited to addressing the 
second objective of examining the differences between patients enrolled in the recifercept 
phase 2 clinical trial and those enrolled in the concurrent external control. For the purposeof 
consistency with the analysis of the primary endpoint Study C4181005, consideration of 
study size for this protocol is further limited to a comparison of height growth, defined as the 

Recifercept 
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ratio of change from baseline of standing height at 6 months or 12 months of a patient taking 
recifercept to a matched subject in the concurrent external control. The null hypothesis is the 
median value (ie, 50 percentile) of the aforementioned ratio is equal to 1. 
A table and figure presented below displays the number of pairs required to detect the 
median ratio (denoted as ) under the alternative hypothesis. 
Table 1. Sample size and power calculation 
 
Type I 
error 
Power 
Number of Pairs to detect  
 = 1.5 
 = 2 
 = 2.5 
 = 3 
 = 3.5 
 = 4 
.05 
.8 
88 
22 
10 
6 
4 
3 
.05 
.9 
115 
29 
13 
8 
5 
4 
.1 
.8 
71 
18 
8 
5 
3 
2 
.1 
.9 
96 
24 
11 
6 
4 
3 
.2 
.8 
55 
14 
7 
4 
3 
2 
.2 
.9 
77 
20 
9 
5 
4 
3 
 
Data analysis 
Descriptive statistics will be tabulated on patient demographic and baseline clinical 
characteristics between achondroplasia patients from Study C4181005 and patients from 
Study C4181001 who meet all the inclusion and exclusion criteria of Study C4181005. To 
construct a concurrent external control for Study C4181005, a propensity score (PS) will be 
created to achieve balance across covariates between achondroplasia patients from Study 
C4181005 and patients from Study C4181001 who meet all the eligibility criteria of Study 
C4181005. The PS will be estimated using standard logistic regression approaches with the 
“outcome” variable being the data source (whether patients were included in Study 
C4181005 and exposure to recifercept treatment) and the predictors being the variables 
associated with both the exposure (recifercept treatment) and the outcomes of interest (i.e. 
height growth). This model will provide the predicted probability of being in the trial cohort 
relative to the concurrent external control cohort as a function of the covariates (the 
propensity score of being included in Study C4181005). The potential covariates may include 
demographics (e.g. age, gender, race and ethnicity), clinical characteristics (e.g. presence of 
achondraplasia-related complications, Tanner stage, and other non-achondroplasia-related 
conditions of medical significance). The distribution of the PS will be reviewed and patients 
with a PS in the areas of nonoverlap and/or with extreme PS values might be excluded to 
improve validity (PS trimming). Each patient in the PS trimmed receifercept group will be 

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matched on a ratio of 1:1 with patients in the PS trimmed concurrent external control using 
optimal nearest neighbour matching with a maximum caliper of 1%. Pre- and post-matching 
balance will be assessed using standardized differences between these two PS-matched 
groups. A negative control outcome may also be identified to evaluate the pre- and post- 
matching balance. 
After the concurrent external control is constructed by PS matching, descriptive statistics will 
be tabulated on patient demographic and baseline clinical characteristics between 
achondroplasia patients from PS-matched recifercept phase 2 trial cohort and those from PS- 
matched concurrent external control. Two-sample T-tests will be used for continuous 
variables, and chi-square tests for categorical variables assuming the distribution is normal. 
Frequency of primary, secondary CCI 
 outcomes of interest and 95% confidence 
intervals will be computed. 
Hazard ratios and associated 95% confidence intervals of dichotomous outcomes (including 
height growth in the achondroplasia reference population +50%, and occurrence of selected 
achondroplasia-related complications) in PS-matched groups will be estimated by 
multivariable cox proportional hazards regression models. The effect of recifercept on 
continuous outcomes (including height growth, anthropometric measures, CCI 
 
in PS-matched groups will be estimated by linear mixed 
models. 
To maximize the number of patients in the trial cohort and the concurrent external control 
cohort included in this pilot project, additional methods will be explored. Coarsened 
weighting and full matching may be explored. Other than matching, inverse probability 
weight (IPW) and/or the fine stratification weighting may also be used to balance the key 
covariates between patients in the concurrent external control cohort (patients in C4181001 
who meet the inclusion and exclusion criteria of Study C4181005) and patients in Study 
C4181005 (details of these methods will be outlined in the SAP). 

