A PHASE 3 MULTICENTER, OPEN LABEL, MULTI COHORT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SOMATROPIN IN JAPANESE PARTICIPANTS WITH PRADER-WILLI SYNDROME (PWS)
Phase: PHASE3
Conditions: Prader-Willi Syndrome
Sponsor: Pfizer

Somatropin
Protocol A6281323
Protocol Amendment 1, 13 December 2021
PFIZER CONFIDENTIAL
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Title Page
A PHASE 3 MULTICENTER, OPEN LABEL, MULTI COHORT STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF SOMATROPIN IN JAPANESE 
PARTICIPANTS WITH PRADER-WILLI SYNDROME (PWS)
Study Intervention Number:
PNU-180307
Study Intervention Name:
somatropin
US IND Number:
N/A
EudraCT Number:
N/A
ClinicalTrials.gov ID:
NCT04697381
Protocol Number:
A6281323
Phase:
3
Brief Title: Phase 3 study of the efficacy and safety of somatropin in Japanese 
participants with PWS
This document and accompanying materials contain confidential information belonging to Pfizer. Except 
as otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) 
or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Document History
Document 
Version Date
Amendment 1
13 December 2021
Original protocol
21 August 2020
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative 
clarification letter.
Protocol Amendment Summary of Changes Table
Amendment 1 (13-December-2021)
Overall Rationale for the Amendment: This protocol amendment enables study 
participants to complete study visits during extension period by utilizing Decentralized 
Clinical Trial component (Home health visit and Telehealth) deemed appropriate based on 
the participant’s preference and the investigator’s discretion.
Section # and 
Name
Description of Change
Brief Rationale
Overall
Minor corrections, clarifications to text, and
correction of typographical errors have been 
made throughout the protocol to improve 
overall readability.
Not applicable
1.1. Synopsis,
6.1.1 
Administration
Text for Adult cohort was updated to 
correct typographical error; Dose increase 
should occur at Month 1 visit.
To reflect changes made 
by PACL#1 dated 27-Oct-
2020
1.3 Schedule of 
Activities
Month 42 is added to header row to clarify 
and write down all specific visit timing in 
the case the extension period continues for 
36 months (ie, Month 48 visit).
To reflect changes made 
by PACL#1 dated 27-Oct-
2020
1.3 Schedule of 
Activities
Reference date for each protocol required 
visit was added for clarification.
To reflect changes made 
by PACL#5 dated 21-Jul-
2021
1.3 Schedule of 
Activities
Footnote j was updated to clarify DEXA 
scan performed within 7 days before Day 1 
visit is acceptable.
To reflect changes made 
by PACL#1 dated 27-Oct-
2020
1.3 Schedule of 
Activities
Footnote k was added to clarify Follow-up 
visit (28 days after EOS visit) can be done 
as telephone visit.
To reflect changes made 
by PACL#1 dated 27-Oct-
2020
1.3 Schedule of 
Activities
Footnote l was added to clarify that protocol 
specified visits for Extension period can be 
done by utilizing Telehealth/Home health 
To allow participant to 
utilize one of 
Decentralized Clinical 
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visit, instead of conventional on-site visit 
when deemed appropriate based on the 
participant’s preference and the 
investigator’s discretion.
Trial component in this 
study
1.3 Schedule of 
Activities
Footnote m was added to clarify 
assessments for Height (pediatric 
participants only where required), BMI, and 
BIA can be exempted if a participant 
utilizes Telehealth/Home health visit for 
each protocol specified visit during 
Extension Period.
To allow participant to 
utilize one of 
Decentralized Clinical 
Trial component in this 
study
4.1 Overall 
Design
Screening period was updated to “up to 28 
days” to make sure consistency with visit 
window for screening.
To reflect changes made 
by PACL#1 dated 27-Oct-
2020
6.1.3 Shipment 
and Collection 
of Study 
Intervention
New section added to clarify Study 
intervention shipment/collection by an 
appropriate third-party courier can be utilized 
in this study.
To reflect changes made 
by PACL#6 dated 09-
Sep-2021
6.8
Concomitant 
Therapy
Text was updated to clarify non-drug 
treatments are within scope of the 
requirements for concomitant therapy.
To reflect changes made 
by PACL#7 dated 02-
Dec-2021
6.8.2 Permitted 
During the 
Study
Text was updated to clarify if the 
investigator judges that the dose change will 
fall within the expected range of dose 
adjustment, then the dose change is 
permitted.
To reflect changes made 
by PACL#2 dated 15-Jan-
2021
7.1 
Discontinuation 
of Study 
Intervention
In response to the ongoing global pandemic 
COVID-19 and the increasing restrictions 
and concerns on public health, text was 
added to clarify alternative solutions to 
accommodate study procedures during the 
COVID-19 pandemic.
To reflect changes made 
by PACL#3 dated 19-
Feb-2021
9.2 Analysis 
Sets
Text was updated to maintain consistency 
across sections.
To reflect changes made 
by PACL#7 dated 02-
Dec-2021
10.2 Appendix 
2: Clinical 
Laboratory 
Tests
Text for footnote a. was updated to clarify a 
serum hCG testing can be selected as an 
alternative to a serum -hCG when 
clinically appropriate at the discretion of the 
investigator.
To reflect changes made 
by PACL#4 dated 28-
May-2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................13
1.3. Schedule of Activities .............................................................................................14
2. INTRODUCTION ...............................................................................................................17
2.1. Study Rationale .......................................................................................................17
2.2. Background .............................................................................................................17
2.2.1. Clinical Overview.......................................................................................17
2.3. Benefit/Risk Assessment.........................................................................................18
2.3.1. Risk Assessment.........................................................................................19
2.3.2. Benefit Assessment.....................................................................................20
2.3.3. Overall Benefit/Risk Conclusion................................................................20
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................20
4. STUDY DESIGN.................................................................................................................21
4.1. Overall Design.........................................................................................................21
4.2. Scientific Rationale for Study Design.....................................................................22
4.2.1. Participant Input Into Design......................................................................22
4.2.2. Choice of Contraception/Barrier Requirements .........................................22
4.3. Justification for Dose ..............................................................................................22
4.4. End of Study Definition ..........................................................................................23
5. STUDY POPULATION......................................................................................................23
5.1. Inclusion Criteria.....................................................................................................23
5.2. Exclusion Criteria....................................................................................................24
5.3. Lifestyle Considerations..........................................................................................25
5.3.1. Contraception (WOCBP Only)...................................................................25
5.4. Screen Failures ........................................................................................................25
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................25
6.1. Study Intervention(s) Administered........................................................................26
6.1.1. Administration............................................................................................26
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6.1.2. Medical Devices .........................................................................................26
6.1.3. Shipment and Collection of Study Intervention .........................................27
6.2. Preparation, Handling, Storage, and Accountability...............................................27
6.2.1. Preparation and Dispensing........................................................................28
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................28
6.3.1. Allocation to Study Intervention ................................................................28
6.4. Study Intervention Compliance...............................................................................29
6.5. Dose Modification...................................................................................................29
6.6. Continued Access to Study Intervention After the End of the Study......................29
6.7. Treatment of Overdose............................................................................................29
6.8. Concomitant Therapy..............................................................................................30
6.8.1. Prohibited During the Study.......................................................................30
6.8.2. Permitted During the Study ........................................................................30
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................30
7.1. Discontinuation of Study Intervention ....................................................................30
7.2. Participant Discontinuation/Withdrawal From the Study.......................................31
7.2.1. Withdrawal of Consent...............................................................................32
7.3. Lost to Follow-Up ...................................................................................................32
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................32
8.1. Efficacy Assessments..............................................................................................33
8.1.1. Body Composition Measured by DEXA....................................................33
8.1.2. Body Composition Measured by BIA ........................................................33
8.1.3. Adipose Tissue Distribution by Abdominal CT.........................................34
8.1.4. Waist Circumference ..................................................................................34
8.2. Safety Assessments .................................................................................................34
8.2.1. Physical and Auxological Examinations ....................................................34
8.2.2. Vital Signs ..................................................................................................34
8.2.3. Clinical Safety Laboratory Assessments ....................................................34
8.2.4. Diet/Exercise Management Compliance Check.........................................35
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................35
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......36
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8.3.1.1. Reporting SAEs to Pfizer Safety...............................................36
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................36
8.3.2. Method of Detecting AEs and SAEs ..........................................................37
8.3.3. Follow-Up of AEs and SAEs......................................................................37
8.3.4. Regulatory Reporting Requirements for SAEs...........................................37
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................37
8.3.5.1. Exposure During Pregnancy......................................................38
8.3.5.2. Exposure During Breastfeeding ................................................39
8.3.5.3. Occupational Exposure .............................................................40
8.3.6. Cardiovascular and Death Events...............................................................40
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................40
8.3.8. Adverse Events of Special Interest.............................................................40
8.3.8.1. Lack of Efficacy........................................................................40
8.3.9. Medical Device Deficiencies......................................................................40
8.3.9.1. Time Period for Detecting Medical Device Deficiencies .........41
8.3.9.2. Follow-Up of Medical Device Deficiencies..............................41
8.3.9.3. Prompt Reporting of Device Deficiencies to the Sponsor ........41
8.3.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................42
8.3.10. Medication Errors.....................................................................................42
8.5. Genetics...................................................................................................................43
8.5.1. Specified Genetics ......................................................................................43
8.7. Immunogenicity Assessments.................................................................................43
8.8. Health Economics ...................................................................................................43
9. STATISTICAL CONSIDERATIONS ................................................................................43
9.1. Statistical Hypotheses .............................................................................................43
9.1.1. Estimands....................................................................................................43
9.2. Analysis Sets ...........................................................................................................44
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9.3. Statistical Analyses .................................................................................................45
9.3.1. General Considerations...............................................................................45
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ................................................45
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis............................................45
9.3.5. Other Safety Analyses ................................................................................46
9.3.6. Other Analyse(s).........................................................................................46
9.4. Interim Analyses .....................................................................................................46
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................47
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............47
10.1.1. Regulatory and Ethical Considerations ....................................................47
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................47
10.1.2. Financial Disclosure .................................................................................48
10.1.3. Informed Consent Process ........................................................................48
10.1.4. Data Protection .........................................................................................49
10.1.5. Committees Structure ...............................................................................49
10.1.5.1. Data Monitoring Committee ...................................................49
10.1.6. Dissemination of Clinical Study Data ......................................................49
10.1.7. Data Quality Assurance ............................................................................50
10.1.8. Source Documents....................................................................................51
10.1.9. Study and Site Start and Closure ..............................................................52
10.1.10. Publication Policy...................................................................................53
10.1.11. Sponsor’s Qualified Medical Personnel .................................................53
10.2. Appendix 2: Clinical Laboratory Tests .................................................................55
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................56
10.3.1. Definition of AE .......................................................................................56
10.3.2. Definition of an SAE ................................................................................57
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................59
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10.3.4. Reporting of SAEs....................................................................................63
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................64
10.4.1. Male Participant Reproductive Inclusion Criteria....................................64
10.4.2. Female Participant Reproductive Inclusion Criteria.................................64
10.4.3. Woman of Childbearing Potential ............................................................64
10.4.4. Contraception Methods.............................................................................65
10.5. Appendix 5: Genetics............................................................................................67
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......68
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................70
10.8. Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting in Medical Device Studies .............................................71
10.8.1. Definition of AE and ADE .......................................................................71
10.8.2. Definition of SAE, SADE, and USADE ..................................................71
10.8.3. Definition of Device Deficiency...............................................................72
10.8.4. Recording/Reporting and Follow-Up of Medical Device 
Deficiencies......................................................................................................72
10.8.5. Reporting of SAEs....................................................................................74
10.8.6. Reporting of SADEs.................................................................................74
10.9. Appendix 9: Country-Specific Requirements .......................................................75
10.9.1. Japan .........................................................................................................75
10.9.1.1. Definitions of Serious Adverse Event, Serious Adverse 
Event Caused by Medical Device, and Unanticipated Serious 
Adverse Event Caused by Medical Device .......................................75
10.10. Appendix 10: Alternative Measures During Public Emergencies.......................76
10.10.1. Telehealth Visits.....................................................................................76
10.10.2. Alternative Facilities for Safety Assessments ........................................76
10.10.2.1. Laboratory Testing ................................................................76
10.10.3. Study Intervention ..................................................................................77
10.10.4. Home Health Visits.................................................................................77
10.10.5. Adverse Events and Serious Adverse Events.........................................78
10.10.6. Efficacy Assessments .............................................................................78
10.11. Appendix 11: Abbreviations ...............................................................................79
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11. REFERENCES ..................................................................................................................82
LIST OF TABLES
Table 1.
Protocol-Required Safety Laboratory Assessments .................................55
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: Phase 3 study of the efficacy and safety of somatropin in Japanese participants 
with PWS
Rationale
Somatropin is a recombinant human growth hormone (r-hGH) indicated for the long-term 
treatment of children with growth disturbance due to various conditions and replacement 
therapy in AGHD.
GH replacement therapy is recommended for both pediatric and adult patients with PWS. In 
Japan, GH replacement therapy is approved for short stature associated with PWS in 2002 
but not approved for the use of maintaining or improving body composition in pediatric PWS 
patients or any use in adults with PWS.
Somatropin for the indication "improvement of body composition in pediatric and adult 
PWS" was officially judged as drug/indication in high medical needs at the “MHLW 
committee on unapproved/off-label used drugs”. The present study is to evaluate the efficacy 
and safety of somatropin in Japanese patients with PWS in response to the MHLW 
development request issued 
Objectives, Endpoints, and Estimands
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To evaluate the efficacy 
of somatropin in 
participants with PWS.

