Conditions: Healthy
Keywords: Ponsegromab Healthy Volunteers
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: yes

Brief summary:
The purpose of this clinical trial is to learn about the safety of the study medicine (ponsegromab) and how it undergoes change and elimination in healthy Chinese adults. This study is seeking male and female Chinese participants who are very healthy as confirmed after some medical tests.

All participants in this study will receive Ponsegromab only once:

* for half of the participants, ponsegromab will be given as a shot in the front of the thigh, abdomen, or outer area of the upper arm at the study clinic.
* for another half of the participants, ponsegromab will be given as four shots in the front of the thigh, abdomen, or outer area of the upper arm at the study clinic.

We will measure the amount of the study medicine in the blood of the participants after giving the shots. Later we will examine experiences of people receiving the study medicine. This will help us understand how the medicine is changed and eliminated from your body and to decide if the study medicine is safe. Participants will take part in this study for 22 weeks. During this time, they will stay at the study clinic for the first 8 days and will visit the study clinic about 8 times.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Ponsegromab intervention 2: Ponsegromab
Intervention descriptions: intervention 1: Participants will receive one subcutaneous injection intervention 2: Participants will receive four subcutaneous injections

Protocol document:
Prot_000.pdf: 
Ponsegromab (PF-06946860) 
Protocol C3651012 
Final Protocol, 22 April 2022 
Page 1 
 
 
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. 
 
 
 
 
 
A PHASE 1, OPEN-LABEL, SINGLE DOSE STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY, AND 
TOLERABILITY OF PONSEGROMAB ADMINISTERED SUBCUTANEOUSLY IN 
HEALTHY ADULT CHINESE PARTICIPANTS 
 
 
 
Study Intervention Number: 
Study Intervention Name: 
US IND Number: 
PF-06946860 
Ponsegromab 
N/A 
EudraCT Number: 
N/A 
ClinicalTrials.gov ID: 
N/A 
Protocol Number: 
C3651012 
Phase: 
1 
Brief Title: A Phase 1 PK, PD, Safety, and Tolerability Study With Ponsegromab 
Single-Dose Subcutaneously Administered in Healthy Adult Chinese Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Ponsegromab (PF-06946860) 
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Final Protocol, 22 April 2022 
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Document History 
 
Document 
Version Date 
Original protocol 
22 April 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFIZER CONFIDENTIAL 


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Protocol C3651012 
Final Protocol, 22 April 2022 
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CCI 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 7 
1. PROTOCOL SUMMARY ..................................................................................................... 8 
1.1. Synopsis ..................................................................................................................... 8 
1.2. Schema..................................................................................................................... 10 
1.3. Schedule of Activities .............................................................................................. 11 
2. INTRODUCTION ................................................................................................................ 13 
2.1. Study Rationale ........................................................................................................ 13 
2.2. Background .............................................................................................................. 13 
 
 
 
 
 
 
 
 
 