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5. AMENDMENTS AND UPDATES 
 
Amendment 
number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 
1.1 
Nov 09, 
2023 
Milestones 
Realigned end of data collection 
date; Updated CSR approval date to 
be 11 months after end of data 
collection, and BR tables to be 12 
months after end of data collection. 
Recifercept discontinued, never reached 
POC; hence not a Pfizer authorized 
product, not subject to Article 46, and 
CSR approval deadline should be 11 
months after end of data collection date 
not 6 months; BR tables deadline 
should be 12 months after end of data 
collection. 
Team agreed, Kofi suggested to do 
protocol administrative amendment. 
 
6. MILESTONES 
 
Milestone 
Timeline 
Study Protocol 
May 2022 
Statistical analysis plan 
June 2022 
Start of data collection 
October 2022 
End of data collection 
May 2023 
Data analysis and internal study report 
April 2024 
Basic Results tables for CT.gov 
May 2024 
 
7. RATIONALE AND BACKGROUND 
Achondroplasia is a heritable autosomal dominant disorder and is the most common form of 
skeletal dysplasia in humans, with a global birth prevalence of 1 in 25-30,000 or ~250,000 
individuals worldwide (1–3). Achondroplasia is caused by a single-point gain-of-function 
mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) (2,4). FGFR 
is a key inhibitory regulator of endochondrial ossification and its over-activiation interferes 
with normal chondrocyte maturation and causes shorter long bones and changes in flat bones 
such as the occipital bone and vertebrae. 

Recifercept 
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Achondroplasia results in short stature and a range of severe complications due to abnormal 
ossification centers in the cranial base, facial bones, vertebrae, rib cage, and joints. Lordosis, 
kyphosis, small foramen magnum, and spinal stenosis are the most common achondroplasia- 
related orthopaedic complications. Other achondroplasia related complications include sleep- 
disordered breathing, otitis media, and hydrocephalus. Medical complications associated with 
achondroplasia greatly impact physical and psychosocial functioning, self-esteem, and 
patient quality of life (3,5). 
Currently, vosoritide is the only treatment approved by EMA (for achondroplasia patients 
aged 2 years and older with open growth plates) and FDA (for achondroplasia patients aged 5 
years and older with open growth plates) to increase linear growth. It is an analog of C-type 
natriuretic peptide and works by binding to a receptor called natriuretic peptide receptor type 
B (NPR-B), which reduces the activity of FGFR3. Other available treatments are either 
aimed at limb lengthening with surgery or are interventions to treat the complications 
associated with achondroplasia. Recifercept is a modified soluble recombinant human FSFR3 
under development 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. 
A recifercept phase 2 clinical study (Study C4181005) is ongoing to investigate the safety, 
tolerability, pharmacokinetics (PK) and efficacy of recifercept in children aged 3 months to 
10 years with achondroplasia. Fifty-four eligible participants aged 2-10 years and 9 patients 
aged 3 months to 2 years will be enrolled and randomized to receive one of three doses of 
recifercept subcutaneously (1mg/kg once-weekly, 2mg/kg twice weekly, or 1.5mg/kg once- 
daily, n=21 per dose). Once participants complete the phase 2 trial, they will be offered 
enrollment into an open-label extension study at the dose previously received in the phase 2 
trial or at the therapeutic dose once it is identified. A separate multi-country prospective 
observational natural history study (Study C4181001) is ongoing to examine the 
anthropometric characteristics, and achondroplasia-related symptoms, tests, and treatments 
among children with achondroplasia. A total of 300 achondroplasia patients aged 0 and 15 
years of age will be recruited and followed up for a duration of 5 years. All patients 
participating in Study C4181005 were or will be recruited from Study C4181001. 
Objectives of this project are to evaluate the feasibility of constructing a concurrent external 
control for the recifercept phase 2 clinical trial (Study C4181005) using achondroplasia 
patients from the ongoing prospective natural history study (Study C4181001) and to 
compare selected outcomes of interest such as height growth, achondroplasia-related 
complications, and quality of life between achondroplasia patients in Study C4181005 and 
those in the concurrent external control. Ultimately, this project will assess the feasibility of 
leveraging the ongoing Study 4181001 as a concurrent external control arm for the 
recifercept pivotal trial. 