Population: Japanese 
participants with PWS in each 
cohort;

Variable: Change from baseline 
to Month 12 in lean body mass 
(%) measured by DEXA;

Intercurrent events: All data 
after an intercurrent event 
(major deviation of 
diet/exercise, discontinuation of 
treatment, discontinuation of 
study, etc.), if collected, will 
not be considered;

Population level summary: 
Mean (GH naïve pediatric and 

Change from baseline to 
Month 12 in lean body mass 
(%) measured by DEXA.
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Objectives
Estimands
Endpoints
GH treated pediatric cohort) or 
LS mean (adult cohort).
Secondary: 
Secondary:
Secondary: 

To evaluate the effects of 
somatropin on other body 
composition parameters. 

Population: Japanese 
participants with PWS 
syndrome in each cohort;

Variable: Each secondary 
endpoint;

Intercurrent events: All data 
after an intercurrent event 
(major deviation of 
diet/exercise, discontinuation of 
treatment, discontinuation of 
study, etc.), if collected, will 
not be considered;

Population level summary: 
Mean (GH naïve pediatric and 
GH treated pediatric cohort) or 
mean/LS mean (adult cohort).

[KEY SECONDARY] Change 
from baseline to Month 12 in 
lean body mass (%) measured 
by BIA;

Change from baseline to 
Month 12 in body fat 
(%) measured by DEXA;

Change from baseline to 
Month 12 in adipose tissue 
distribution measured by 
abdominal CT; 

Change from baseline to 
Month 6 in lean body mass (%) 
measured by DEXA (adult 
cohort only).

