An International, Prospective Registry Investigating the Natural History of Participants With Achondroplasia
Conditions: Achondroplasia
Sponsor: Pfizer

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Study Information 
 
Title 
An International, Prospective Registry Investigating the 
Natural History of Participants with Achondroplasia 
Study Phase 
N/A 
Protocol number 
C4181001 
Protocol version identifier 
3.0 
Date 
20 April 2020 
Research question and 
objectives 
To investigate the natural history of participants with 
achondroplasia in terms of: 
• 
Anthropometric characteristics; 
• 
Achondroplasia-related symptoms, tests, and 
treatments; 
• 
Biomarkers of bone growth. 
Author 
PPD 
Unit 
, Clinician, Pfizer Rare Disease Research 
 
 
 
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, by 
accepting or reviewing this document, 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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TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS ................................................................................................ 5 
2. RESPONSIBLE PARTIES .................................................................................................... 7 
3. SUMMARY ........................................................................................................................... 8 
4. AMENDMENTS AND UPDATES ..................................................................................... 11 
5. SCHEDULE OF ACTIVITIES ............................................................................................ 14 
6. RATIONALE AND BACKGROUND ................................................................................ 16 
7. RESEARCH QUESTION AND OBJECTIVES .................................................................. 18 
7.1. Achondroplasia Complications, Tests & Treatments .............................................. 18 
7.2. Anthropometric Parameters ..................................................................................... 19 
7.3. Biomarkers ............................................................................................................... 19 
7.3.1. Collagen X .................................................................................................. 19 
7.3.2. CNP/proCNP ............................................................................................... 19 
7.3.3. Additional Bloods Biomarkers .................................................................... 20 
7.4. Physical Activity Assessments ................................................................................ 20 
8. RESEARCH METHODS ..................................................................................................... 20 
8.1. Study Design ............................................................................................................ 20 
8.1.1. Inclusion Criteria ......................................................................................... 22 
8.1.2. Exclusion Criteria ....................................................................................... 23 
8.1.3. Variables ..................................................................................................... 23 
8.1.3.1. Data Sources .............................................................................. 24 
9. STUDY PROCEDURES ...................................................................................................... 25 
9.1. Demographics .......................................................................................................... 25 
9.2. Medical and Surgical History .................................................................................. 25 
9.3. Physical Examination .............................................................................................. 26 
9.4. Assessment of Obesity ............................................................................................ 26 
9.5. Tanner Stage of Puberty .......................................................................................... 26 
9.6. Achondroplasia-related Interventions ...................................................................... 26 
9.6.1. Follow-up of Achondroplasia-related Complications ................................. 26 
9.7. Non-achondroplasia-related Conditions of Medical Significance ........................... 26 

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9.8. Achondroplasia-related Complications .................................................................... 26 
9.8.1. Sleep Disordered Breathing ........................................................................ 27 
9.8.2. Otitis Media ................................................................................................ 27 
9.8.3. Orthopaedic Complications ......................................................................... 27 
9.8.4. Neurological ................................................................................................ 28 
9.9. Anthropometric Measurements ................................................................................ 28 
9.10. Study Treatments ................................................................................................... 29 
9.11. Concomitant Treatments ........................................................................................ 30 
9.12. Prohibited Treatments ............................................................................................ 30 
9.13. Health-related Quality of Life (HRQoL) Measures ............................................... 30 
9.13.1. Childhood Health Assessment Questionnaire (CHAQ) ............................ 30 
9.13.2. Quality of Life in Short Stature Youth (QoLISSY) Brief ......................... 30 
9.14. Sample Collection .................................................................................................. 31 
9.15. Physical Activity (Accelerometery) ....................................................................... 31 
9.16. Wearability Questionnaire ..................................................................................... 32 
9.17. Gait Walking Assessment ...................................................................................... 32 
10. ASSESSMENTS ................................................................................................................ 32 
10.1. Additional Research .............................................................................................. 32 
10.2. Assessment of Suicidal Ideation and Behaviour (If Applicable) ........................... 32 
10.3. Biological Samples ................................................................................................ 32 
10.4. Imaging Assessments ............................................................................................. 32 
10.5. Management of Incidental Findings ...................................................................... 32 
10.6. Rater Qualifications ............................................................................................... 32 
11. DATA ANALYSIS/STATISTICAL METHODS ............................................................. 33 
11.1. Study Size .............................................................................................................. 33 
11.2. Data Management .................................................................................................. 33 
11.3. Case Report Forms/Data Collection Tools/Electronic Data Record ..................... 33 
11.4. Record Retention ................................................................................................... 35 
11.5. Data Analysis ......................................................................................................... 35 
12. QUALITY CONTROL AND QUALITY ASSURANCE ................................................. 36 
13. LIMITATIONS OF THE RESEARCH METHODS ......................................................... 37 

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14. PROTECTION OF HUMAN PARTICIPANTS ............................................................... 37 
14.1. Participant Information and Consent .................................................................... 37 
14.1.1. Screen Failures ......................................................................................... 39 
14.2. Participant Withdrawal ......................................................................................... 39 
14.2.1. Lost to Follow-up ..................................................................................... 39 
14.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............ 40 
14.4. Ethical Conduct of the Study ................................................................................ 40 
15. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ...................................................................................................................... 41 
15.1. Adverse Events (AE) ............................................................................................ 41 
15.2. Research-Related Injury ....................................................................................... 41 
16. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ....... 51 
16.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ........................................................................................................................... 51 
16.2. Publications by Investigators ................................................................................ 51 
17. REFERENCES .................................................................................................................. 53 
18. LIST OF TABLES ............................................................................................................ 54 
19. LIST OF FIGURES ........................................................................................................... 54 
20. ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .................................................. 54 
21. ANNEX 2. ADDITIONAL INFORMATION .................................................................. 54 

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1. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AGV 
Annual Growth Velocity 
CHAQ 
Childhood Healthcare Assessment Questionnaire 
CNP 
C-type natriuretic peptide 
COM 
Chronic Otitis Media 
CONSORT 
Consolidated Standards of Reporting Trials 
CPAP 
Continuous Positive Airway Pressure 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CTX 
C-Terminal Telopeptide 
CTX-1 
C-Terminal Telopeptide -1 
CXM 
Collagen X Marker 
DCT 
Data Collection Tool 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDP 
Exposure During Pregnancy 
EU 
European Union 
FDA 
Food & Drug Administration 
FGFR3 
Fibroblast Growth Factor Receptor 3 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practice 
HRQoL 
Health Related Quality of Life 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation - 
ID 
Identification 
IEC 
Independent Ethics Committee 

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Abbreviation 
Definition 
IGF-1 
Insulin-like Growth Factor 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging 
NPRB 
Natriuretic Peptide Receptor B Pathway 
NSAE 
Non-Serious Adverse Event 
PI 
Principle Investigator 
proCNP 
C-type natriuretic peptide (CNP) amino-terminal 
propeptide (proCNP) 
P1NP 
Procollagen type 1 N-terminal propeptide 
QoLISSY Brief 
Quality of Life in Short Stature youth 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDS 
Standard Deviation Score 
SEDC 
Spondyloepiphyseal Dysplasia Congenital 
SLE 
Systemic Lupus Erythematosus 
SoA 
Schedule of Activities 
SOC 
Standard of Care 

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2. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
International Coordinating Investigator 
Professor Dr. PPD 
 
Department of Medical Genetics, 
PPD 
 
 
 
 

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3. SUMMARY 
 
PRODUCT 
NAME/NUMBER 
Not applicable; no investigational treatment will be administered 
PROTOCOL 
NUMBER 
C4181001 
DEVELOPMENT 
PHASE 
N/A 
PROTOCOL TITLE 
An International, Prospective Registry Investigating the Natural History of Children 
with Achondroplasia 
INDICATION 
Achondroplasia 
OBJECTIVES 
To investigate the natural history of children with achondroplasia in terms of: 
• 
Anthropometric characteristics; 
• 
Achondroplasia-related symptoms, tests, and treatments; 
• 
Biomarkers of bone growth. 
STUDY DESIGN 
This is a registry study in children with achondroplasia, age 0-15 years, to be 
conducted at multiple clinical sites globally. Children’s information will be collected 
in the registry at baseline and at every 3-month interval visits, for a maximum of 
5 years. 
There will be a visit at Screening, Baseline, 3-month intervals, yearly (±3 weeks) and 
an end of study Visit. The end of this study is defined as the date of the last visit of 
the last child participating in the study. 
PLANNED 
NUMBER OF 
PARTICIPANTS 
The total number of participants planned to be enrolled across all sites is 
approximately 300. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
The following criteria must be met for study inclusion: 
1. Written informed consent/assent is obtained from the participant and/or 
parent(s)/legal guardian(s) before any study-related activity is carried out. 
2. The participant/parent(s)/legal guardian(s) is able to provide written informed 
assent, where this is required according to national legislation, before any 
study-related activity is carried out. 
3. The participant has been diagnosed as having achondroplasia documented by 
clinical diagnosis. 
4. The participant is between 0 years and 15 years of age, up to day before 15th 
birthday, on the date of consent/assent. 
5. The investigator has considered the family and prospective participating child 
being able to comply with the study procedures. 
Evidence of a personally signed and dated informed consent/assent document 
indicating that the participant (or a legally acceptable representative) has been 
informed of all pertinent aspects of the study. 
Participants who are willing and able to comply with scheduled visits, laboratory tests 
and other study procedures. 