Recifercept 
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8. RESEARCH QUESTION AND OBJECTIVES 
There are two research questions: 
1) Can a concurrent external control for the recifercept phase 2 clinical trial be constructed 
using achondroplasia patients from a prospective observational natural history study? 
2) What are differences in height growth, achondroplasia-related complications, patient 
functional status, and quality of life between patients enrolled in the recifercept phase 2 
clinical trial and those in the concurrent external control? 
Objectives of this pilot project include: 
1. Construct a concurrent external control arm for recifercept phase 2 clincial trial using 
achondroplasia patients from a prospective observal natural history study 
2. If objective #1 is met, the following will be compared to examine differences between 
patients enrolled in the recifercept phase 2 clincial trial and those in the concurrent external 
control: 
• Height growth 
• Selected anthropometric measurements, including but not limited to: standing 
height, sitting height, knee height, arm span, length of the legs, sitting 
height/standing height ratio, arm span to height/length difference, knee 
height/lower segment ratio 
• Achondroplasia-related orthopaedic complications (including lordosis, kyphosis, 
small foramen magnum, spinal stenosis), and other achondroplasia-related 
complications (including apnea, AOM, and hydrocephalus) 
• Differences in functional status and health-related quality of life 
 
 
9. RESEARCH METHODS 
9.1. Study design 
This is a retrospective cohort study using existing data from two ongoing studies: C4181001 
and C4181005. The study population will include two independent study cohorts: a) patients 
from Study C4181005 who have completed Visits 1 through 11 (at D183); b) patients from 
Study C4181001 who meet the eligibility criteria for Study C4181005 and have at least 6 
months follow-up data. Eligible patients from Study C4181001 will be included as potential 
external controls for patients in Study C4181005, using propensity score methodology. 
This pilot study has the potential to demonstrate the feasibility of Study C4181001 as 
concurrent external controls and provide viable study design options for the recifercept 

Recifercept 
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pivotal trial. It will also provide information on the efficacy of recifercept compared to 
clinical practices in the real world. Having an external control arm in the trial allows for 
increased efficiency and decreased product development time. 
9.2. Setting 
This retrospective cohort study will include achondroplasia patients from Study C4181005 
and those from Study C4181001 who meet the inclusion and exclusion criteria of Study 
C4181005. Study C4181005 is a single-arm trial to evaluate the safety and tolerability of 
recifercept doses and dosing regimen, and efficacy to increase height growth in 
achondroplasia patients. Study C4181005 will include approximately 63 children with 
achondroplasia aged 3 months to 10 years (inclusive) with Tanner Stage 1, who are enrolled 
and randomized to receive one of three doses of recifercept (1mg/kg once-weekly, 2mg/kg 
twice-weekly, or 1.5mg/kg once-daily) subcutaneously for 12 months. Demographics, 
medical history, anthropometric measurements, and patient-reported outcomes in functional 
status and quality of life are collected approximately every 3 months. Study C4181001 is a 
prospective natural history study to collect the longitudinal anthropometric and disease- 
related complication data in children with achondroplais. It will include approximately 300 
achondroplasia patients aged 0-15 years with Tanner Stage I recruited from global sites. 
Patient data will be collected at baseline and at every 3-month interval visits, for a maximum 
of 5 years. Further details on data sources are presented in Table 1. 
Table 2. Data sources* 
 
Recifercept phase 2 Clinical Trial (Study 
C4181005) 
Natural History Study (Study C4181001) 
Study population 
3m-10y, Tanner Stage 1 
0-10y, Tanner Stage 1 
Study duration 
12 months 
Up to 5 years 
Visit interval 
- Medical history collected at baseline 
- Anthropometric measurements every 3 
months 
- Biomarkers baseline, D1, D4, D8, D15, 
D29, M2, M3, M6, M9, M12 
- Complications collected every 3 months 
- Anthropometric measures every 3 
months 
- Biomarkers sample taken once annually 
CCI 
CCI 
Sample size 
63 patients 
300 patients anticipated 
Primary objective 
- Evaluate the safety and tolerability of 
recifercept doses and dosing regimens in 
participants aged ≥ 2 to <11 years with 
achondroplasia 
- Collection of longitudinal 
anthropometric and disease-related 
complication data in children with 
achondroplasia 