To evaluate the safety and 
tolerability of somatropin.

N/A.

AE.

SAE.

Clinical laboratory values.

Bone maturation.
 
 
 
 
 
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Overall Design
Brief Summary
This is a multicenter, open label, multi cohort study of participants with PWS. This study has 
3 cohorts (GH naïve pediatric cohort, GH treated pediatric cohort and adult cohort) and all 
participants will receive somatropin.
Number of Participants
Approximately 30 Japanese participants (5 GH naïve pediatric participants, 5 GH treated 
pediatric participants and 20 adult participants) will be enrolled to study intervention.
Intervention Groups and Duration
The study consists of a screening period, treatment period of 12 months and extension period 
which continues for 36 months or until regulatory approval, whichever occurs first. Upon 
commencement of active treatment with somatropin, participants will be dosed 6 or 7 times 
in a week, subcutaneously.
Dose regimens in each of the cohorts are as below (the weekly dose should be divided into 
6 or 7 subcutaneous injections):

GH naïve pediatric cohort: 0.245 mg/kg/week;

GH treated pediatric cohort: 0.084 mg/kg/week. The dosage may be adjusted
according to participants’ symptoms and serum IGF-1 levels but should not exceed
1.6 mg/day;

Adult cohort: starting with 0.042 mg/kg/week, then titrated up to 0.084 mg/kg/week
from Month 1 visit. The dosage may be adjusted according to participants’ symptoms
and serum IGF-1 levels but should not exceed 1.6 mg/day.
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Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
Statistical hypothesis testing will not be performed. 
Data will be evaluated individually and descriptively for each cohort. 
For adult cohort, the least squares (LS) mean and its 95% CI of change from baseline to 
Month 6 and 12 in lean body mass (%) measured by dual energy X-ray absorptiometry 
(DEXA) or in other secondary efficacy endpoints will be estimated based on a Mixed-effects
Models for Repeated Measures (MMRM).
1.2. Schema
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
Screening 
Period
Treatment Period
Extension Periodl
End of Study
Follow-up
Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 11
Screening
Day 1h Month 
1
Week
4
Month 
2b
Week
8
Month 
3
Week
12
Month
6
Week
26
Month
9
Week
39
Month 
12
Week
52
Month
18/24/30/36/42
Week
78/104/130/156/182
End of 
Study/Early 
Termination/
Discontinuation
28 days 
after EOS 
visitk
Visit Window
Day -28 to -1
N/A
±3d
±3d
±3d
±3d
±7d
±7d
±14d
+7d
Informed consent/assent
X
Registration
X
Inclusion/exclusion criteria
X
X
Medical history
X
X
Demographics
X
X
Physical examination, including 
behavioral and mental health 
status
X
X
Vital signs
X
X
X
Xb
X
X
X
X
X
X
Diet/exercise management 
compliance check
X
X
X
X
X
X
X
X
Weight, BMI
X
X
X
X
X
X
X
Xm
X
Heighti
X
Xc
Xc
Xc
Xc
Xc
X
Xc, m
X
Bone agec
X
X
Xd
Assessment of childbearing 
potential
X
Pregnancy testing (WOCBP 
only)
X
X
X
X
X
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Screening 
Period
Treatment Period
Extension Periodl
End of Study
Follow-up
Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 11
Screening
Day 1h Month 
1
Week
4
Month 
2b
Week
8
Month 
3
Week
12
Month
6
Week
26
Month
9
Week
39
Month 
12
Week
52
Month
18/24/30/36/42
Week
78/104/130/156/182
End of 
Study/Early 
Termination/
Discontinuation
28 days 
after EOS 
visitk
Visit Window
Day -28 to -1
N/A
±3d
±3d
±3d
±3d
±7d
±7d
±14d
+7d
Contraception check (WOCBP 
only)
X
X
X
X
X
X
X
X
X
Study intervention
Dispense study intervention
X
X
X
X
X
X
Xf
Review injection diary
X
X
X
X
X
X
X
Assessments
Efficacy
Body composition (DEXA) j
X
Xe
X
Xd
Abdominal CTj
X
X
Xd
Body composition (BIA)
X
X
X
X
X
X
Xm
X
Waist circumference
X
X
Xd
Safety
Concomitant treatment(s)
X