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Exclusion criteria: 
The following criteria exclude participation: 
1. The participant has a diagnosis of hypochondroplasia or any short stature 
condition other than achondroplasia (eg, spondyloepiphyseal dysplasia congenital 
[SEDC], pseudo achondroplasia, trisomy 21). 
2. The participant has any medical condition that may impact growth or where the 
treatment is known to impact growth, such as but not limited to hypothyroidism or 
hyperthyroidism, insulin-requiring diabetes mellitus, autoimmune inflammatory 
disease (including celiac disease, systemic lupus erthematosus (SLE), juvenile 
dermatomyositis, scleroderma, and others), autonomic neuropathy, or 
inflammatory bowel disease. 
3. Treatment in the previous 12 months prior to consent/assent with growth 
hormone, insulin-like growth factor 1 (IGF-1), anabolic steroids, or any other 
drug expected to affect growth velocity. 
4. Any surgery that affects the growth plate of the long bones that is planned, or has 
occurred in the past 18 months. 
5. Participation in any interventional study (investigational product or device) for 
treatment of achondroplasia or short stature. 
6. Has had bone-related surgery impacting assessment of anthropometric 
measurements or is expected to have it during the study period. Participants with 
previous limb-lengthening surgery may enroll if surgery occurred at least 
18 months prior to the date of consent/assent and healing is complete without 
sequelae as determined by the investigator. 
7. Has any condition or circumstance that in the view of the investigator places the 
child at high risk of poor compliance with the visit schedule or of not completing 
the study. 
8. Any concurrent disease or condition that in the view of the investigator would 
interfere with study participation. 
PLANNED STUDY 
SITES 
There will be a total of approximately 35 study sites globally. 
CRITERIA FOR 
EVALUATION 
Anthropometric measurements will be the primary assessments, including but not 
limited to Annual Growth Velocity (AGV). 
Clinical course of children with achondroplasia with focus on achondroplasia-related 
symptoms, tests and treatments. 
STATISTICAL 
METHODS 
A detailed master Statistical Analysis Plan (SAP) will be developed covering the 
analytical principles and statistical techniques to be employed both for interim and 
final analyses. This study plans a primary master SAP, as well as supplemental SAPs. 
An advantage of this study design is its ability to answer questions that emerge during 
the study. 
Subsequent and supplemental SAPs - triggered by new research questions emerging 
after the initial master SAP is developed or needed because the registry may evolve - 
can be developed when enough data become available to analyze a research question 
not included in the master SAP. 

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The main purpose of this study is descriptive. 
Generally, descriptive statistics will be reported for all measured variables captured in 
this study. 
Continuous (quantitative) variable summaries will include the number of participants 
(n) with non-missing values, number of missing values, mean and 95% confidence 
interval, standard deviation, median, minimum, and maximum. 
Continuous variables may be classed into groups and analyzed as a categorical 
variable when appropriate. Categorical (qualitative) variable summaries will include 
the frequency and percentage of participants who are in the category or each possible 
value. 
Event data will generally be listed. In case of frequent events, tabulations might be 
considered. 
All analyses will be conducted on all enrolled participant. Data after procedures or 
treatments that may affect growth velocity will be excluded from the analysis of 
anthropometric parameters. 
Interim analyses will be performed regularly. 
CCI 
STUDY DURATION 
The overall study period is foreseen to be 5 years. 
The participant may continue study participation until any of the following criteria is 
met: 
• 
 Growth plates are considered to have fused, defined as standing height gain less 
than 1 cm within the last 6 months; 
• 
The participant has reached end of puberty (Tanner Stage V); 
• 
The participant is enrolled in any interventional study; 
• 
 The participant is diagnosed or develops any of the coniditions related to 
exclusion crtieria 1, 2 & 6; 
• 
The participant is to receive any growth hormone, insulin-like growth factor 
1 (IGF-1), anabolic steroids, or any other drug expected to affect growth velocity; 
• 
The participant has participated in the study for 5 years; 
• 
The participant is considered lost to follow-up. 

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4. AMENDMENTS AND UPDATES 
Document History 
 
Document 
Version 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
section(s) 
changed 
Rationale 
3.0 
20-Apr- 
2020 
Substantial 
N/A 
Change of Sponsor from 
Therachon to Pfizer due to 
acquisition. 
Addition of China and Japan to 
enrich the size of the database 
collected by enrolling 
participants in different regions. 
Additional biomarkers of 
interest were added. 
Demography- Month & Year of 
birth to be collected. To allow 
for analyzing growth 
parameters Achondroplasia in 
natural history against 
population growth charts. 
Revised number of participants 
to approximately enrich the size 
of the database collected. 
Addition of QoLISSY Brief tool 
(HRQoL) & Childhood Health 
Assessment (CHAQ) as an 
assessment of quality of life. 
Addition of optional physical 
activity tracking and wearability 
questionnaire. 
Addition of optional gait 
walking assessments. 
2.0 
31-Jan- 
2019 
Substantial 
N/A 
Clarify that those performed at 
3 monthly visits are also 
required at the yearly visit. 

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Document 
Version 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
section(s) 
changed 
Rationale 
Remove waist circumference 
(already included in 
anthropometric measurements). 
Amend footnotes. 
Amended trial age up to 
15 years to expand range of data 
collected by the study. 
Stratification by age was added 
to better reflect the age range of 
participants that will be enrolled 
in interventional trials with 
TA-46 and the paucity of data 
in the youngest participants 
with achondroplasia who have 
the most severe complications. 
Australia added as Additional 
region now added to the study. 
Clarification of lost to follow up 
criteria as Minimum of 
3 attempted contacts over 1 year 
to be considered lost to follow 
up. 
Add the specific list of 
measurements to be undertaken 
to remove the need to submit 
the anthropometric manual 
which now only serves as a 
manual of the specific 
techniques to be used in 
measurement. 
Remove metabolic system from 
physical examination since it is 
unclear what a metabolic 
system examination involves 
and information is captures 

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Document 
Version 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
section(s) 
changed 
Rationale 
elsewhere (eg, chest/waist 
circumference, weight). 
Amend fasting criteria from 
“are required to” to “should’. 
Acknowledge that some facets 
of sampling are not feasible in 
young participants and whilst 
all efforts should be made to 
adhere to sampling guidelines, 
this is not always possible. 
Addition of derived 
anthropometric measurements. 
Original 
14-Mar- 
2018 
N/A 
N/A 
N/A 
 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs). 

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5. SCHEDULE OF ACTIVITIES 
STUDY PROCEDURES and ASSESSMENTS sections 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 
schedule of activities table, in order to conduct evaluations or assessments required to protect 
the well-being of the participant. 
 
Procedure/Assessment 
Screening Visita 
Baseline Visitb 
Every 3 Monthsc 
(±3 weeks) 
End of Study Visitd 
(±3 weeks) 
Informed Consent & 
Assent (as applicable) 
X 
Eligibility criteria 
X 
X 
Demographics 
X 
Specific Medical & 
Surgical History 
X 
X 
Physical Examination 
X 
X 
X 
Genetic Confirmation of 
Achondroplasiae 
X 
Anthropometric 
Measurements 
X 
X 
X 
Achondroplasia-related 
complications, tests & 
treatments 
X 
X 
X 
Non-achondroplasia-related 
important medical 
conditions and treatmentsf 
Xf 
Xf 
X 
Tanner Stage of Pubertyg 
Xg 
Xg 
X 
Collection of Biomarker 
Blood Sampleh 
X 
(X) 
Every 12 Months 
Concomitant treatments 
X 
X 
→ 
Adverse event monitoring 
X 
X 
→ 
→ 
QoLISSY Brief tool 
(HRQoL) 
X 
X 
X 
Childhood Health 
Assessment Questionnaire 
(CHAQ) 
X 
X 
X 
Physical activity via 
accelerometry (digital 
wearable sensors)i 
(selected sites only) 
X 
X 
X 
X 
Gait walking assessmentj 
(selected sites only) 
X 
X 
X 
X 
Wearability Questionnaire 
of digital sensorsk 
(selected sites only) 
X 
X 
X 
X 
Abbreviations: → = ongoing/continuous event. 

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a. 
Screening may be scheduled within 1 month prior to the Baseline visit. 
b. 
Screening visit and Baseline visit can be combined, if applicable. 
c. 
Three-month follow-up visits are scheduled relative to the date the Baseline Visit was conducted. 
d. 
The End of study visit is conducted if any one of the termination criteria listed are met or after a decision is made by 
the investigator to withdraw the participant from the study. The end of study visit may be combined with a three- 
monthly visit. 
e. 
If not available in medical records, then the result of genetic testing should become available as soon as possible, but 
not later than prior to end of study visit. 
f. 
Any important non-achondroplasia related important medical condition (s) that may potentially jeopardize the 
participant’s health and any treatment based on the medical judgment of the investigator that may affect the 
participant’s growth trajectory (see Section 11.3). 
g. 
Tanner Stage of Puberty: Only for participants ≥7 years of age (providing the investigator confirms there is no 
suspicion of a diagnosis of precocious puberty). 
h. 
Fasting 8-hour blood sample for biomarker analyses should be drawn in the morning. A less than 8-hour prior to 
biomarker analysis should be recorded in the source notes. 
i. 
Physical activity: This assessment is optional for participants and will be performed at selected sites. Wrist and lumbar 
digital wearable sensors will be provided to the participant and worn continuously for 14 days after each three-month 
visit. The sensors will be returned by the participant to the site via a self-addressed stamped envelope after the 14-day 
period of data collection. Only for participants ≥2 years who can walk independently. Participants with any skin 
nickel allergy or silicone or adhesive allergy as well as participants with any implanted medical device (ie, pacemaker 
or electric pumps) should excluded from participation in the physical activity assessments. 
j. 
Walking Assessment: This assessment is optional for participants and will be performed at selected sites. The walking 
assessment will be performed once per participant during any given in-clinic visit. 
Only for participants ≥2 years who can walk independently. Participants with any skin nickel allergy or silicone or 
adhesive allergy as well as participants with any implanted medical device (ie, pacemaker or electric pumps) should 
excluded from participation in the physical activity assessments. 
k. 
Wearability Questionnaire: This assessment is only required for participants who are performing the optional physical 
activity activity. The participant/caregiver will rate the overall comfort of the wrist and lumbar devices at the 
conclusion of the 14 days of wearing the sensors. This will be returned to the site via self-addressed stamped envelope 
along with the sensors. 