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- Assess efficacy of recifercept to 
increase height growth in children with 
achondroplasia 
Secondary outcomes 
CCI 
- To evaluate the pharmacokinetics of 
recifercept in participants aged ≥ 2 to 
<11 years with achondroplasia 
- To assess efficacy of recifercept to 
improve ahondroplasia-related 
complications 
- To assess change in individual safety 
parameters 
- Investigation of potential serum 
biomarkers in children with 
achondroplasia 
CCI 
 
9.2.1. Inclusion criteria 
All patients from Study C4181005 who have completed Visits 1 through 11 (at D183) will be 
included in this project. 
To construct a concurrent external control, patients from Study C4181001 will need to meet 
the following inclusion criteria from Study C4181005 to be eligible for inclusion: 
• Documented, confirmed genetic diagnosis of achondroplasia from historical medical 
records (test must have been performed at a laboratory fully accredited for genetic 
testing under local regulations) 
 
• Aged ≥ 3 months to <11 years (up to the day before 11th birthday inclusive) at time of 
enrollment into the observational natural history study. 
• Havecompleted at least 2 valid height/length measurements (at least 3 months apart) 
• Assessed for Tanner stage 1 during physical examination before or at enrollment 
(must include assessment of breast development for females, testicular stage for 
males) 

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• Able to stand independently for height measurements (if ≥ 2 years of age at 
enrollment); If aged <2 years at enrollment, has a documented historical MRI 
brain/cervical spine performed in the previous 12 months. 
• Have at least 6 months of available follow-up data after enrollment into the natural 
history study 
9.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
• Presence of severe obesity (BMI>95% percentile on Hoover-Fong BMI charts); 
• Body weight <7kg or >30kg 
• History of chronic kidney disease (CKD) or renal impairment 
• History of receipt of any treatment that are known to potentially affect growth 
(including oral steroids > 5 days in the last 6 months before enrollment, high dose 
inhaled corticosteroids (>800 mcg/day beclametasone equivalent) and medication for 
attention deficient hyperactivity disorder. 
• Less than 6 months since fracture or surgical procedure of any bone determined from 
the baseline visit date. 
• Presence of any internal guided growth plates/devices 
• History of removal of internal guided growth plates/devices within 6 months prior to 
enrollment 

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9.3. Variables 
Table 3. Listing of all variables of importance 
 
Variable 
Role 
Phase II Recifercept Clinical Trial 
(C4181005) 
Natural History Study (C4181001) 
Operational definition 
Achondroplasia 
treatment 
Exposure 
Recifercept dosage and duration: 
Recifercept dosage: 
1mg/kg once-weekly 
2mg/kg twice-weekly 
1.5mg/kg once-daily 
Achondroplasia-related treatment and 
duration 
Collected every 3 months 
Height Growth 
Primary 
outcome 
Collected every 3 months until end of 
study participation 
Collected every 3 months until end of 
study participation 
Defined as increase in height 
growth above expected growth in 
reference population, defined as the 
height growth in the achondroplasia 
reference population +50% 
Anthropometric 
Secondary 
- Standing height 
- Standing height 
Length of the legs will be 
Measurements 
outcome 
- Sitting height 
- Sitting height 
calculated as the difference 
- Knee height 
- Knee height 
between standing and sitting height 
- Arm span 
- Arm span 
- Length of the legs 
- Length of the legs 
- Sitting height/standing height ratio 
- Sitting height/standing height ratio 
- Arm span to height/length 
- Arm span to height/length 
difference 
difference 
- knee height: lower segment ratio 
- knee height: lower segment ratio 
- Collected at 1m, 3m, 6m, 9m, 1y 
-collected at baseline, every 3m, and 
end of study visit 
Achondroplasia- 
Secondary 
Baseline collection 
- Lordosis 
related 
outcome 
- foramen magnum decompression 
- Kyphoscoliosis 
orthopaedic 
- cranial surgery 
- Small foramen magnum 
complications 
Occurrence during follow-ups 
- Spinal stenosis 
- collected at 6m, 1y, 2y, 3y, and 4y 
Collected every 3 months until end of 
study participation 