X
Serious and nonserious adverse 
event monitoring
X









X
Laboratoryg
Blood count
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
IGF-1, IGF-1 SDS
X
X
X
X
X
X
X
X
Thyroid function (TSH, FT4)
X
X
X
X
X
X
X
X
Cortisol
X
X
X
X
X
X
X
X
Gonadal function (LH, FSH, E2, 
testosterone)
X
X
X
X
X
X
HbA1c
X
X
X
Xb
X
X
X
X
X
X
Casual blood glucose
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Lipid profile
X
X
X
X
X
X
X
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Screening 
Period
Treatment Period
Extension Periodl
End of Study
Follow-up
Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 11
Screening
Day 1h Month 
1
Week
4
Month 
2b
Week
8
Month 
3
Week
12
Month
6
Week
26
Month
9
Week
39
Month 
12
Week
52
Month
18/24/30/36/42
Week
78/104/130/156/182
End of 
Study/Early 
Termination/
Discontinuation
28 days 
after EOS 
visitk
Visit Window
Day -28 to -1
N/A
±3d
±3d
±3d
±3d
±7d
±7d
±14d
+7d
a.
Day relative to start of study intervention (Day 1).
b.
Applicable only for participants with diabetes.
c.
For pediatric cohorts only. If the participant reaches bone age of 17 for boys and 15 for girls, the assessment is not necessary after that.
d.
Applicable only for early termination before Month 12.
e.
For adult cohort only.
f.
For extension period, study intervention can be dispensed every 3 months in case a participant cannot bring home a 6-month drug supply at once. If a 
participant chooses to receive drug supply every 3 months, safety assessment (at least but not limited to: AE/SAE, concomitant treatment) should be 
confirmed via physical site visit or telehealth before dispensing for the remaining 3 months. If a participant choose a 6-month drug supply, he/she will come 
back to the site for next protocol specified visits and complete assessments according to protocol.
g.
All laboratory testing can be performed locally at the site. Fasting is not required for any of lab tests in this study. 
h.
Laboratory test result at Screening can be used for Day 1 if the test was performed within 7 days before Day 1 visit. 
i.
Height measurement at Screening can be used for Day 1 if the measurement was performed within 14 days before Day 1 visit.
j.
DEXA/Abdominal CT scan prior to Day 1 visit is acceptable if the evaluation was performed within 7 days before Day 1 visit.
k.
Follow-up visit may become telephone visit at investigator’s discretion.
l.
Protocol specified visits for Extension period can be done by utilizing Telehealth/Home health visit, instead of conventional on-site visit when deemed 
appropriate based on the participant’s preference and the investigator’s discretion.
m. Assessments for Height (pediatric participants only where required), BMI, and BIA can be exempted if a participant utilizes Telehealth/Home health visit
for each protocol specified visit during Extension Period.
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2. INTRODUCTION
Somatropin is a r-hGH currently being investigated in participants with PWS.
2.1. Study Rationale 
The purpose of the study is to evaluate the efficacy and safety of somatropin in a cohort of 
Japanese participants with PWS.
This study is planned to support a supplemental new drug application in Japan in response to 
the official development request issued by Research and Development Division, Health 
Policy Bureau and Pharmaceutical Evaluation Division, Pharmaceutical Safety and 
Environmental Health Bureau, MHLW.
2.2. Background
Somatropin is indicated for the long-term treatment of children with growth disturbance due 
to various conditions and replacement therapy in AGHD and marketed in more than 100 
countries over 30 years.
GH replacement therapy is recommended for both pediatric and adult patients with PWS1
and somatropin is approved for pediatric PWS regardless of stature in European countries 
and for adult PWS in New Zealand. In Japan GH replacement has been approved since 2002 
for "short stature without epiphyseal closure associated with PWS", and is not approved for 
the use of improving body composition in pediatric patients and any use in adult patients 
with PWS.
A nation-wide patient advocacy group submitted a petition for somatropin for the indication 
"improvement of body composition in pediatric and adult PWS" and the requested indication 
was judged as a high medical need at the 39th MHLW Committee on Unapproved/Off-label 
used Drugs on 26 Aug 2019. Thereafter the official development request was issued to Pfizer 
Japan on 
 by Research and Development Division, Health Policy Bureau and 
Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health 
Bureau, MHLW. 
The outline of the study was agreed upon with the Pharmaceuticals and Medical Devices
Agency (PMDA) on 
2.2.1. Clinical Overview
The safety and efficacy of somatropin in the treatment of pediatric participants with PWS 
were evaluated in two randomized, open-label, controlled clinical trials.2 No Japanese 
participants were enrolled to these studies. Participants received either somatropin or no 
treatment for the first year of the studies, while all participants received somatropin during 
the second year. In Study 1, the treatment group received somatropin at a dose of 
0.24 mg/kg/week during the entire study. During the second year, the control group received 
somatropin at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received 
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somatropin at a dose of 0.36 mg/kg/week during the entire study. During the second year, the 
control group received somatropin at a dose of 0.36 mg/kg/week.
In both of these studies, participants who received somatropin showed significant increases 
in linear growth during the first year of study, compared with participants who received no 
treatment. Linear growth continued to increase in the second year, when both groups 
received treatment with somatropin. Changes in body composition were also observed in the 
participants receiving somatropin. These changes included a decrease in the amount of fat 
mass, and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while 
changes in body weight were similar to those seen in participants who received no treatment. 
Treatment with somatropin did not accelerate bone age, compared with participants who 
received no treatment.
There has been no clinical study conducted in Japanese PWS patients evaluating 
improvement in body composition as a primary endpoint. Approval in Japan for the 
indication "short stature associated with PWS" was based on the randomized studies 
mentioned above. Post marketing surveillance for the indication was conducted in pediatric 
PWS population and no new safety issues were identified. The re-evaluation process was 
completed based on the result from the surveillance.
The efficacy and safety of GH for adult PWS has been shown in several clinical 
studies.3,4,5,6,7 A meta-analysis8 also supports the effectiveness of GH in improving the body 
composition in PWS patients.
Although the evidence in Japanese PWS patients is limited, the efficacy and safety of GH has 
been shown in many studies with both pediatric and adult PWS populations.
2.3. Benefit/Risk Assessment
There are data regarding clear benefits to GH treatment in PWS populations. At the same 
time there have been reports of AEs associated with the use of GH in several conditions and 
therefore eligibility criteria for this study have been selected to ensure that only appropriate 
participants are included in the study. More detailed information about the known and 
expected benefits and risks and reasonably expected AEs of somatropin may be found in the 
IB, which is the SRSD for this study.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) somatropin
Potential risks associated with somatropin include 
the following: fatalities due to upper airway 
obstruction, myositis, type 2 diabetes mellitus, 
hyperthyroidism, hypoadrenalism, slipped epiphyses 
of the hip, benign intracranial hypertension, 
scoliosis.
The potential risks are based on product labeling 
for somatropin which is based on data from
clinical trials and pharmacovigilance activities.

Eligibility criteria have been selected to 
ensure that only appropriate participants are 
included in the study (see Section 5).

More intensive monitoring is required for 
participants with preexisting diabetes.
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2.3.2. Benefit Assessment
Treatment with somatropin in this study is anticipated to improve participants’ body 
composition.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with somatropin are justified by the 
anticipated benefits that may be afforded to participants with PWS.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To evaluate the efficacy 
of somatropin in 
participants with PWS.

Population: Japanese 
participants with PWS in each 
cohort;

Variable: Change from baseline 
to Month 12 in lean body mass 
(%) measured by DEXA;

Intercurrent events: All data 
after an intercurrent event 
(major deviation of 
diet/exercise, discontinuation of 
treatment, discontinuation of 
study, etc.), if collected, will 
not be considered;

Population level summary: 
Mean (GH naïve pediatric and 
GH treated pediatric cohort) or 
LS mean (adult cohort).

Change from baseline to 
Month 12 in lean body mass 
(%) measured by DEXA.
Secondary: 
Secondary:
Secondary: 

To evaluate the effects of 
somatropin on other body 
composition parameters. 

Population: Japanese 
participants with PWS 
syndrome in each cohort;

Variable: Each secondary 
endpoint;

Intercurrent events: All data 
after an intercurrent event 
(major deviation of 
diet/exercise, discontinuation of 
treatment, discontinuation of 

[KEY SECONDARY] Change 
from baseline to Month 12 in 
lean body mass (%) measured 
by BIA;

Change from baseline to 
Month 12 in body fat 
(%) measured by DEXA;

Change from baseline to 
Month 12 in adipose tissue 
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Objectives
Estimands
Endpoints
study, etc.), if collected, will 
not be considered;

Population level summary: 
Mean (GH naïve pediatric and 
GH treated pediatric cohort) or 
mean/LS mean (adult cohort).
distribution measured by 
abdominal CT; 

Change from baseline to 
Month 6 in lean body mass (%) 
measured by DEXA (adult 
cohort only).

To evaluate the safety and 
tolerability of somatropin.

N/A.

AE.

SAE.

Clinical laboratory values.

Bone maturation.
 
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, open label, multi cohort study to evaluate the efficacy and safety of 
somatropin in Japanese participants with PWS. This study has 3 cohorts (GH naïve pediatric 
cohort, GH treated pediatric cohort and adult cohort) and all participants will receive 
somatropin.
The durations of the study periods are listed below:

Screening Period up to 28 days;
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
Treatment Period: 12 months;

Extension Period: 36 months or until regulatory approval, whichever is sooner.
4.2. Scientific Rationale for Study Design
An open-label study design was chosen. Rarity of disease necessitated a single arm study and 
the high unmet need required an efficient design.
4.2.1. Participant Input Into Design
Protocol design and schedules of activities were shared and discussed with 
patients/caregivers with PWS at the web-based advisory board meeting and confirmed as 
acceptable. 
4.2.2. Choice of Contraception/Barrier Requirements 
Somatropin is approved for use in treatment of children with growth disturbance due to 
various conditions and replacement therapy in AGHD without any contraceptive precautions. 
There is no suspicion of human teratogenicity based on the intended pharmacology. See 
Appendix 4 for contraceptive requirements.
4.3. Justification for Dose
The planned somatropin doses in this study are as below (the weekly dose should be divided 
into 6 or 7 subcutaneous injections):

GH naïve pediatric cohort: 0.245 mg/kg/week.
Rationale: (1)dose identical to the current approved dose for short stature associated 
with PWS in Japan; (2)dose identical to the approved dose for pediatric PWS 
(regardless of their stature) in European countries; (3)consistent with the 
recommendation in the Consensus Guideline1.

GH treated pediatric cohort: 0.084 mg/kg/week. The dosage may be adjusted 
according to participants’ symptoms and serum IGF-1 levels but should not exceed 
1.6 mg/day.
Rationale: (1)similarities between PWS and AGHD in clinical characteristics; 
(2)dose identical to the maximum approved dose for AGHD in Japan; (3)dose used in 
the study is about three times lower than the dose participants have received; (4)dose 
adjustment based on IGF-1 level and maximum dose of 1.6 mg/day are consistent 
with the recommendation in the Consensus Guideline.