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6. RATIONALE AND BACKGROUND 
Achondroplasia is a heritable autosomal dominant disorder and is the most common form of 
short-limbed dwarfism in humans. Achondroplasia is caused by a single-point gain-of- 
function mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). 
FGFR3 is a key inhibitory regulator of endochondrial ossification and its over-activation 
interferes with normal chondrocyte maturation and causes shorter long bones and changes in 
flat bones such as the occipital bone and vertebrae. 
 
In addition to the compromised average height in adult men and woman with achondroplasia 
(ie, 131±5.6 cm and 124±5.9 cm, respectively),1,2 the most severe, potentially debilitating 
and life-threatening complications are associated with respiratory difficulties with prolonged 
periods of intermittent hypoxia due to obstructive sleep apnoea and neurological impairments 
resulting in episodes of central sleep apnoea and other severe cervico-medullary compression 
syndromes.3,4 These achondroplasia manifestations occur with a relatively high frequency 
and severity in the youngest group of participants.5 Respiratory difficulties and neurological 
compression syndromes correlate to dysplasia of the basioccipital, exoccipital bone, and 
craniovertebral junction which lead to contraction of the skull base and facial 
underdevelopment.6 
In addition, a narrow trunk, shortened extremities, particularly proximally, shortened fingers, 
restricted elbow range of motion, limited hip extension, genu varum, and lumbar 
hyperlordosis and thoracolumbar kyphosis contribute to delay in developmental milestones 
and longer-term complications such as osteoarticular problems, chronic pain and stiffness 
and spinal stenosis. 
 
There are relatively few data available on the actual types, rates and timing of 
achondroplasia-related symptoms and complications in the youngest subset of participants. 
Evidence of the natural history of the disease course in relation to symptoms and 
development of complications, the level of actual disease burden over time due to tests and 
treatments, as well as data to support identification of possible risk factors, is lacking. 
 
The design of future interventional trials with potentially disease-modifying therapies to treat 
the underlying morphological disproportions of the skull and skeletal system will benefit 
from a better understanding of the natural history of the disease course in the youngest group 
of participants, where final skeletal and morphological proportions are being established 
prior to entering the final longitudinal growth phase during later stages of childhood and 
adolescents. 
 
The rationale for the prospective, longitudinal registry design to collect information about 
important achondroplasia-related symptoms, tests and treatments is the aim to characterize 
the natural history of the disease course in the youngest participants in relation to symptoms 
and development of complications, the level of actual disease burden over time due to tests 
and treatments, as well as data to support identification of possible risk factors. 

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Despite its importance as a key parameter, growth velocity is difficult to determine in real 
time in achondroplasia, because skeletal growth is slow and clinical tools to accurately detect 
very small increments of growth do not exist. During development, bone is created by a 
process called endochondral ossification, which results in the production of a fragment of 
type X collagen. Endochondral ossification also occurs during long bone growth and fracture 
healing. 
 
Recently, Coghlan et al. discovered that the type X collagen fragment could be isolated from 
blood and its concentration correlated with skeletal growth velocity (Coghlan 2017).8 
Fragment concentration was inversely correlated with age and fluctuated during fracture 
healing in adults. The authors developed an assay to quantify the fragment that could be 
useful as a real-time marker of skeletal growth in participants and for monitoring response to 
treatment for growth and bone disorders. Recently, the same authors established that type X 
collagen fragment corresponds to the rate of linear bone growth at time of measurement. 
Serum concentrations of Collagen X Marker (CXM) plotted against age show a pattern 
similar to well-established height growth velocity curves and correlate with height growth 
velocity calculated from incremental height measurements in this study. Hence, CXM 
testing may be useful for monitoring growth in the pediatric population, especially responses 
of infants and participants with genetic and acquired growth disorders to interventions that 
target the underlying growth disturbances, such as currently planned studies in participants 
with achondroplasia. 
 
In this clinical study, CXM testing as well as measurement of C-type natriuretic peptide 
(CNP) and its amino-terminal propeptide (proCNP) will be done. The rationale for also 
assessing CNP/proCNP, P1NP and CTX is to establish whether treatment with a ligand trap 
may lead to normalization of CNP levels due to restoration of the physiological signalling 
pathway or changes in associated biomarkers of growth plate metabolism. 
 
The Tanner Stage of puberty will not be required in participants under 7 years of age, 
providing the investigator confirms there is no suspicion of a diagnosis of precocious 
puberty. 
 
The rationale for the termination criteria is the consideration that once growth plates have 
fused, the participant will not be considered eligible for participation in future clinical trials. 
 
The potential risks of study participation include risks of medical evaluation, anthropometric 
measurements and venepuncture. The risks associated with participation in this study are 
considered minimal, since the nature of the anthropometric assessments and medical 
observations tracked and documented are all considered to be established as part of current 
standard of care (SOC). The extent of repeated anthropometric measurements as well as 
repeated venepuncture may not be considered SOC at all sites; however, the frequency is 
considered acceptable to be associated with a minimal risk. There is no direct benefit to the 
participant, their parent(s) or the health care providers other than being able to track the 
participating participant’s development compared to their peers, something that will be 

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CCI 
increasingly important with disease-modifying therapies being developed targeting the 
consequences of the mutation of the FGFR3 on the human body. 
 
7. RESEARCH QUESTION AND OBJECTIVES 
Primary Objective(s): 
Primary Endpoint(s): 
• Collection of longitudinal 
anthropometric and disease-related 
complication data in children with 
achondroplasia. 
 
Secondary Objective(s): 
• Investigation of potential serum 
biomarkers in children with 
achondroplasia. 
Standing height, sitting height, knee height, 
head circumference, arm span, length of the 
legs (calculated as the difference between 
standing and sitting height)and 
achondroplasia related AEs. 
Secondary Endpoint(s): 
• Baseline and post-baseline 
measurements of serum collagen 
X marker. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1. Achondroplasia Complications, Tests & Treatments 
Achondroplasia related complications, tests and treatments will be collected in a prospective 
and standardized fashion to allow characterization of the natural history of the disease course 
in the youngest participants in relation to symptoms and development of complications, the 
level of actual disease burden over time due to tests and treatments, as well as data to support 
identification of possible risk factors. 

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7.2. Anthropometric Parameters 
Anthropometric data will be collected in a prospective and standardized fashion to allow 
correlation to disease severity and serve as baseline data for future interventional clinical 
trials. Standing height is most commonly used measure of growth in participants. As one of 
the morphological characteristics of participant with achondroplasia is the shorter limbs, any 
biomarker used for the study of these participants should be able to reflect this impaired 
growth. 
 
The arm span and the length of the legs (calculated as the difference between standing and 
sitting height) will be used as robust measures of the growth of the limbs. All other 
measurements collected are considered CCI 
 in nature and may be used to support 
further endpoints in later development trials. 
 
7.3. Biomarkers 
Blood samples will be collected to investigate potential biomarkers of bone growth that can 
be used to improve efficacy assessment and dose finding in future therapeutic trials for 
RECIFERCEPT. To minimize the burden of the blood sampling, it is estimated that it will 
be limited to once yearly in this study. 
 
7.3.1. Collagen X 
Collagen X Marker (CXM), is a degradation by-product of endochondral ossification that is 
released into the circulation in proportion to overall growth plate activity. This marker 
corresponds to the rate of linear bone growth at time of measurement as recently 
demonstrated in children of normal average growth. Serum concentrations of CXM plotted 
against age showed a pattern similar to well-established height growth velocity curves and 
correlated with height growth velocity calculated from incremental height measurements in 
this study (Coghlan 2017, Olney 2012).8,9 This study will be the first time the CXM will be 
studied in the achondroplasia population. The study will provide important new data to 
understand the circulating levels of a chondrocytic differentiation marker in children with 
achondroplasia. 
 
7.3.2. CNP/proCNP 
C-type natriuretic peptide (CNP) and its amino-terminal propeptide (proCNP) are known 
biomarkers for chondrocyte activity related to growth (Olney 2012)9 and have been shown to 
be expressed in elevated levels in children with achondroplasia suggesting a desensitization 
to CNP/proCNP in this population (Olney 2015).10 Only very limited longitudinal 
CNP/proCNP data are available in children with achondroplasia. This study will generate 
data to confirm and support the earlier finding. Our interest to understand the mechanism of 
achondroplasia requires that we establish additional data on the levels of CNP/proCNP in 
achondroplasia children of different ages. This data will provide further insight into the 
pathophysiology of the condition and help to understand whether the CNP/natriuretic peptide 
receptor B(NPRB) pathway contributes to the regulation of linear bone growth in 
achondroplasia children. 

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7.3.3. Additional Bloods Biomarkers 
Additional biomarkers such as P1NP and CTX will be analysed. These analyses will be 
limited to biomarkers known to be related to bone growth, potential markers for treatment 
response or to the pathology of Achondroplasia. 
 
CTX-1 is a crosslink peptide sequence of type I collagen, found, among other tissues, in 
bone. This specific peptide sequence relates to bone turnover because it is the portion that is 
cleaved by osteoclasts during bone resorption, and its serum levels are therefore proportional 
to osteoclastic activity. 
 