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Other 
achondroplasia- 
related 
complications 
Secondary 
outcome 
- Sleep disordered breathing 
- Acute Otitis Media (AOM) 
- Hydrocephalus 
- Sleep disordered breathing 
- Acute Otitis Media (AOM) 
- Hydrocephalus 
CCI 
 
 
 
 
Demographics 
Covariate 
- Age 
- Gender 
- Race and ethnicity 
Collected at baseline 
- Age 
- Gender 
- Race and ethnicity 
Collected at baseline 
Puberty 
Covariate 
Tanner stage 
Collected at baseline 
Tanner stage 
Collected at baseline 
Weight 
Covariate 
Body weight 
Collected every 3 months until end of 
study participation 
Body weight 
Collected every 3 months until end of 
study participation 
History of 
achondroplasia- 
related medical 
conditions 
Covariate 
Sleep-disordered breathing 
Chronic otitis media 
Lordosis 
Kyphosis 
Spinal stenosis 
Hydrocephalus 
Assessed at baseline 
Sleep-disordered breathing 
Chronic otitis media 
Lordosis 
Kyphosis 
Spinal stenosis 
Hydrocephalus 

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9.4. Study size 
The determination of study size of this protocol is exclusively limited to addressing the 
second objective of examining the differences between patients enrolled in the recifercept 
phase 2 clinical trial and those enrolled in the concurrent external control. For the purposeof 
consistency with the analysis of the primary endpoint Study C4181005, consideration of 
study size for this protocol is further limited to a comparison of height growth, defined as the 
ratio of change from baseline of standing height at 6 months or 12 months of a patient taking 
recifercept to a matched subject in the concurrent external control. The null hypothesis is the 
median value (ie, 50 percentile) of the aforementioned ratio is equal to 1. 
A table and figure presented below displays the number of pairs required to detect the 
median ratio (denoted as ) under the alternative hypothesis (Table 1). 
Figure 1. Sample Size 
 
 
 
9.5. Data management 
All data for the described analysis will be obtained from Study C4181001 and Study 
C4181005 databases. Data management procedures including data collection, retrieval, 
preparation and retention are described in those protocols. 
In summary, for study C4181001 data management involved the completion of a CRFfor 
each study participant. The investigator was responsible for the collection and reporting of all 
clinical, safety, and laboratory data entered on the CRFs and any other data collection forms 
(source documents). Additionally, all study data was required to be verifiable by source 

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documents. Study records were retained by the investigator in accordance with International 
Council for Harmonisation (ICH), local guidelines, or clinical study agreement (CSA). 
Records were required to be kept for a minimum of 25 years after study completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
For study C4181005, all participant data relating to the study was recorded on printed or 
electronic CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator was responsible for verifying that data entries were accurate and 
correct, maintaining accurate documentation of source data that supports the CRF, and 
ensuring that CRF were securely stored in electronic form. Sponsors or designees were 
responsible for data management and quality checking the data. Study monitors also 
performed ongoing source data verification to confirm that entered into the CRF were 
accurate, complete, and verifiable from source documents. Records and documents 
pertaining to study conduct were required to be maintained for at least 15 years, unless local 
policies or institutional regulations required a longer retention period. 
9.6. Data analysis 
A single pooled dataset will be released for analysis. The release will occur when for 
selected, targeted data (in Table 3): a) review and documentation of relevant CRF and non- 
CRF data; and b) all open queries are resolved. There will be two releases of data. The first 
release coincides with approximately 30 pairs of patients – that is, a patient from C4181001 
matched to a patient from C4181005 – having 6 months of growth data. The second release 
will take place at the beginning of the interim analysis for C4181005. There may be an 
additional release of data from both studies that coincides with the completion of C4181005. 
Descriptive statistics will be tabulated on patient demographic and baseline clinical 
characteristics between achondroplasia patients from Study C4181005 and patients from 
Study C4181001 who meet all the inclusion and exclusion criteria of Study C4181005. To 
construct a concurrent external control for Study C4181005, a propensity score (PS) will be 
created to achieve balance across covariates between achondroplasia patients from Study 
C4181005 and patients from Study C4181001 who meet all the eligibility criteria of Study 
C4181005. The PS will be estimated using standard logistic regression approaches with the 
“outcome” variable being the data source (whether patients were included in Study 
C4181005 and exposure to recifercept treatment) and the predictors being the variables 
associated with both the exposure (recifercept treatment) and the outcomes of interest (i.e. 
height growth). This model will provide the predicted probability of being in the trial cohort 
relative to the concurrent external control cohort as a function of the covariates (the 
propensity score of being included in Study C4181005). The potential covariates may 
include demographics (e.g. age, gender, race and ethnicity), clinical characteristics (e.g. 
presence of achondraplasia-related complications, Tanner stage, and other non- 
achondroplasia-related conditions of medical significance). The distribution of the PS will be 
reviewed and patients with a PS in the areas of nonoverlap and/or with extreme PS values 
might be excluded to improve validity (PS trimming). Each patient in the PS trimmed 
receifercept group will be matched on a ratio of 1:1 with patients in the PS trimmed 
concurrent external control using optimal nearest neighbour matching with a maximum 