Adult cohort: starting with 0.042 mg/kg/week, then titrated up to 0.084 mg/kg/week 
from Month 1 visit. The dosage may be adjusted according to participants’ symptoms 
and serum IGF-1 levels but should not exceed 1.6 mg/day.
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Rationale: (1)similarities between PWS and AGHD in clinical characteristics; 
(2)dose identical to the maximum approved dose for AGHD in Japan; (3)initiate 
treatment at a lower dose to ensure participants’ safety; (4)dose adjustment based on 
IGF-1 level and maximum dose of 1.6 mg/day are consistent with the 
recommendation in the Consensus Guideline.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit which is defined as the follow-up telephone call 28 days 
from EOS or the Termination visit.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics:
1. Male or female participants with documentation of genetically confirmed diagnosis of 
PWS.
2. No plan to initiate a new treatment that may affect the body composition, such as 
gonadal hormone replacement therapy.
3. Currently on appropriate diet and exercise programs and willing to continue 
throughout the study period at the discretion of the investigator.
4. Participants, and if required by local/site regulations their parent(s)/legal guardian(s) 
must be willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, lifestyle considerations, and other study procedures.
Informed Consent: 
5. Evidence of a personally signed and dated ICD (and written assent where applicable 
based on age and country regulation) indicating that the participant or a legally 
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acceptable representative/parent(s)/legal guardian has been informed of all pertinent 
aspects of the study. Refer to Appendix 1 for the detailed process of obtaining 
consent.
For inclusion of GH naïve pediatric cohort, participants must meet criteria 6 to 8:
6. 18 years or younger.
7. Naïve to GH treatment.
8. Tanner stage 1 (for testes in males, for breasts in females).
For inclusion of GH treated pediatric cohort, participants must meet criteria 9 and 10:
9. Continued GH treatment for at least 2 years with stable dose for the last 6 months and 
being on GH at time of inclusion. The recent dose should be higher than 
0.084 mg/kg/week.
10. Participants who are about to complete GH treatment for his/her short stature (eg, due 
to meeting the treatment stopping criteria defined as a height SDS more than -2.5 for 
Japanese adult standards).
For inclusion of adult cohort, participants must meet criteria 11 to 13:
11. 18 years of chronological age or older at Day 1 visit.
12. Off from GH treatment for at least 1 year.
13. Serum IGF-1 level within +2 SDS, adjusted for age and sex.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Participants with uncontrolled diabetes at the discretion of the investigator.
2. Participants with malignant tumors.
3. Participants with severe obesity or serious respiratory impairment. 
4. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concurrent Clinical Study Experience:
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5. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention 
used in this study (whichever is longer).
Other Exclusions:
6. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.  
5.3. Lifestyle Considerations
It is important that participants continue their typical dietary habits and physical activity 
throughout the study period. Participants will be asked not to change their diet and their 
exercise routine.
5.3.1. Contraception (WOCBP Only)
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant from the permitted list of contraception methods (see Appendix 4 Section 10.4.4) 
and will confirm that the participant has been instructed in its consistent and correct use. At 
time points indicated in the SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart (participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception) 
considering that their risk for pregnancy may have changed since the last visit. In addition, 
the investigator or designee will instruct the participant to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the participant 
or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
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For the purposes of this protocol, study intervention refers to somatropin.
6.1. Study Intervention(s) Administered
Intervention Name
Somatropin
ARM Name
(group of participants receiving a specific 
treatment or no treatment)
Somatropin
Type
Biologic
Dose Formulation
Device
Unit Dose Strength(s)
5.3 mg, 12 mg
Dosage Level(s)
For GH naïve pediatric cohort: 0.245 mg/kg/week
For GH treated pediatric cohort: 0.084 mg/kg/week
For adult cohort: 0.042 0.084 mg/kg/week
Route of Administration
Subcutaneously
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided centrally by the sponsor.
Packaging and Labeling
Study intervention will be provided in container. 
Each container will be labeled as required per 
country requirement.
6.1.1. Administration
Dose regimens in each cohorts are as below (the weekly dose should be divided into 6 or 
7 subcutaneous injections):

GH naïve pediatric cohort: 0.245 mg/kg/week;

GH treated pediatric cohort: 0.084 mg/kg/week. The dosage may be adjusted 
according to participants’ symptoms and serum IGF-1 levels at the discretion of the 
investigator. The weekly dose can be increased but should not exceed 1.6 mg/day;

Adult cohort: starting with 0.042 mg/kg/week, then titrated up to 0.084 mg/kg/week 
from Month 1 visit. The dosage may be adjusted according to participants’ symptoms 
and serum IGF-1 levels at the discretion of the investigator. The weekly dose can be 
increased but should not exceed 1.6 mg/day.
Site personnel will instruct the participant or designated person on the proper sterile 
technique to administer a subcutaneous injection when using the pen device at home. During 
the baseline visit, the initial dose of study intervention must be administered in the office by 
study personnel, while the participant or participant’s caregiver observes.
6.1.2. Medical Devices
1. The sponsor-manufactured medical devices (or devices manufactured for sponsor by 
a third party) provided for use in this study are Genotropin GoQuick 5.3 mg or 12 mg.
2. Instructions for medical device use are provided in the IP manual.
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3. All medical device deficiencies (including malfunction, use error, and inadequate 
labeling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.3.9) and appropriately managed by the sponsor.
6.1.3. Shipment and Collection of Study Intervention
Study intervention may be shipped by an appropriate third-party courier to study participants 
(or be collected by an appropriate third-party courier from study participants) if permitted by 
local regulations and in accordance with storage and transportation requirements for Study 
intervention. Pfizer does not permit the shipment of Study intervention by mail. The tracking 
record of shipments and the chain of custody of Study intervention must be kept in the 
participant’s source documents/medical records. Study intervention can continue to be 
administered at home in accordance with the protocol.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
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7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. All somatropin that is taken 
home by the participant, both used and unused, must be returned to the investigator 
by the participant. Returned study intervention must not be redispensed to the 
participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
Somatropin will be provided as pen devices packaged and dispensed in cartons with 
tamper-evident seals. A qualified staff member will dispense the study intervention using an 
IRT drug management system via unique container numbers in the cartons provided, and in 
quantities appropriate to the SoA. A second staff member will verify the dispensing. The 
participant/caregiver should be instructed to maintain the product in the cartons provided, 
and the cartons should not be opened until the study intervention is to be administered.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
This is an open-label study; however, the specific study intervention dispensed to the 
participant will be assigned using an IRT. The site will contact the IRT prior to the start of 
study intervention administration for each participant.  
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
Study intervention will be dispensed at the study visits summarized in the SoA. 
Returned study intervention must not be redispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
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6.4. Study Intervention Compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by counting returned 
devices during the site visits (or upon receipt of study intervention from study participants in 
case they utilize third-party courier for the collection of study drug) and documented in the 
source documents and CRF. Deviation(s) from the prescribed dosage regimen should be 
recorded in the CRF.
A record of the number of somatropin pen devices dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions, will also be recorded in the CRF.
6.5. Dose Modification
The dose in this study will be based on the participant's weight. The investigator should 
review participants’ weight at every protocol-specified visit and recalculate the prescribed 
dose if necessary.
For GH treated pediatric and adult cohorts, dose modification is permitted according to the 
participant’s symptoms and serum IGF-1 levels at the discretion of the investigator, in 
addition to the modification based on their weight. The weekly dose can be increased but 
should not exceed 1.6 mg/day (see Section 6.1.1).
6.6. Continued Access to Study Intervention After the End of the Study
This extension period of the study continues for 36 months or until regulatory approval 
whichever occurs first. No intervention will be provided to study participants at the end of 
the study.
6.7. Treatment of Overdose
For this study, any dose of somatropin greater than prescribed dose will be considered an 
overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
6.8. Concomitant Therapy
Medications/treatments that are taken in the screening period as well as any 
medications/treatments taken for the management of PWS will be documented as prior 
medications/treatments. Medications/treatments taken after the first dose of study 
intervention has been administered will be documented as concomitant 
medications/treatments. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with: 

Reason for use;

Dates of administration;

Dosage information.
6.8.1. Prohibited During the Study
The following medications and treatments are prohibited for use during the study. If 
medically necessary, the investigator should consult with the sponsor in advance.