P1NP is derived from type I procollagen cleavage during collagen synthesis and is a widely 
used bone formation marker representing osteoblast activity. Both markers are included in 
the ongoing Pfizer Achondroplasia Natural History studies and are strong candidate 
biomarkers to measure the efficacy of recifercept treatment in particular on bone growth. 
 
7.4. Physical Activity Assessments 
Physical activity assessments will be collected using wrist and lumbar sensors and will 
provide data to support assessment of daily activity and gait characteristics in children with 
achondroplasia. This may support future trial endpoints around daily functioning. 
 
8. RESEARCH METHODS 
8.1. Study Design 
This is a prospective, registry study, to be conducted at multiple clinical centers globally, in 
which participants with achondroplasia will be followed over a five-year period with respect 
to achondroplasia symptoms, tests & treatments, anthropometric parameters and biomarkers 
of bone growth collagen X, CNP/proCNP, CTX and P1NP. No study drug will be 
administered, and no other type of therapy will be provided. 
 
There will be a Screening visit, a Baseline visit, 3-month interval visits (±3 weeks) including 
an annual visit every 12 months and an end of study visit. The end of study visit will be 
scheduled (or a given visit will be considered the end of study visit) as soon as any of the 
following criteria is met: 
 
•  Growth plates are considered to have fused, defined as standing height gain less than 
1 cm within the last 6 months; 
• The participant has reached end of puberty (Tanner Stage V); 
• The participant is enrolled in any interventional study; 
•  The participant is diagnosed or develops any of the coniditions related to exclusion 
crtieria 1, 2 & 6; 
•  The participant is to receive any growth hormone, insulin-like growth factor 1 
(IGF-1), anabolic steroids, or any other drug expected to affect growth velocity; 
• The participant has participated in the study for 5 years; 

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• The participant is considered lost to follow-up. 
 
The end of this study is defined as the date of the last visit of the last child participating in the 
study. 
 
The study will enroll participants in the following approximate proportions: 
 
• 40% 0-5y; 
• 40% 5-10y; 
• 20% 10-15y. 
Any treatment received during the study in relation to important medical events and any 
treatment based on the medical judgment of the investigator that may affect the participant’s 
growth trajectory must be recorded in the eCRF: 
• Description of the treatment (for medical treatment: route of administration, 
frequency and dose); 
• Indication; 
• Start and stop date. 
Treatment is defined as any medical, surgical or other intervention to treat the underlying 
condition. 
 
The rationale for the study design is summarised as follows: 
 
A prospective longitudinal design is selected to collect blood samples and anthropometric 
data simultaneously in a standardized fashion, and thereby allowing for estimation of 
between and within participant variability laboratory parameters as well as testing for 
possible correlations between laboratory parameters and growth. 
 
A five-year data collection period is chosen to allow detection of substantial growth as 
measured by the anthropometric endpoints, in order to enhance the strength of a possible 
correlation. 
 
Fasting prior to blood sampling is required to avoid variability due to impact of the digestive 
process on circulating levels of metabolic proteins related to bone growth. The fluctuation in 
bone metabolism markers after eating has been documented in other studies. 
 
The age range 0 - 15 years is chosen to provide a broad knowledge of the serum-levels of 
collagen X during different stages of growth in childhood. 
 
Information on Tanner Stage of Puberty will be collected in participants at 7 years of age and 
above to capture signs of initiation of puberty, which may affect growth. 

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Laboratory assays will be applied for the analysis of collagen X & other associated 
biomarkers based on venous blood draws. 
 
Health related quality of life measures will be collected to provide information about the 
quality of life of children, families and caregivers of children with achondroplasia. 
 
Physical activity monitoring will be collected in participants at 2 years of age and above to 
capture activities of daily living ‘in the real world’ by using digital accelerometery sensors. 
 
8.1.1. Inclusion Criteria 
Participants must meet all the following inclusion criteria to be eligible for inclusion in the 
study: 
 
1. Written informed consent/assent is obtained from the participant and/or 
parent(s)/legal guardian(s) before any study-related activity is carried out. 
 
2. The participant/parent(s)/legal guardian(s) is able to provide written informed assent, 
where this is required according to national legislation, before any study-related 
activity is carried out. 
 
3. The participant has been diagnosed as having achondroplasia documented by clinical 
diagnosis. 
 
4. The participant is between 0 years and 15 years of age, up to day before 15th birthday, 
on the date of consent/assent. 
 
5. The investigator has considered the family and prospective participating participant 
being able to comply with the study procedures. 
 
Evidence of a personally signed and dated informed consent/assent document indicating that 
the participant (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study. 
 
Participants who are willing and able to comply with scheduled visits, laboratory tests and 
other study procedures. 

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8.1.2. Exclusion Criteria 
Participants meeting any of the following criteria will not be included in the study: 
 
1. The participant has a diagnosis of hypochondroplasia or any short stature condition 
other than achondroplasia (eg, spondyloepiphyseal dysplasia congenital [SEDC], 
pseudo-achondroplasia, trisomy 21). 
 
2. The participant has any medical condition that may impact growth or where the 
treatment is known to impact growth, such as but not limited to hypothyroidism or 
hyperthyroidism, insulin-requiring diabetes mellitus, autoimmune inflammatory 
disease (including celiac disease, lupus [SLE], juvenile dermatomyositis, 
scleroderma, and others), autonomic neuropathy or inflammatory bowel disease. 
 
3. Treatment in the previous 12 months prior to consent/assent with growth hormone, 
insulin-like growth factor 1 (IGF-1), anabolic steroids, or any other drug expected to 
affect growth velocity. 
 
4. Any surgery that affects the growth plate of the long bones that is planned, or has 
occurred in the past 18 months. 
 
5. Participation in any interventional study (investigational product or device) for 
treatment of achondroplasia or short stature. 
 
6. Has had bone-related surgery impacting assessment of anthropometric measurements 
or is expected to have it during the study period. Participants with previous 
limb-lengthening surgery may enroll if surgery occurred at least 18 months prior to 
the date of consent/assent and healing is complete without sequelae as determined by 
the investigator. 
 
7. Has any condition or circumstance that in the view of the investigator places the child 
at high risk of poor compliance with the visit schedule or of not completing the study. 
 
8. Any concurrent disease or condition that, in the view of the investigator, would 
interfere with study participation. 
 
8.1.3. Variables 
 
Variable 
Role 
Data source(s) 
Operational definition 
Anthropometric 
Measurements 
Analysis of growth 
parameters 
Anthropometric 
measurements 
Collection every 3 months 
& End of Study 
Tanner Staging 
Assess stage of sexual 
development 
Physical Examination 
Collection every 3 months 
& End of Study 
Achondroplasia related 
complications, tests & 
treatments 
Characterize treatments for 
Achondroplasia 
Medical Records 
Collection every 3 months 
& End of Study 
Non-Achondroplasia 
Characterize medical 
Medical records 
Collection every 3 months 

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Variable 
Role 
Data source(s) 
Operational definition 
co-morbidities and 
treatments 
history 
& End of Study 
Biomarker Blood Sample 
Analysis for potential 
biomarkers of bone growth 
Blood sample 
Blood sample every 
12 months & End of Study 
Activity Tracker & Gait 
Measurement 
Analysis of daily activity & 
gait when walking 
Activity Tracker & Gait 
Mat 
Collection every 3 months 
& End of Study 
Quality of Life 
Assess Quality of Life in 
Participant & families with 
Achondroplasia 
Questionnaire 
Collection every 3 months 
& End of Study 
8.1.3.1. Data Sources 
Source documents provide evidence for the existence of the participating child and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s study site. 
 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents and the discrepancies must be explained. The investigator may need to 
request medical records from other healthcare professionals, if appropriate. Also, current 
medical records must be available. The use of electronic source data is described in FDA, 
EU Chinese and Japanese Guidance for Industry – Electronic Source Data in Clinical 
Investigations (2013). 
 
All study data must be verifiable by source documents. Additionally, the following data 
entered into the eCRF, should be verifiable by source documents in the participant’s medical 
record, or other records, at the study site, as applicable: 
 
• Details of study participation (study ID and unique identifier); 
• Date(s) of informed consent of parent(s)/legal guardian(s); 
• Date of informed assent of participant; 
•  Date of each study visit including signature and/or initials of person(s) conducting the 
study visit; 
•  The participant’s date of birth, or – as per local regulations – the month and year of 
birth relative to the date of the signing of consent/assent; 
• Confirmation by genetic testing, documenting the diagnosis of achondroplasia; 
• Results of anthropometric measurements. 

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Information recorded in the eCRF system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited 
to, hospital records, clinic and office charts, laboratory notes, and recorded data from 
automated instruments, and memoranda. 
 
Clinical laboratory data for the biomarkers required by the protocol will be electronically 
transferred from the central laboratory to the sponsor or its designee. 
 
Confirmation of genetic testing should be available as source documents from the local 
laboratory when the testing is performed. Results should be available and recorded in the 
eCRF prior to the end of study visit. 
 
9. STUDY PROCEDURES 
As applicable, all visits and their timings must occur within the predefined windows outlined 
in this protocol in the Schedule of Activities (Section 5). 
 
After signature of the informed consent/assent, 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. 
 
9.1. Demographics 
At the Screening Visit, the following information will be obtained and reported in the eCRF: 
 
• Date of birth, or – the age at the date of consenting (years and months of age MUST 
be provided); 
 
• Gender; 
• Race (American Indian or Alaska native, Asian, black or African American, native 
Hawaiian or other pacific islander, White, Other); 
 
• Height of (biological) parent(s); 
• (Biological) Parent(s) have/do not have achondroplasia. 
Since one of the primary objectives of this study is to document the natural history of growth 
in achondroplasia, it is essential that the age of participants is accurately recorded. Thus, it is 
necessary to collect at least the Month & Year of birth of the study participant. 
 