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caliper of 1%. Pre- and post-matching balance will be assessed using standardized 
differences between these two PS-matched groups. A negative control outcome may also be 
identified to evaluate the pre- and post-matching balance. 
After the concurrent external control is constructed by PS matching, descriptive statistics will 
be tabulated on patient demographic and baseline clinical characteristics between 
achondroplasia patients from PS-matched recifercept phase 2 trial cohort and those from PS- 
matched concurrent external control. Two-sample T-tests will be used for continuous 
variables, and chi-square tests for categorical variables assuming the distribution is normal. 
Frequency of primary, secondary and exploretary outcomes of interest and 95% confidence 
intervals will be computed. 
Hazard ratios and associated 95% confidence intervals of dichotomous outcomes (including 
height growth in the achondroplasia reference population +50%, and occurrence of selected 
achondroplasia-related complications) in PS-matched groups will be estimated by 
multivariable cox proportional hazards regression models. The effect of recifercept on 
continuous outcomes (including height growth, anthropometric measures,CCI 
 
in PS-matched groups will be estimated by linear mixed 
models. 
To maximize the number of patients in the trial cohort and the concurrent external control 
cohort included in this pilot project, additional methods will be explored. Coarsened 
weighting and full matching may be explored. Other than matching, inverse probability 
weight (IPW) and/or the fine stratification weighting may also be used to balance the key 
covariates between patients in the concurrent external control cohort (patients in C4181001 
who meet the inclusion and exclusion criteria of Study C4181005) and patients in Study 
C4181005 (details of these methods will be outlined in the SAP). 
9.7. Data sources 
For this pilot study, the data in Table 9.3 from C4181001 and C4181005 will be pooled to 
create a single dataset. With respect to patients the component datasets will be mutually 
exclusive – that is, there are no patients common to both studies. 
This retrospective cohort external control arm study will include achondroplasia patients 
from Study C4181005 and those from Study C4181001 who meet the inclusion and 
exclusion criteria of Study C4181005. Study C4181005 is a single-arm trial to evaluate the 
safety and tolerability of recifercept doses and dosing regimen, and efficacy to increase 
height growth in achondroplasia patients. Study C4181005 will include approximately 63 
children with achondroplasia aged 3 months to 10 years (inclusive) with Tanner Stage 1, who 
are enrolled and randomized to receive one of three doses of recifercept (1mg/kg once- 
weekly, 2mg/kg twice-weekly, or 1.5mg/kg once-daily) subcutaneously for 12 months. 
Demographics, medical history, anthropometric measurements, and patient-reported 
outcomes in functional status and quality of life are collected approximately every 3 months. 
Study C4181001 is a prospective natural history study to collect the longitudinal 
anthropometric and disease-related complication data in children with achondroplais. It will 