Newly initiated medications/non-drug treatments which could affect body 
composition, such as hormonal replacement therapy, medications for hyperlipidemia, 
anti-obesity medication, and surgery accompanied with metal implants.

Growth hormone products other than study intervention and investigational drugs.
6.8.2. Permitted During the Study
Medications and treatments for conditions associated with PWS which are optimized and 
stable treatment regimen, as determined by the investigator, for at least 3 months prior to 
Day 1, are permitted. Participants should remain on stable dosages/treatment regimens 
required to maintain stability of conditions associated with PWS during the study period. If 
dose modification or any other changes are medically necessary, the investigator should 
consult with the sponsor in advance. However, if the investigator judges that the dose change 
will fall within the expected range of dose adjustment, then the dose change is permitted.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
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intervention include the following: refused further follow-up, lost to follow-up, death, study 
terminated by sponsor.  
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
treatment/intervention must be considered. For participant discontinuation reporting in the 
CRF: select the most appropriate status for discontinuation; if the discontinuation is 
associated with the current COVID-19 pandemic including SARS-CoV-2 infection or 
quarantine related to SARS-CoV-2 exposure, enter “COVID-19” in the “Specify Status” 
field.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
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7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
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Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
430 mL. The actual collection times of blood sampling may change.
8.1. Efficacy Assessments
Refer to the SoA table for required procedures for each visit.
8.1.1. Body Composition Measured by DEXA
Body fat and lean body mass will be measured by DEXA. All scans for the same participant 
are made on same machine, with regular quality assurance at the site throughout the study. 
Regular quality assurance should include calibration following site’s standard operational 
procedure.
8.1.2. Body Composition Measured by BIA
Body fat and lean body mass will be measured by BIA. All scans for the same participant are 
made on same machine, with regular quality assurance at the site throughout the study. 
Regular quality assurance should include calibration following site’s standard operational 
procedure.
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8.1.3. Adipose Tissue Distribution by Abdominal CT
The areas of subcutaneous adipose tissue (cm2), visceral adipose tissue (cm2) will be 
measured at the level of the umbilicus by abdominal CT. All scans for the same participant 
are made on same machine, with regular quality assurance at the site throughout the study. 
Regular quality assurance should include calibration following site’s standard operational 
procedure.
8.1.4. Waist Circumference
Waist circumference will be measured at the level of the umbilicus.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical and Auxological Examinations
A physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Assessments of the behavioral/mental 
health status will also be included. Investigators should pay special attention to clinical signs 
related to previous serious illnesses. Any abnormal findings at Screening visit should be 
recorded as Medical History. Study participants who have any abnormal findings related to 
behavioral/mental health status must also be followed by a PWS multispecialty team that 
includes at least a primary physician and/or a mental health specialist.
Height and weight will also be measured and recorded. Bone age will be assessed only in 
pediatric participants by an X-ray picture of the left hand and wrist. If the participant reaches 
bone age of 17 for boys and 15 for girls, the assessment is not necessary after that.
8.2.2. Vital Signs
Vital signs will be measured with the participant in a sitting position after 5 minutes of rest 
and will include temperature, systolic and diastolic blood pressure, and pulse rate.
8.2.3. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
For participants with preexisting diabetes, casual blood glucose tests are to be performed in 
addition to HbA1c at the specified visits to make sure the participants’ blood glucose level is 
maintained within acceptable range. Last mealtime before blood draw should be recorded 
along with the casual glucose tests.
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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.4. Diet/Exercise Management Compliance Check
The investigator will confirm the diet and exercise programs which the individual participant 
is currently on and needs to continue throughout the study period at Screening visit. At time 
points indicated in the SoA, the investigator will inform the participant of the need to 
continue diet/exercise programs consistently and correctly and document the participant’s 
confirmation in the participant’s chart.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Appendix 8. Device deficiencies are covered in Section 8.3.9.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc.).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant/parent will 
be questioned about the occurrence of AEs in a nonleading manner.
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In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, after the last administration of the study intervention. 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.  
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
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8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-Up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
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exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then exposes his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until at least 
5 terminal half-lives after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion, inhalation, or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
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information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form, regardless of whether 
there is an associated SAE. Since the information about the occupational exposure 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 must be maintained in the 
investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Medical devices are being provided for use in this study. In order to fulfill regulatory 
reporting obligations worldwide, the investigator is responsible for the detection and 
documentation of events meeting the definitions of device deficiency that occur during the 
study with such devices.
The definition of a medical device deficiency can be found in Appendix 8.
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Note: AEs and/or SAEs that are associated with a medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Sections 8.3.1 through 8.3.4 and 
Appendix 3 of the protocol.
8.3.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
Importantly, reportable device deficiencies are not limited to problems with the device itself 
but also include incorrect or improper use of the device and even intentional misuse, etc. 
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such deficiency is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Appendix 8.
8.3.9.2. Follow-Up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the investigator.
8.3.9.3. Prompt Reporting of Device Deficiencies to the Sponsor
When a device deficiency occurs: 
1. The investigator notifies the sponsor by telephone or email within 1 business day of 
determining that the incident meets the protocol definition of a medical device 
deficiency.
2. The device deficiency must be recorded on the Medical Device Complaint form.
3. If an AE (either serious or non-serious) associated with the device deficiency occurs, 
then the AE must be entered into the AE section of the CRF.
4. If an SAE associated with the device deficiency is brought to the attention of the 
investigator, the investigator must immediately notify Pfizer Safety of the SAE (see 
Section 8.3.1.1). All relevant details related to the role of the device in the event must 
be included in the CT SAE Report Form as outlined in Sections 8.3.1.1 and 8.3.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
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8.3.9.4. Regulatory Reporting Requirements for Device Deficiencies
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
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8.5. Genetics
8.5.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
In this study, no formal hypothesis testing will be conducted.
The efficacy will be evaluated comprehensively based on individual data and summary 
statistics in each cohort for the primary, secondary, 
In addition, it 
will be confirmed in adult cohort that the point estimate of the least squares (LS) mean of the 
primary endpoint is above 0.
9.1.1. Estimands
1. The estimand for the primary endpoint is the hypothetical estimand, which estimates 
the effect if all participants maintain their treatment and adhere to the protocol. It 
includes the following 4 attributes:

Population: Japanese participants with PWS in each cohort;

Variable: Change from baseline to Month 12 in lean body mass (%) measured by 
DEXA;
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
Intercurrent events: All data after an intercurrent event (major deviation of 
diet/exercise, discontinuation of treatment, discontinuation of study, etc.), if 
collected, will not be considered;

Population level summary: Mean (GH naïve pediatric and GH treated pediatric 
cohort) or LS mean (adult cohort).
2. The estimand for secondary endpoints is the hypothetical estimand, which estimates 
the effect if all participants maintain their treatment and adhere to the protocol. It 
includes the following 4 attributes:

Population: Japanese participants with PWS in each cohort;