9.2. Medical and Surgical History 
At the Screening and Baseline visit, information on any relevant prior or current 
condition/procedure will be obtained and reported in the eCRF system. 

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9.3. Physical Examination 
At the Baseline Visit and at 3-month interval visits thereafter, a physical examination of the 
participant will be done, which will include general appearance and examination of the 
following body systems: Respiratory system, neurological system, musculoskeletal system, 
cardiovascular system, other. 
 
Only findings not recorded elsewhere in the eCRF system should be recorded in the Physical 
Examination eCRF system. 
 
9.4. Assessment of Obesity 
Waist circumference will be measured at the Baseline Visit, yearly and at the End of study 
visit as described in the Anthropometric Measurement Manual. 
 
9.5. Tanner Stage of Puberty 
For participants 7 years and older, at the Baseline Visit and at the 3-monthly interval visits 
thereafter, the Tanner Stage of puberty will be recorded in the eCRF system as stage I-V for 
both external genitalia, testes and pubic hair (males) and for breast development and pubic 
hair (females). Participants under 7 years of age do not require this assessment, providing 
the investigator confirms there is no suspicion of a diagnosis of precocious puberty. 
 
9.6. Achondroplasia-related Interventions 
Investigators should record relevant surgeries, procedures and interventions related to 
achondroplasia at baseline and on an ongoing basis during the study. 
 
9.6.1. Follow-up of Achondroplasia-related Complications 
After the initial report on an important medical symptom, test or treatment, the investigator 
should follow-up on the severity status of the medical symptoms, determine whether the 
symptom is ongoing or is resolved and assess the outcome of a potential treatment via 
contacts with relevant treating personnel and/or via communication with the participant and 
the participant’s parent(s)/legal guardian(s) at subsequent study visits, as applicable. The 
investigator should continue follow-up on the symptoms until the participant’s participation 
in the study has ended. 
 
9.7. Non-achondroplasia-related Conditions of Medical Significance 
Information concerning the diagnosis of any non-achondroplasia related conditions of 
medical significance, including start and stop dates, should be reported. Details will be 
collected at baseline and on an ongoing basis during the study. Information may be provided 
by parent(s)/legal guardian(s) or by the participant if this is applicable. 
 
9.8. Achondroplasia-related Complications 
Details will be collected on achondroplasia-related complications. In particular, the 
following complications and details will be collected at baseline and on an ongoing basis 
during the study. 

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9.8.1. Sleep Disordered Breathing 
• Has the participant ever been diagnosed with sleep-disordered breathing? 
• Results of sleep tests/polysomnography including: 
• Date of test. 
• Conclusion/diagnosis of test. 
• Apnoea-hypopnoea index. 
• Was the test conducted on/off oxygen? 
• Was the test conducted on CPAP? 
• Is the test post-adenotonsillectomy (date of surgery if performed)? 
9.8.2. Otitis Media 
• Has the participant ever been diagnosed with chronic otitis media (COM)? 
• Were tympanostomy tubes (grommets) ever inserted (dates of insertions). 
• Has the participant had hearing loss as a result of COM (including date start/end and 
severity)? 
 
• Does the participant require hearing aids as a result of COM-induced hearing loss? 
9.8.3. Orthopaedic Complications 
• Imaging of the bones or knees. 
• Tibial bowing including the dates of any surgery for. 
• Osteotomy. 
• 8-plates. 
• Kyphoscoliosis including the presence of wedging on imaging and need for surgery. 
• Lumbar lordosis. 
• Diagnosis of lordosis. 
• Presence of neurological signs in legs. 
• Impaired walking. 

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• Any surgical intervention. 
9.8.4. Neurological 
• Is there a history of upper cervical compression including? 
• Neurological examination findings. 
• MRI results. 
• Need for decompression surgery (including dates and nature of procedures). 
• Whether there are any persistent findings on neurological examination 
post-surgery. 
 
• Hydrocephalus and need for shunting. 
• Presence of any neurodevelopmental delay. 
With respect to other complications not listed above, the investigator should record the 
relevant complication and make an assessment of the intensity according to the following 
categories: 
 
• Mild: A symptom that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
 
• Moderate: A symptom that causes sufficient discomfort for the participant and 
interferes with normal everyday activities. 
 
• Severe: A symptom that prevents normal everyday activities for the participant. 
9.9. Anthropometric Measurements 
Anthropometric measurements will be done at all 3 monthly visits and measurement results 
will be reported in the eCRF. Anthropometric measurements will be performed according to 
a study-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 undertake. 
 
2. The tools/instruments to be used, as well as their calibration. 
 
3. Standard procedure for undertaking these measurements. 
The measurements to be taken on a 3-monthly basis are: 
• Standing height (or length for participants <2y); 

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• Sitting height (or crown: rump length for participants <2y); 
• Knee height; 
• Head circumference; 
• Arm span; 
• Body weight; 
• Elbow extension angle; 
• Knee extension angle; 
• Cranial dimensions (occipito-frontal, occipito-nasal lengths); 
• Waist and chest circumference (annually). 
For each participating participant, measurements will have to be performed by the same site 
personnel, trained according to the contents of the study-specific Anthropometric 
Measurement Manual. 
 
Information concerning any achondroplasia-related complications, tests and treatments, 
eg, respiratory difficulties, neurological signs and symptoms, hospitalization, and treatment 
(surgical, medical, pharmaceutical), should be reported at every visit. Information may be 
provided by parent(s)/legal guardian(s) (eg, through a parent-specific notebook) or by the 
participant if this is applicable. 
 
For the anthropometric parameters, only trained site staff will be allowed to perform the 
anthropometric measurements on participants in this study. The measurer must become 
certified to perform selected study assessments before they can participate in the conduct of 
the study. For specifically defined assessments, training and standardization exercises may 
be conducted, and written and signed documentation will be provided by the qualification 
vendor for each rater’s certification. Recertification is required as needed during the study. 
The site staff who administer specific study assessments will be documented in the site study 
documentation during the conduct of the study. 
 
9.10. Study Treatments 
No study treatment will be administered. 

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9.11. Concomitant Treatments 
During the study participation, the participant will continue receiving his/her usual 
treatment(s). 
 
Any concomitant medical treatment received that, based on the investigator’s judgment, may 
affect the child’s growth trajectory will be recorded in the case report form. 
 
9.12. Prohibited Treatments 
Participation in any interventional drug trial is strictly prohibited in this trial. Other 
treatments such as growth hormone are strictly prohibited whilst participating in the study. If 
the investigator wishes to treat a participant with any growth hormone, insulin-like growth 
factor 1 (IGF-1), anabolic steroids, or any other drug expected to affect growth velocity the 
participant must be withdrawn from the study and complete the final study visit. 
 
9.13. Health-related Quality of Life (HRQoL) Measures 
9.13.1. Childhood Health Assessment Questionnaire (CHAQ) 
The Childhood Health Assessment Questionnaire (CHAQ) is a 37-item measure of health 
status and physical function. Subjects aged 1-19 years of age will have the CHAQ completed 
at designated study visits. The parent-report version will be completed for children aged 
1-7 years old. The self-report version will be completed for children aged 8-19 years old. 
Children will start on the age appropriate version and continue with that version throughout 
the study. For younger ages, the caregiver completes and continues to complete throughout 
the study; the children can also complete the self-report version when they are old enough. 
 
Subjects or their caregivers will be asked to provide responses to questions designed to assess 
function in 8 areas/domains in addition to: 2 visual analogue scales (pain and well-being), the 
use of aids and devices, and the requirement for help with the functional areas. The 
8 functional domains are: Dressing and Grooming (4 items); Arising (2 items); Eating 
(3 items); Walking (2 items); Hygiene (4 items); Reach (4 items); Grip (5 items); and 
Activities (5 items). The CHAQ 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 scores indicate better functioning/health-related quality of life. 
 
This will be administered every 3 months. 
 
9.13.2. Quality of Life in Short Stature Youth (QoLISSY) Brief 
Subjects aged 4-18 years of age 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 patient and parent perspectives. The parent-report version 
will be completed for children aged 4-7 years old. The self-report version will be completed 
for children aged 8-18 years old. Children will start on the age appropriate version and 
continue with that version throughout the study. For younger ages, the caregiver completes 
but the children can also complete when they are old enough. There are 9-items that were 
selected from the full QoLISSY physical, social and emotional HRQoL dimensions. The 

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QoLISSY Brief questions ask the patient 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.’ 
 
This will be administered every 3 months. 
 
9.14. Sample Collection 
Samples will be collected at the time points specified in the Schedule of Activities (see 
Section 5). A maximum of 10 mL from each participant will be drawn once yearly for 
biomarker assays. Fasting blood samples for biomarker analyses should be drawn in the 
morning. If the participant has been fasted for less than 8 hours, this will be recorded on the 
sampling documentation. The samples will be sent to a central laboratory contracted for this 
study purpose. These samples will be stored no longer than 1 year after the final clinical 
study report (CSR) has been written. 
 
Additionally, if genetic confirmation of the achondroplasia diagnosis is not available in the 
medical records, then the result of genetic testing should become available as soon as 
possible, but prior to the end of study visit. The assessment can be done at a local laboratory. 
The confirmation of the genetic testing should be reported in the eCRF. 
 
Residuals from the biomarker samples will be kept at the central laboratory for no longer 
than 1 year after the final Clinical Study Report has been written. They will be used to 
investigate potential biomarkers of bone growth that can be used to assess efficacy in future 
therapeutic trials and to improve precision in any dose-finding elements of these trials. 
 
9.15. Physical Activity (Accelerometery) 
In selected sites, participants >2 years and who are able to walk independently will be asked 
to participate in an optional assessment of monitoring of their daily physical activity. The 
continuous monitoring of physical activity via accelerometry will be done by wearable digital 
wristwatch & lumbar sensors. The digital sensors will be worn continuously for 
approximately 14 days as specified in the SoA. 
 