 
2.3.2. Benefit Assessment .................................................................................... 17 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 17 
3. OBJECTIVES AND ENDPOINTS ..................................................................................... 18 
4. STUDY DESIGN ................................................................................................................. 18 
4.1. Overall Design ......................................................................................................... 18 
4.2. Scientific Rationale for Study Design ..................................................................... 19 
4.3. Justification for Dose ............................................................................................... 20 
4.4. End of Study Definition ........................................................................................... 20 
5. STUDY POPULATION ...................................................................................................... 20 
5.1. Inclusion Criteria ..................................................................................................... 21 
5.2. Exclusion Criteria .................................................................................................... 21 
5.3. Lifestyle Considerations .......................................................................................... 23 
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5.3.1. Meals and Dietary Restrictions .................................................................. 23 
5.3.2. Caffeine, Alcohol, and Tobacco ................................................................. 24 
5.3.3. Activity ...................................................................................................... 24 
5.3.4. Contraception ............................................................................................. 24 
5.4. Screen Failures ....................................................................................................... 24 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 25 
6.1. Study Intervention(s) Administered ........................................................................ 25 
6.1.1. Administration ............................................................................................ 25 
6.2. Preparation, Handling, Storage, and Accountability .............................................. 25 
6.2.1. Preparation and Dispensing ........................................................................ 26 
6.3. Measures to Minimize Bias: Randomization and Blinding .................................... 27 
6.3.1. Allocation to Study Intervention ................................................................ 27 
6.4. Study Intervention Compliance .............................................................................. 27 
6.5. Dose Modification .................................................................................................. 27 
6.6. Continued Access to Study Intervention After the End of the Study ..................... 27 
6.7. Treatment of Overdose ........................................................................................... 28 
6.8. Concomitant Therapy ............................................................................................. 28 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 29 
7.1. Discontinuation of Study Intervention .................................................................... 29 
7.1.1. Potential Cases of Acute Kidney Injury ..................................................... 29 
7.2. Participant Discontinuation/Withdrawal From the Study ...................................... 29 
7.2.1. Withdrawal of Consent .............................................................................. 30 
7.3. Lost to Follow up .................................................................................................... 30 
8. STUDY ASSESSMENTS AND PROCEDURES .............................................................. 31 
8.1. Efficacy Assessments ............................................................................................. 32 
8.2. Safety Assessments ................................................................................................. 32 
8.2.1. Physical Examinations ............................................................................... 32 
8.2.2. Injection Site Assessment .......................................................................... 33 
8.2.3. Vital Signs .................................................................................................. 33 
8.2.4. Electrocardiograms ..................................................................................... 33 
8.2.5. Clinical Safety Laboratory Assessments .................................................... 34 
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8.2.6. COVID-19 specific assessments ................................................................. 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 ....... 35 
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 ........................................................... 36 
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 .......... 40 
8.3.9.2. Follow-Up of Medical Device Deficiencies .............................. 40 
8.3.9.3. Prompt Reporting of Device Deficiencies to the Sponsor ......... 40 
8.3.9.4. Regulatory Reporting Requirements for Device 
Deficiencies ........................................................................................ 40 
8.3.10. Medication Errors ...................................................................................... 41 
8.4. Pharmacokinetics ..................................................................................................... 41 
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8.6. Genetics ................................................................................................................... 43 
8.6.1. Specified Genetics ....................................................................................... 43 
8.7. Biomarkers ............................................................................................................... 43 
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8.9. Health Economics .................................................................................................... 44 
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9. STATISTICAL CONSIDERATIONS ................................................................................ 44 
9.1. Statistical Hypotheses ............................................................................................. 44 
9.2. Analysis Sets ........................................................................................................... 44 
9.3. Statistical Analyses ................................................................................................. 45 
9.3.1. Pharmacokinetic Analyses ......................................................................... 45 
9.3.1.1. Derivation of PK Parameters .................................................... 45 
9.3.1.2. Statistical Methods for Pharmacokinetic Data ......................... 46 
9.3.2. Safety Analyses .......................................................................................... 46 
9.3.2.1. Electrocardiogram Analyses ..................................................... 46 
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9.4. Interim Analyses ..................................................................................................... 47 