Variable: Each secondary endpoint;

Intercurrent events: All data after an intercurrent event (major deviation of 
diet/exercise, discontinuation of treatment, discontinuation of study, etc.), if 
collected, will not be considered;

Population level summary: Mean (for GH naïve pediatric and GH treated 
pediatric cohort) or mean/LS mean (for adult cohort).
For change from baseline endpoints, it would require that a participant have a baseline value 
and at least 1 post baseline value to be included in the analysis for that endpoint.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Full Analysis Set (FAS)
All participants assigned to study intervention and who 
take at least one dose of study intervention.
Efficacy Evaluable Set
All participants assigned to study intervention and who 
take at least one dose of study intervention and have at 
least one efficacy evaluation.
Defined Analysis Set
Description
Adherence to protocol 
regimen
For participants who experience major deviation of 
diet/exercise or other major protocol deviation and/or
discontinuation of treatment or study withdrawal, all data 
after the major deviation or discontinuation will not be 
considered.
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9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. General Considerations
All efficacy analyses will be performed on the efficacy evaluable set and all safety analyses 
will be performed on the FAS. All listings will be generated on the FAS.
Descriptive statistics consists of measures such as N, counts and percentages for categorical 
variables and N, mean, SD, median, range, min, max for continuous variables.
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
The primary endpoint for the study is change from baseline to Month 12 in lean body mass 
(%) measured by DEXA. 
Data will be evaluated individually and descriptively for each cohort.
For adult cohort, the least squares (LS) mean and its 95% CI of change from baseline to 
Month 6 and 12 in lean body mass (%) measured by DEXA will be estimated based on a 
Mixed-effects Models for Repeated Measures (MMRM). The model will include fixed 
effects for visit as a categorical variable, and baseline lean body mass value (%) and
interaction between baseline lean body mass value (%) and visit as a continuous variable.
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
The secondary endpoints for the study are as follows.

[KEY SECONDARY] Change from baseline to Month 12 in lean body mass 
(%) measured by BIA.

Change from baseline to Month 12 in body fat (%) measured by DEXA.

Change from baseline to Month 12 in adipose tissue distribution measured by 
abdominal CT.

Change from baseline to Month 6 in lean body mass (%) measured by DEXA (adult 
cohort only).
Data will be evaluated individually and descriptively for each cohort.
For adult cohort, excluding adipose tissue distribution measured by abdominal CT, the least 
squares (LS) mean and its 95% CI of change from baseline to Month 6 and Month 12 in each 
variable will be estimated based on a Mixed-effects Models for Repeated Measures 
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(MMRM). The model will include fixed effects for visit as a categorical variable, and 
baseline each variable value (%) and interaction between baseline each variable value (%) 
and visit as a continuous variable.
9.3.5. Other Safety Analyses
AEs and SAEs (including local tolerability), discontinuations, and changes in vital signs, 
bone maturation, and clinical laboratory parameters will be descriptively summarized, and 
will be presented in tabular and/or graphical format. No imputation will be made for missing 
safety data.
9.3.6. Other Analyse(s) 
Not Applicable.
9.4. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, and/or supporting clinical development.
 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process 

Participants and their legally authorized representative must be informed that their 
participation is voluntary. Participants and their legally authorized representative will 
be required to provide a statement of informed consent/assent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 

The medical record must include a statement that legally authorized representative 
(parent/guardian) consent and child/adolescent assent (if deemed appropriate by local 
ethics review) was obtained before the participant was enrolled in the study and the 
date the written consent/assent was obtained. The medical record should also describe 
how the clinical investigator determined that the person signing the ICD was the 
participant’s legally authorized representative (parent/guardian). The authorized 
person obtaining the informed consent must also sign the ICD.

Participants and their legally authorized representative (parent/guardian) must be 
re-consented and re-assented to the most current version of the ICD(s) during their 
participation in the study. 

Minor participants must be re-consented if they reach the age of majority during the 
course of the study, in order to continue participating.

A copy of the ICD(s) must be provided to the participant or the participant’s 
parent/guardian.

As appropriate, children may be given the opportunity to meet privately with a 
member of the site staff to ask confidential questions and to decline assent for 
confidential reasons, which, at their request, would not be shared with their 
parent/guardian, unless required by local law.
Participants who are rescreened are required to sign a new ICD.
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10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use a DMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
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EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory retain  
notification in relation to the study. Furthermore, the investigator will cooperate with the 
sponsor or its agents to prepare the investigator site for the inspection and will allow the 
sponsor or its agent, whenever feasible, to be present during the inspection. The investigator 
site and investigator will promptly resolve any discrepancies that are identified between the 
study data and the participant's medical records. The investigator will promptly provide 
copies of the inspection findings to the sponsor or its agent. Before response submission to 
the regulatory authorities, the investigator will provide the sponsor or its agents with an 
opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
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Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the clinical 
monitoring plan, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator; 

Discontinuation of further study intervention development.
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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications, 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
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the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site.
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 1.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Endocrinology
WBC count
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
General condition
Total protein
Albumin
Lipid
Total cholesterol
Triglyceride
HDL cholesterol
LDL cholesterol
Liver function
AST
ALT
Alkaline phosphatase
Total bilirubin
Renal function
BUN
Creatinine
Electrolyte
Calcium
Sodium
Potassium
Chloride
Glucose metabolism
HbA1c
Casual blood glucoseb
Pregnancy test 
β-hCGa
Growth hormone
IGF-1
Adrenal glands function
Cortisol
Thyroid function
TSH
FT4
Gonadal function
LH
FSH
E2
Testosterone
a.
Both local serum and urine testing will be acceptable. A urine pregnancy test should have 
sensitivity of at least 25 mIU/mL. A serum hCG testing can be selected as an alternative to a 
serum -hCG when clinically appropriate at the discretion of the investigator.
b.
For participants with preexisting diabetes.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a 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 pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during pregnancy 
or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, 
All AEs or SAEs associated 
with exposure during 
pregnancy or breastfeeding
Note:  Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF.
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated SAE). 
**
Environmental or 
occupational exposure to 
the product under study to 
a non-participant (not 
involving EDP or EDB).
None.  Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using CT SAE Report Form and EDP Supplemental Form; if the EDP is associated with an SAE, 
then the SAE is reported to Pfizer Safety using the CT SAE Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form which would also include details 
of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 
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
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.  

Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self 
care ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.  
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
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Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below 
during the intervention period (for a minimum of 28 days after the last dose of 
study intervention). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
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Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. Items 
marked with an asterisk (*) denote contraceptives that are not approved for use in Japan.
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.*
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion (eg, bilateral tubal ligation).
5. Vasectomized partner:

A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and 
the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. The spermatogenesis cycle is 
approximately 90 days.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;
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
Intravaginal*;

Transdermal*;

Injectable*.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral*;

Injectable*.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.*
10. Male or female* condom with or without spermicide*.
11. Cervical cap*, diaphragm*, or sponge with spermicide*.
12. A combination of male condom with either cervical cap*, diaphragm*, or sponge 
with spermicide* (double-barrier methods).
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10.5. Appendix 5: Genetics
Not applicable.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated 
within the same laboratory sample). In rare instances, by the time TBili elevations are 
detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
Not applicable.
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10.8. Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs, and Device Deficiencies: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting in 
Medical Device Studies 
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this appendix are in accordance with ISO 14155
and the European MDR 2017/745 for clinical device research (if applicable).
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2 for the list of sponsor 
medical devices).
10.8.1. Definition of AE and ADE
AE and ADE Definition

An AE is defined in Appendix 3 (Section 10.3.1).