One sensor will be placed on the lumbar region and one sensor will be placed on the non- 
dominant wrist. Participants will be asked to wear the sensor on the wrist continuously 
(including at night to monitor sleep metrics), and the lumbar sensor during waking hours 
only. Participants will be asked to return the sensors back to the site via self-addressed 
stamped envelope after the 14 days of data collection. A technical training manual will be 
provided separately to site, it will include the Edinburgh Handedness Inventory – Short Form 
to determine the non-dominant wrist as reference, if required. 

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9.16. Wearability Questionnaire 
In sites participating in the physical activity monitoring optional assessment, a wearability 
questionnaire will be provided to the participant or their caregiver to complete at the end of 
each 14-day wearing period. Participants or their caregivers will be asked to rate the overall 
comfort of wrist & lumbar devices using a scale. Site staff will be required to transcribe the 
information from the questionnaire into the eCRF system. 
 
9.17. Gait Walking Assessment 
In selected sites, participants >2 years and who are able to walk independently will be asked 
to participate in an optional assessment of monitoring of their gait while walking on a 
specialized GAITRite walking mat of at least 8 meters (16 feet). The assessment will be 
performed whilst wearing the digital sensors (wrist and lumbar) at least once and a maximum 
of three times. 
 
GAITRite technical training guide will be provided separately to the site. 
 
10. ASSESSMENTS 
10.1. Additional Research 
Not Applicable. 
 
10.2. Assessment of Suicidal Ideation and Behaviour (If Applicable) 
Not Applicable. 
 
10.3. Biological Samples 
For samples being collected and shipped, detailed instructions on collection, processing, 
storage, and shipment and contact information will be provided to the investigator site prior 
to initiation of the study. 
 
10.4. Imaging Assessments 
Not Applicable. 
 
10.5. Management of Incidental Findings 
Not Applicable. 
 
10.6. Rater Qualifications 
Not Applicable. 

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CCI 
11. DATA ANALYSIS/STATISTICAL METHODS 
11.1. Study Size 
The sample size was not formally calculated. 
 
All analyses will be conducted on all enrolled participants. 
 
11.2. Data Management 
The standard procedures for handling and processing records will be followed per GCP in 
addition to Sponsor & Premier Research’s standard operating procedures. A comprehensive 
data management plan will be developed, including a data management overview, 
description of database contents, annotated CRF, eCRF completion guidelines, pre-entry 
review list, self-evident correction conventions, query contacts, coding requirements, and 
consistency checks. 
 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review and must provide his or her 
electronic signature to ensure the accuracy of the corrected and/or clarified data. Procedures 
for soliciting and documenting resolution to data queries are described in the Clinical 
Monitoring Plan for CRAs monitoring the conduct of the study and the eCRF data. 
 
11.3. Case Report Forms/Data Collection Tools/Electronic Data Record 
As used in this protocol, the term CRF[/DCT] should be understood to refer to either a paper 
form or an electronic data record or both, depending on the data collection method used in 
this study. 
 
A CRF[/DCT] is required and should be completed for each included participant. The 
completed original CRFs[/DCTs] are the sole property of Pfizer and should not be made 
available in any form to third parties, except for authorized representatives of Pfizer or 
appropriate regulatory authorities, without written permission from Pfizer. The investigator 
shall ensure that the CRFs[/DCTs] are securely stored at the study site in encrypted electronic 
form and will be password protected to prevent access by unauthorized third parties. 
 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs[/DCTs] and any other data collection forms 
(source documents) and ensuring that they are accurate, authentic/original, attributable, 
complete, consistent, legible, timely (contemporaneous), enduring, and available when 
required. Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents and the discrepancies must be explained. The 
investigator may need to request medical records from other healthcare professionals, if 
appropriate. Also, current medical records must be available. The use of electronic source 
data is described in FDA, EU Chinese and Japanese Guidance for Industry – Electronic 
Source Data in Clinical Investigations (2013). 

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All study data must be verifiable by source documents. Additionally, the following data 
entered into the eCRF, should be verifiable by source documents in the participant’s medical 
record, or other records, at the study site, as applicable: 
 
• Details of study participation (study ID and unique identifier); 
• Date(s) of informed consent of parent(s)/legal guardian(s); 
• Date of informed assent of participant; 
• Date of each study visit including signature and/or initials of person(s) conducting the 
study visit; 
 
• The participant’s date of birth, or – as per local regulations – the month and year of 
birth relative to the date of the signing of consent/assent; 
 
• Confirmation by genetic testing, documenting the diagnosis of achondroplasia; 
• Results of anthropometric measurements. 
Information recorded in the eCRF system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited 
to, hospital records, clinic and office charts, laboratory notes, and recorded data from 
automated instruments, and memoranda. 
 
Clinical laboratory data for the biomarkers required by the protocol will be electronically 
transferred from the central laboratory to the sponsor or its designee. 
 
Confirmation of genetic testing should be available as source documents from the local 
laboratory when the testing is performed. Results should be available and recorded in the 
eCRF prior to the end of study visit. 
 
The CRFs[/DCTs] must be signed by the investigator or by an authorized staff member to 
attest that the data contained on the CRFs[/DCTs] are true. Any corrections to entries made 
in the CRFs[/DCTs] or source documents must be dated, initialled and explained (if 
necessary) and should not obscure the original entry. 
 
In most cases the source documents are the hospital or the physician's chart. In these cases, 
data collected on the CRFs[/DCTs] must match those charts. Source documents provide 
evidence for the existence of the participating child and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s study site. 
 
In some cases, the CRF[/DCT] may also serve as the source document. In these cases, a 
document should be available at the investigator site and at Pfizer that clearly identifies those 
data that will be recorded on the CRF[/DCT], and for which the CRF[/DCT] will stand as the 
source document. 

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11.4. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating participants 
(sufficient information to link records, eg, CRFs[/DCTs] and hospital records), all original 
signed informed consent[/assent] documents, copies of all CRFs[/DCTs], safety reporting 
forms, source documents, detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (eg, letters, meeting minutes, and telephone call 
reports). The records should be retained by the investigator according to the International 
Council for Harmonisation (ICH) guidelines, according to local regulations, or as specified in 
the clinical study agreement (CSA), whichever is longer. The investigator must ensure that 
the records continue to be stored securely for so long as they are retained. 
 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
 
Investigator records must be kept for a minimum of 25 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
 
11.5. Data Analysis 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be dated, filed and maintained 
by the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment. 
 
As the main purpose of this study is to collect data to be used as reference for future 
interventional clinical studies, no hypothesis testing will be made. 
 
A detailed master statistical analysis plan (SAP) will be developed covering the analytical 
principles and statistical techniques to be employed both for interim and final analysis. This 
study plans a primary master SAP, as well as supplemental SAPs. An advantage of this 
study design is its ability to answer questions that emerge during the study. 
 
Subsequent and supplemental SAPs - triggered by new research questions emerging after the 
initial master SAP is developed or needed because the registry may evolve - can be 
developed when enough data become available to analyze a particular research question not 
included in the master SAP. 
 
The main purpose of this study is descriptive. 

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Generally, descriptive statistics will be reported for all measured variables captured in this 
study. Derived Anthropometric measurements include: 
 
• Annual Growth Velocity (AGV); 
• Height Standard Deviation Score (SDS) with reference to normal population; 
• Height SDS with reference to achondroplasia population; 
• Sitting height/standing height (%) (or length: crown-rump length); 
• Difference or ratio of Arm span/standing height/length (%); 
• Knee height: lower segment length (lower segment=standing height – sitting height); 
• Ratios between the cranial measurements taken. 
Continuous (quantitative) variable summaries will include the number of participants (n) 
with non-missing values, number of missing values, mean and 95% confidence interval, 
standard deviation, median, minimum, and maximum. 
 
Continuous variables may be classed into groups and analyzed as a categorical variable when 
appropriate. Categorical (qualitative) variable summaries will include the frequency and 
percentage of participants who are in the particular category or each possible value. 
 
Event data will generally be listed. In case of frequent events tabulations might be 
considered. 
 
Interim analyses will be performed on a regular basis. 
 
Data following procedures or treatments that may affect growth velocity will be excluded 
from the analysis of anthropometric parameters. 
 
Subgroup analysis should be made by gender, age groups, and the combination of gender and 
age group. 
Biomarker CCI 
 will be described in a separate SAP and presented separately 
from the main CSR. 
 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) and/or Good Pharmacoepidemiology Practices (GPP), as relevant, are being 
followed. The monitors may review source documents to confirm that the data recorded on 
CRFs [/data collection tools (DCTs)] are accurate. The investigator and institution will allow 
Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct access to 

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source documents to perform this verification. This verification may also occur after study 
completion. 
 
During study conduct and/or after study completion, the investigator site may be participant 
to review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities. 
 
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 Pfizer or its agent. Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings. 
 
For studies conducted at non-Pfizer investigator sites, 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. 
 
13. LIMITATIONS OF THE RESEARCH METHODS 
The study design is limited by pragmatic considerations around available participants, 
minimizing burden on young participants and theCCI 
 nature of many of the growth 
biomarkers. 
 
14. PROTECTION OF HUMAN PARTICIPANTS 
14.1. Participant Information and Consent 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant personal data. 
Such measures will include omitting participant names or other directly identifiable data on 
any sponsor forms, reports, publications, or in any other disclosures, except where required 
by applicable laws. 
 
The 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 shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law. 