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include approximately 300 achondroplasia patients aged 0-15 years with Tanner Stage I 
recruited from global sites. Patient data will be collected at baseline and at every 3-month 
interval visits, for a maximum of 5 years. Further details on data sources are presented in 
Table 2. 
9.8. Quality control 
Quality control procedures are described in the protocols of Study C4181001 and Study 
C4181005. No additional quality control will be performed in this study. 
9.9. Limitations of the research methods 
There are several limitations to this study. Externally controlled studies do not rely on 
randomization, resulting in inherent bias and a potential lack of comparability between 
treated and untreated groups (Tjiete & Brouder, 2010)(6). We will apply the same inclusion 
and exclusion criteria to select patients in the external control arm and use propensity score 
methodology to adjust for the differences between patients included in the Study C4181005 
and patients as external controls. However, depending on the extent of data collection in 
Study C4181001 and Study C4181005, the propensity score modeling may not adjust for all 
potential confounders. Additionally, even though Study C4181001 is a multi-country study, 
patients included in Study C4181001 and Study C4181005 may not represent the entire 
achondroplasia patient population, and generalizability of study results may be limited. 
9.10. Other aspects 
Not applicable. 
 
 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information 
This study involves data that exist in anonymized structured format and contain no patient 
personal information. 
10.2. Patient consent 
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required. 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) 
Not applicable. 
10.4. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 

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described in Guidelines for Good Pharmacoepidemiology Practices (GPP), The ENCePP 
Code of Conduct for scientific independence and transparency in the conduct 
of pharmacoepidemiological and pharmacovigilance studies, FDA Guidance for Industry: 
Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (7–9). 
 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves data that exist as structured data by the time of study start. In these data 
sources, individual patient data are not retrieved or validated, and it is not possible to link 
(i.e., identify a potential association between) a particular product and medical event for any 
individual. Thus, the minimum criteria for reporting an adverse event (AE) (i.e., identifiable 
patient, identifiable reporter, a suspect product, and event) cannot be met. 
 
 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately. 
 
 
13. REFERENCES 
1. Ireland P, Pacey V, Zankl A, Edwards P, Johnson L, Savarirayan R. Optimal 
management of complications associated with achondroplasia. The Application of 
Clinical Genetics. 2014 Jun;117. 
2. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis. 2019 
Dec;14(1):1. 
3. Constantinides C, Landis SH, Jarrett J, Quinn J, Ireland PJ. Quality of life, physical 
functioning, and psychosocial function among patients with achondroplasia : a targeted 
literature review. Disability and Rehabilitation. 2021 Aug 17;1–13. 
4. Ward J, Gargan A, Smithson S, Atherton G. Orthopaedic manifestations of 
achondroplasia. Orthopaedics and Trauma. 2013 Aug;27(4):229–32. 
5. Gollust SE, Thompson RE, Gooding HC, Biesecker BB. Living with achondroplasia in 
an average-sized world: An assessment of quality of life. Am J Med Genet. 2003 Aug 
1;120A(4):447–58. 
6. Tietje C, Brouder A, editors. International Conference On Harmonisation Of Technical 
Requirements For Registration Of Pharmaceuticals For Human Use. In: Handbook of 

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Transnational Economic Governance Regimes [Internet]. Brill | Nijhoff; 2010 [cited 
2022 Mar 3]. p. 1041–53. Available from: 
https://brill.com/view/book/edcoll/9789004181564/Bej.9789004163300.i-1081_085.xml 
7. Public Policy Committee IS of P. Guidelines for good pharmacoepidemiology practice 
(GPP). Pharmacoepidemiology and Drug Safety. 2016;25(1):2–10. 
8. ENCePP Home Page [Internet]. [cited 2022 Mar 23]. Available from: 
https://www.encepp.eu/code_of_conduct/ 
9. Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic 
Assessment. :23. 
 
 
14. LIST OF TABLES 
Table 1. Sample size and power calculation 
Table 2. Data sources 
Table 3. Listing of all variables of importance 
 
 
15. LIST OF FIGURES 
Figure 1. Sample Size 
 
 
16. ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None. 
 
 
17. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable. 
 
 
18. ANNEX 3. ADDITIONAL INFORMATION 
Not applicable.