An ADE is defined as an AE related to the use of an investigational medical device. 
This definition includes any AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device as well as any event resulting 
from use error or from intentional misuse of the investigational medical device.
10.8.2. Definition of SAE, SADE, and USADE
SAE Definition

An SAE is defined in Appendix 3 (Section 10.3.2).
SADE Definition

An SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of an SAE.

Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.
USADE Definition
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
A USADE is a serious adverse device effect that by its nature, incidence, severity, 
or outcome has not been identified in the current version of the risk analysis 
management file.
10.8.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequate information supplied by the 
manufacturer.
10.8.4. Recording/Reporting and Follow-Up of Medical Device Deficiencies
Device Deficiency Recording

When a device deficiency occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.

The investigator will then record all relevant device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice and will also capture the required information on the Medical Device 
Complaint form.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of following the reporting process described 
in the Medical Device Complaint form.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

If the investigator determines that the medical device deficiency may have injured 
the participant (ie, the medical device deficiency is associated with an AE or SAE), 
then the investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis will be documented in the participant’s medical record and recorded as 
the AE or SAE rather than the individual signs/symptoms. Requirements for 
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recording and reporting an AE or SAE are provided in Appendix 3 (Section 
10.3.3).

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence.
Assessment of Causality Occuring in Conjunction With a Medical Device Deficiency

If an AE or SAE has occurred in conjunction with a medical device deficiency, the 
investigator must assess the relationship between each occurrence of the AE or 
SAE and the medical device deficiency. The investigator will use clinical judgment 
to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the product information in his/her assessment.

For each device deficiency, the investigator must document in the medical notes 
that he/she has reviewed the device deficiency and has provided an assessment of 
causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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Follow-Up of Medical Device Deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint form.

New or updated information regarding any SAE that was potentially associated 
with the medical device deficiency will be submitted to Pfizer Safety on the CT
SAE Report Form within 24 hours of receipt of the information, according to the 
requirements provided in Appendix 3.
10.8.5. Reporting of SAEs
Reporting of an SAE to Pfizer Safety must be performed according to the processes 
described in Appendix 3 (Section 10.3.4).
10.8.6. Reporting of SADEs
SADE Reporting to Pfizer Safety
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs (ie, a SADE) that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.

The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.
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10.9. Appendix 9: Country-Specific Requirements
10.9.1. Japan 
10.9.1.1. Definitions of Serious Adverse Event, Serious Adverse Event Caused by 
Medical Device, and Unanticipated Serious Adverse Event Caused by Medical Device
Definition of Serious Adverse Event Caused by Medical Device
A serious adverse event caused by medical device is defined as an adverse event caused by a 
medical device which led to an outcome characteristic to serious adverse events, or a device-
related incident whose recurrence might lead to death or serious deterioration in health.
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10.10. Appendix 10: Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally or specific location(s) and will become effective for other 
public emergencies only upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories).
10.10.1. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the Schedule of 
Activities or unscheduled visits. Telehealth visits may be used to continue to assess 
participant safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (eg, audio, video, video-
conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit:

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing (if 
available). Confirm that the participant is adhering to the contraception method(s) 
required in the protocol. Refer to Appendix 4 and Section 10.10.2.1 of this appendix 
regarding pregnancy tests.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.10.2. Alternative Facilities for Safety Assessments
10.10.2.1. Laboratory Testing
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital. The 
following safety laboratory evaluations may be performed at a local laboratory:  

All protocol required lab draws as defined in Section 10.2.

Hematology panel.
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
Chemistry panel.

Endocrinology panel, including pregnancy testing (for WOCBP).
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF.
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
10.10.3. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
Somatropin may be shipped by courier to study participants if permitted by local regulations 
and in accordance with storage and transportation requirements for the study intervention.
Pfizer does not permit the shipment of somatropin by mail. The tracking record of shipments 
and the chain of custody of somatropin must be kept in the participant’s source 
documents/medical records.
10.10.4. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the participant’s location, rather than an in-person study visit at the site. The 
following may be performed during a home health visit:

All protocol required lab draws as defined in Section 10.2.

Hematology panel.

Chemistry panel.

Endocrinology panel, including pregnancy testing (for WOCBP).

Vital signs.
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
Weight.
10.10.5. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an AE or SAE and 
appropriate medical intervention provided. Study treatment should continue unless the 
investigator/treating physician is concerned about the safety of the participant, in which case 
temporary or permanent discontinuation may be required.  
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor.  
10.10.6. Efficacy Assessments
Efficacy assessments listed in Section 8.1 are only to be collected during on-site visits.
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10.11. Appendix 11: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ADE
adverse device effect
ADL
activities of daily living
AE
adverse event
AGHD
adult growth hormone deficiency 
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-hCG
beta-human chorionic gonadotropin
BIA
bioelectrical impedance analysis
BMI
body mass index
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CT SAE
clinical trial serious adverse event (report form)
DEXA
dual energy X-ray absorptiometry
DILI
drug-induced liver injury
DMC
data monitoring committee
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
EMA
European Medicines Agency
EOS
end of study
EU
European Union
EudraCT
European Clinical Trials Database
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HbA1c
hemoglobin A1c
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Abbreviation
Term
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
IEC
independent ethics committee
IGF-1
insulin-like growth factor 1
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRT
interactive response technology
ISO
International Organization for Standardization
LDL
low-density lipoprotein
LFT
liver function test
LH
luteinizing hormone
LS
least squares
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
medical device regulation
MHLW
Ministry of Health, Labour and Welfare
MMRM
mixed-effects models for repeated measures
N/A
not applicable
NIMP
noninvestigational medicinal product
PMDA
Pharmaceuticals and Medical Devices Agency
PT
prothrombin time
PWS
Prader-Willi syndrome
RBC
red blood cell
r-hGH
recombinant human growth hormone
SADE
serious adverse device effect
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SDS
standard deviation score
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
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Protocol Amendment 1, 13 December 2021
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Page 81
Abbreviation
Term
TBili
total bilirubin
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
WBC
white blood cell
WOCBP
woman of childbearing potential
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Protocol Amendment 1, 13 December 2021
PFIZER CONFIDENTIAL
Page 82
11. REFERENCES
1 Deal CL, et al. Growth Hormone Research Society Workshop Summary: Consensus 
Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome. J 
Clin Endocrinol Metab 2013;98(6):E1072-87.
2 Genotropin USPI.
3 Höybye C, et al. Growth hormone treatment improves body composition in adults with 
Prader-Willi syndrome. Clin Endocrinol (Oxf) 2003;58(5):653-61.
4 Mogul HR, et al. Growth hormone treatment of adults with Prader-Willi syndrome and 
growth hormone deficiency improves lean body mass, fractional body fat, and serum 
triiodothyronine without glucose impairment: results from the United States multicenter 
trial. J Clin Endocrinol Metab 2008;93(4):1238-45.
5 Sode-Carlsen R, et al. One year of growth hormone treatment in adults with Prader-Willi 
syndrome improves body composition: results from a randomized, placebo-controlled 
study. J Clin Endocrinol Metab 2010;95(11):4943-50.
6 Sode-Carlsen R, et al. Growth hormone treatment for two years is safe and effective in 
adults with Prader-Willi syndrome. Growth Horm IGF Res 2011;21(4):185-90.
7 Kuppens RJ, et al. Beneficial Effects of GH in Young Adults With Prader-Willi Syndrome: 
A 2-Year Crossover Trial. J Clin Endocrinol Metab 2016;101(11):4110-6.
8 Sanchez-Ortiga R, et al. Effects of recombinant human growth hormone therapy in adults 
with Prader-Willi syndrome: a meta-analysis. Clin Endocrinol (Oxf) 2012;77(1):86-93.
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