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To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, participant names will be removed and will be replaced by a single, specific 
numerical code, based on a numbering system defined by Pfizer. All other identifiable data 
transferred to Pfizer or other authorized parties will be identified by this single, 
participant-specific code. The investigator 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. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of participant’s personal data consistent with the clinical study 
agreement (CSA) and applicable privacy laws. 
 
The informed consent[/assent] documents and any participant recruitment materials must be 
in compliance with ICH GCP, local regulatory requirements, and legal requirements, 
including applicable privacy laws. 
 
The informed consent[/assent] documents used during the informed consent process and any 
participant recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection. 
 
The investigator must ensure that each study participant[,or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor,] is fully informed about the nature 
and objectives of the study, the sharing of data relating to the study and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. The investigator further must ensure that each study participant 
[,or his or her legally acceptable representative, or parent(s) or legal guardian if a minor,] 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. 
 
Whenever consent is obtained from a participant’s [legally acceptable 
representative/parent(s) or legal guardian], the participant’s assent (affirmative agreement) 
must subsequently be obtained when the participant has the capacity to provide assent, as 
determined by the IRB/EC. If the investigator determines that a participant’s decisional 
capacity is so limited that he or she cannot reasonably be consulted, then, as permitted by the 
IRB/EC and consistent with local regulatory and legal requirements, the participant’s assent 
may be waived with source documentation of the reason assent was not obtained. If the 
study participant does not provide his or her own consent, the source documents must record 
why the participant did not provide consent (eg, minor, decisionally impaired adult), how the 
investigator determined that the person signing the consent was the participant’s legally 
acceptable representative, the consent signer’s relationship to the study participant (eg, 
parent, spouse), and that the participant’s assent was obtained or waived. If assent is 
obtained verbally, it must be documented in the source documents. 

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If the study includes minor participants who reach the age of majority during the study, as 
recognized under local law, they must reconsent as adults to remain in the study. If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian. 
 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each participant [or the participant’s legally acceptable representative, 
parent(s), or legal guardian and the participant’s assent, when applicable,] before any 
study-specific activity is performed, unless a waiver of informed consent has been granted by 
an IRB/EC. The investigator will retain the original of each participant’s signed 
consent/assent document. 
 
14.1.1. Screen Failures 
A participant who fail inclusion and/or exclusion criteria may be rescreened for the study. 
The re-screening can occur at a time interval considered appropriate by the investigator. If a 
participant is eligible to enter the study after having previously failed screening, they will be 
assigned a new identification number. However, participants who are withdrawn from the 
study will not be replaced. 
 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, and eligibility criteria. 
 
14.2. Participant Withdrawal 
Participants may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioural, 
or administrative reasons. In any circumstance, every effort should be made to document 
participant outcome, if applicable. The investigator should inquire about the reason for 
withdrawal and follow-up with the participant regarding any unresolved adverse events. 
 
If the participant withdraws from the study, and also withdraws consent 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. 
 
14.2.1. Lost to Follow-up 
The study site personnel must attempt to contact the participant’s parent(s)/legal guardian(s) 
and counsel the parent(s)/legal guardian(s) on the assigned visit schedule and ascertain 
whether or not the participant and the parent(s)/legal guardian(s) wish study participation to 
continue. 

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A participating participant will be considered lost to follow-up in case a 1-year period has 
passed without return for scheduled visits and if the parent(s)/legal guardian(s) are unable to 
be contacted by the study site personnel on 3 occasions. 
 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the parent(s)/legal guardian(s) in the form of (where 
possible) 3 telephone calls and, if necessary, a certified letter to the parent(s)/legal 
guardian(s) last known mailing address or local equivalent methods. These contact attempts 
should be documented in the participant’s medical record. 
 
Should the parent(s)/legal guardian(s) continue to be unreachable, the participant will be 
considered as withdrawn from the study with the reason category “lost to follow-up.” 
 
14.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/IEC. All correspondence with 
the IRB/IEC should be retained in the investigator file. Copies of IRB/IEC approvals should 
be forwarded to Pfizer. 
 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the participants. 
In that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately 
after the implementation. 
 
14.4. Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Participants (Council for International Organizations 
of Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 

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15. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
REQUIREMENTS 
 
This study includes qualifying diagnostic or monitoring procedures required per protocol to 
collect clinical data needed to meet the study objectives, which are not standard-of-care but 
that do not pose more than a minimal risk or burden to the study participant. The qualifying 
procedures in this study are: 
 
Qualifying diagnostic or monitoring procedure(s) 
Recording Time Period 
Biomarker Blood Sample (Venous) 
12 hours 
 
15.1. Adverse Events (AE) 
An AE is defined as any untoward medical occurrence and can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease, 
whether or not related to the participant’s participation in the study. 
 
Any AE that occurs from the time the participant consents to the clinical research 
through and including 12 hours after completion of the qualifying procedure must be 
recorded. 
 
The investigator is required to assess whether the AE may be related to the participant’s 
participation in the study. All AEs (ie, serious and non-serious, including those attributed to 
qualifying procedure identified as research-related injury) are collected in the clinical study 
database. 
 
The investigator must pursue and obtain information adequate to determine the outcome of 
the AE and to assess whether it meets the criteria for classification as a research-related 
injury requiring immediate notification to Pfizer as described below. 
 
15.2. Research-Related Injury 
Should a participant, in the investigator’s opinion, suffer a medically important 
research-related injury caused by their participation in the study, the designated Pfizer 
clinician or medical monitor must be notified immediately. 
 
A medically important research-related injury is any untoward medical occurrence that: 
 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inparticipant hospitalization or prolongation of existing hospitalization; 

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• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
 
• Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an injury is an 
important medical event. An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization. However, if it is determined that the 
event may jeopardize the participant or may require intervention to prevent one of the other 
outcomes listed in the definition above, the important medical event should be reported as a 
research-related injury. 
 
An investigator may be requested by the designated Pfizer clinician or medical monitor to 
obtain specific additional follow-up information in an expedited fashion. In general, this will 
include a description of the injury in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality. Information on 
other possible causes of the event, such as concomitant treatments, vaccines, and/or 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 or its designated representative. 
 
The table below summarizes the requirements for recording safety events on the eCRF and 
for reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report 
form. These requirements are delineated for three types of events: (1) serious adverse events 
(SAEs); (2) non-serious adverse events (NSAE) (as applicable); and (3) scenarios involving 
exposure to a Pfizer product, including exposure during pregnancy or breast feeding, 
medication error, lack of efficacy, overdose, misuse, extravasation, and occupational 
exposure. These events are defined in the section “Definitions of Safety Events.” 
 
Safety event 
Recorded on the case report 
form 
Reported on the CT SAE 
Report Form Report 
Form to Pfizer Safety 
within 24 hours of 
awareness 
SAE 
All 
Only SAEs determined 
by the investigator to be 
related to a Pfizer product 
Non-serious AE 
All 
None 

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Safety event 
Recorded on the case report 
form 
Reported on the CT SAE 
Report Form Report 
Form to Pfizer Safety 
within 24 hours of 
awareness 
Scenarios involving exposure 
to a Pfizer product, including 
exposure during pregnancy or 
breast feeding, medication 
error, overdose, misuse, 
extravasation, and 
occupational exposure 
All involving exposure to a 
Pfizer product (regardless of 
whether associated with an 
AE), except occupational 
exposure 
All (regardless of whether 
associated with an AE) 
involving exposure to a 
Pfizer product 
Note: Any associated 
adverse event (either serious 
or non-serious) is reported 
together with the exposure 
scenario 
 
 
Safety events as specified in the table above must be reported to Pfizer within 24 hours of 
awareness of the event by the investigator. In particular, if the SAE is fatal or 
life-threatening, notification to Pfizer must be made immediately, irrespective of the extent of 
available event information. This timeframe also applies to additional new (follow-up) 
information on previously forwarded safety event reports. In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the events. 
 
For safety events that are considered serious or that are identified in the far-right column of 
the table above that are reportable to Pfizer within 24 hours of awareness, the investigator is 
obligated to pursue and to provide any additional information to Pfizer in accordance with 
this 24-hour timeframe. 
 
For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
(see section "Serious Adverse Events” below). 
 
In addition, an investigator may be requested by Pfizer to obtain specific follow-up 
information in an expedited fashion. This information is more detailed than that recorded on 
the eCRF. In general, this will include a description of the adverse event in sufficient detail 
to allow for a complete medical assessment of the case and independent determination of 
possible causality. 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 or its designated 
representative. 
 
All AEs (ie, serious and non-serious, including those attributed to qualifying assessments 
identified as research-related injury) are collected in the clinical study database. 

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Reporting period 
 
For each participant, the safety event reporting period begins at the time of the participant’s 
informed consent, which is obtained prior to the participant’s enrollment in the study, and 
lasts through the end of the observation period of the study; a report must be submitted to 
Pfizer Safety (or its designated representative) for any of the types of safety events listed in 
the table above occurring during this period. Most often, the date of informed consent is the 
same as the date of enrollment. In some situations, there may be a lag between the dates of 
informed consent and enrollment. In these instances, if a patient provides informed consent 
but is never enrolled in the study (eg, patient changes his/her mind about participation or 
failed screening criteria), the reporting period ends on the date of the decision to not enroll 
the patient. If the investigator becomes aware of a SAE occurring at any time after 
completion of the study and s/he considers the serious AE to be related to a Pfizer product, 
the SAE also must be reported to Pfizer Safety. 
 
Causality assessment 
 
The investigator is required to assess and record the causal relationship. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of 
each adverse event. For AEs with a causal relationship to a Pfizer product, follow-up by the 
investigator is required until the event and/or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment. 
 
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that a Pfizer product caused or contributed to an adverse event. If the 
investigator’s final determination of causality is “unknown” and s/he cannot determine 
whether a Pfizer product caused the event, the safety event must be reported within 24 hours. 
 
If the investigator cannot determine the etiology of the event but s/he determines that a Pfizer 
product did not cause the event, this should be clearly documented on the eCRF and the CT 
SAE Report Form. 
 
DEFINITIONS OF SAFETY EVENTS 
 
Adverse events 
 
An AE is any untoward medical occurrence in a participant administered a medicinal 
product. The event need not necessarily have a causal relationship with the product 
treatment or usage. The same definition is applied for medical devices and nutritional 
products (including infant and toddler formulas [hereinafter “pediatric formulas”]). 
 
Examples of AEs include but are not limited to: 
 
• Abnormal test findings (see below for circumstances in which an abnormal test 
finding constitutes an adverse event); 

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• Clinically significant signs and symptoms; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of underlying disease; 
• Lack of efficacy; 
• Drug abuse; 
• Drug dependency. 
Additionally, for medicinal products, they may include the signs or symptoms resulting from: 
 
• Drug overdose; 
• Drug withdrawal; 
• Drug misuse; 
• Off-label use; 
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy; 
• Exposure during breast feeding; 
• Medication error; 
• Occupational exposure. 
Abnormal test findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 
 
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 

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• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
 
• Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event. 
 
Serious adverse events 
 
A serious adverse event is any untoward medical occurrence in a participant administered a 
medicinal or nutritional product (including pediatric formulas) at any dose using a medical 
device that: 
 
• Results in death; 
• Is life-threatening; 
• Requires inparticipant hospitalization or prolongation of hospitalization (see below 
for circumstances that do not constitute adverse events); 
 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
 
• Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization. However, if it is determined that the event may jeopardize 
the participant or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious. 
 
Examples of such events are 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. 
 
Additionally, any 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 participant 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 PV personnel. Such cases are also considered for reporting as product defects, if 
appropriate. 

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Hospitalization 
 
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, an event leading to an emergency room visit should be assessed for medical 
importance. 
 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. 
For example, the following reports of hospitalization without a medical AE are not to be 
reported. 
 
• Social admission (eg, participant has no place to sleep). 
• Administrative admission (eg, for yearly exam). 
• Optional admission not associated with a precipitating medical AE (eg, for elective 
cosmetic surgery). 
 
• Hospitalization for observation without a medical AE. 
• Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (eg, for 
work-up of persistent pre-treatment lab abnormality). 
 
• Protocol-specified admission during clinical study (eg, for a procedure required by 
the study protocol). 
 
Scenarios necessitating reporting to Pfizer Safety within 24 hours 
 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, lack of efficacy, and occupational exposure are described below. 
 
Exposure during pregnancy 
 
An exposure during pregnancy (EDP) occurs if: 
 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (eg, environmental) a Pfizer product, or the female becomes, or is found to 
be, pregnant after discontinuing and/or being exposed to a Pfizer product (maternal 
exposure). 

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An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
 
2. A male has been exposed, either due to treatment or environmental exposure to a 
Pfizer product prior to or around the time of conception and/or is exposed during the 
partner pregnancy (paternal exposure). 
 
As a general rule, prospective, and retrospective exposure during pregnancy reports from any 
source are reportable irrespective of the presence of an associated AE and the procedures for 
SAE reporting should be followed. When exposure during pregnancy is associated with an 
adverse event, it is reported to Safety regardless of the seriousness criterion associated with 
that adverse event. 
 
If a study participant or study participant’s partner becomes, or is found to be, pregnant 
during the study participant’s treatment with a Pfizer product, this information must be 
submitted to Pfizer, irrespective of whether an adverse event has occurred, must be submitted 
using the CT SAE Report Form and the EDP Supplemental Form. 
 
In addition, the information regarding environmental exposure to a Pfizer product, in a 
pregnant woman (eg, a participant reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) must be submitted using the CT SAE Report 
Form and the EDP supplemental form. This must be done irrespective of whether an AE has 
occurred. 
 
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
 
Follow-up is conducted to obtain general information on the pregnancy, in addition, 
follow-up is conducted to obtain information on EDP outcome for all EDP reports with 
pregnancy outcome unknown. A pregnancy is followed until completion or until pregnancy 
termination (eg, induced abortion) and Pfizer is notified of the outcome. This information is 
provided as a follow up to the initial EDP report. 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 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
 
If the outcome of the pregnancy meets the criteria for an SAE (eg, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed. 
 
Additional information about pregnancy outcomes that are reported as SAEs follows: 

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• Spontaneous abortion includes miscarriage and missed abortion; 
• 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 investigational product. 
 
Additional information regarding the exposure during pregnancy may be requested. 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 study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner. It must be documented that the 
study participant was given this letter to provide to his partner. 
 
Exposure during breastfeeding 
 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE. 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 AE (either serious or non- 
serious) associated with such a drug’s administration, the AE is reported together with the 
exposure during breastfeeding. 
 
Medication error 
 
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or participant 
harm while in the control of the healthcare professional, participant, or consumer. Such 
events may be related to professional practice, healthcare products, procedures, and systems 
including: prescribing; order communication; product labelling, packaging, and 
nomenclature; compounding; dispensing; distribution; administration; education; monitoring 
and use. 
 
Medication errors include: 
 
• Near misses, involving or not involving a participant directly 
(eg, inadvertent/erroneous administration, which is the accidental use of a product 
outside of labelling or prescription on the part of the healthcare provider or the 
participant/consumer); 
 
• Confusion with regard to invented name (eg, trade name, brand name). 
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE: 

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• Medication errors involving participant exposure to the product, whether or not the 
medication error is accompanied by an AE. 
 
• Medication errors that do not involve a participant directly (eg, potential medication 
errors or near misses). When a medication error does not involve participant 
exposure to the product the following minimum criteria constitute a medication error 
report: 
 
• An identifiable reporter; 
• A suspect product; 
• The event medication error. 
When the medication error is associated with an adverse event, it is reported to Safety 
regardless of the seriousness criterion associated with that the adverse event. 
 
Overdose, Misuse, Extravasation 
 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE. 
 
When the overdose, misuse, and extravasation is associated with an adverse event, it is 
reported to Safety regardless of the seriousness criterion associated with that adverse event. 
 
Lack of Efficacy 
 
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product. 
 
Occupational Exposure 
 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE. 
 
An occupational exposure is reported to Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated AE. 
When the occupational exposure is associated with an adverse event, it is reported to Safety 
regardless of the seriousness criterion associated with that adverse event. 
 
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. 

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16. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
16.1. 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 investigational 
product, Pfizer should be informed immediately. 
 
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. 
 
16.2. Publications by Investigators 
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product. However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed. 
 
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days. 
 
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results. 
 
If the study is part of a multicentre study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, participant to the other 
requirements of this section. 
 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 

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Publication of study results is also provided for in the CSA between Pfizer and the 
institution. In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA. 
 
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control. If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study participants, and the CSA will control as to all 
other issues. 

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17. REFERENCES 
1. 
Horton WA, Rotter JI, et al. Standard growth curves for achondroplasia. J Pediatr 
1978;93(3):435-8. 
 
2. 
Richette P, Bardin T, Stheneur C. Achondroplasia: from genotype to phenotype. Joint 
Bone Spine 2008;75(2):125-30. 
 
3. 
Afsharpaiman S, Saburi A, Waters KA. Respiratory difficulties and breathing disorders 
in achondroplasia. Paediatr Respir Revs 2013;14(4):250-5. 
 
4. 
Gordon N. The neurological complications of achondroplasia. Brain Dev 
2000;22(1):3-7. 
 
5. 
Hunter AG, Bankier A, Rogers JG, Sillence D, Scott CI Jr. Medical complications of 
achondroplasia: a multicentre patient review. J Med Genet 1998;35(9):705-12. 
 
6. 
Tasker RC, Dundas I, Laverty A, Fletcher M, Lane R, Stocks J. Distinct patterns of 
respiratory difficulty in young children with achondroplasia: a clinical, sleep, and lung 
function study. Arch Dis Child 1998;79(2):99-108. 
 
7. 
Registries for Evaluating Patient Outcomes, 3rd edition. Informed Consent for 
Registries. In: Eds Gliklich RE, Dreyer NA, Leavy MB. Rockville (MD): Agency for 
Healthcare Research and Quality (US); 2014 Rockville (MD): Agency for Healthcare 
Research and Quality (US); 2014 Section II Section 8. 
 
8. 
Coghlan et al. A degradation fragment of type X collagen is a real-time marker for bone 
growth velocity. Sci. Transl. Med. 9, 2017. 
 
9. 
Olney RC, Permuy JW, Prickett TC, Han JC, Espiner EA. Amino-terminal propeptide 
of C-type natriuretSectic peptide (NTproCNP) predicts height velocity in healthy 
children. Clin Endocrinol (Oxf) 2012;77:416–422. 
 
10. Olney RC et al. C-type natriuretic peptide plasma levels are elevated in subjects with 
achondroplasia, hypochondroplasia, and thanatophoric dysplasia. J Clin 
EndocrinolMetab. 2015. 
 
11. Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in 
children with juvenile rheumatoid arthritis. Arthritis Rheum. 1994 Dec;37(12):1761-9. 

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18. LIST OF TABLES 
Not applicable. 
 
19. LIST OF FIGURES 
Not applicable. 
 
20. ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
 
Number 
Document reference 
number 
Date 
Title 
v1.0 
12-Feb-20 
English-USA-Qolissy Shortform 
(Children)-v1.0-12-Feb-20 
English-USA-Qolissy Shortform 
(Parents)-v1.0-12-Feb-20 
Original 
1990 
CHAQ Version 
1990 Original version Singh G et al. 
 
21. ANNEX 2. ADDITIONAL INFORMATION 
 
Not applicable.