9.5. Sample Size Determination .................................................................................... 47 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.......................................................................................................... 49 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 49 
10.1.1. Regulatory and Ethical Considerations .................................................... 49 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 49 
10.1.2. Financial Disclosure ................................................................................. 50 
10.1.3. Informed Consent Process ....................................................................... 50 
10.1.4. Data Protection ......................................................................................... 51 
10.1.5. Committees Structure ............................................................................... 51 
10.1.5.1. Data Monitoring Committee ................................................... 51 
10.1.6. Dissemination of Clinical Study Data ...................................................... 51 
10.1.7. Data Quality Assurance ............................................................................ 53 
10.1.8. Source Documents ................................................................................... 54 
10.1.9. Study and Site Start and Closure .............................................................. 54 
10.1.10. Publication Policy .................................................................................. 55 
10.1.11. Sponsor’s Qualified Medical Personnel ................................................. 56 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 57 
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................... 58 
10.3.1. Definition of AE ....................................................................................... 58 
10.3.2. Definition of an SAE ................................................................................ 59 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ........................................................................... 60 
10.3.4. Reporting of SAEs ................................................................................... 64 
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................ 65 
10.4.1. Male Participant Reproductive Inclusion Criteria ................................... 65 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ 65 
10.4.3. Woman of Childbearing Potential ............................................................ 65 
10.4.4. Contraception Methods ............................................................................ 66 
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments ....... 68 
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ................................... 70 
10.7. Appendix 7: Abbreviations ................................................................................... 72 
11. REFERENCES .................................................................................................................. 76 
LIST OF TABLES 
Table 1. 
Serum PK Parameters ............................................................................... 45 
Table 2. 
Protocol-Required Safety Laboratory Assessments .................................. 57 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
A Phase 1, Open-Label, Single Dose Study to Investigate the Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of Ponsegromab Administered Subcutaneously 
in Healthy Adult Chinese Participants 
Brief Title: A Phase 1 PK, PD, Safety and Tolerability Study With Ponsegromab 
Single-Dose Subcutaneously Administered in Healthy Adult Chinese Participants 
Rationale 
The purpose of this study is to evaluate the PK, PD, safety, and tolerability of ponsegromab 
following 100 mg and 400 mg single SC dose in healthy adult Chinese participants. Results 
from this study will be used to inform clinical development of ponsegromab in China, to 
facilitate China’s participation in global pivotal studies, and to support China registration of 
ponsegromab. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To characterize the serum PK of 
ponsegromab following a single SC 
administered dose in healthy adult Chinese 
participants. 
• 
Ponsegromab serum PK parameters 
(unbound and total), as data permit: AUCinf, 
AUClast, Cmax, Tmax, and t½. 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of 
ponsegromab following a single SC 
administered dose in healthy adult Chinese 
participants. 
• 
AEs, clinical safety laboratory tests, vital 
signs (blood pressure, pulse rate), physical 
examinations, and 12-lead ECGs for 
approximately 18 weeks post single dose. 
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Overall Design 
Brief Summary 
This is an open-label, single dose study to characterize the PK, PD, safety, and tolerability of 
ponsegromab following 100 mg or 400 mg single SC dose in healthy adult Chinese 
participants. 
Number of Participants 
Approximately 18 participants will be enrolled in this study (N=9 for each cohort) with the 
goal of attaining approximately 16 participants (N=8 for each cohort) evaluable for the 
primary endpoints. 
Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process and screening. A participant will be considered 
enrolled if the informed consent is not withdrawn prior to participating in any study activity 
after screening. Potential participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
Intervention Groups and Duration 
Participants who meet eligibility criteria at baseline will receive a single SC dose of 
ponsegromab at 100 mg (Cohort 1) or 400 mg (Cohort 2) on Day 1. Participants in the 
100 mg cohort will be dosed firstly, and will be kept under safety monitoring for 8 days at 
the CRU. Progression to 400 mg will occur only if 100 mg is well tolerated after reviewing 
the safety data up to 8 days post-dose as judged by the investigator. Sentinel dosing may be 
implemented in the 400 mg cohort as judged by the investigator: eg, 2 participants may be 
dosed prior to the remaining participants in Cohort 2. If the dose level is determined to have 
an acceptable safety and tolerability profile up to 8 days post-dose, as judged by the 
investigator for the first 2 sentinel participants, the remaining 7 participants in that cohort 
will be dosed. The total duration of each participation in this study is approximately 
22 weeks, including a screening period of up to 4 weeks to confirm eligibility and a 
follow-up period of approximately 18 weeks after the single SC dose. 
Participants who discontinue prior to completion of the study for non-safety related reasons 
may be replaced, at the discretion of the investigator and sponsor study team. 
Data Monitoring Committee or Other Independent Oversight Committee: No 
Statistical Methods 
All data analyses will be descriptive. The serum PK parameters of ponsegromab (unbound 
and total) will be listed and descriptively summarized by cohort. 
For each cohort, 
 
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the serum concentrations of ponsegromab (unbound and total) will be listed and descriptively 
summarized by nominal sampling time and cohort. Within each cohort, individual 
participant and summary profiles (mean and median plots) of the serum concentration-time 
 
Safety data (AEs, ECGs, BP, PR, and safety laboratory data) will be presented in tabular 
and/or graphical format and summarized descriptively by cohort, where appropriate. 
1.2. Schema 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFIZER CONFIDENTIAL 
data will be plotted using actual and nominal sampling times respectively. CCI 


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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 
Inpatient stay at CRU 
Outpatient FU 
ET/DC 
Day relative to Day 1 
For abbreviations, refer to Appendix 7 
Day -28 
to Day -2 
Admit to 
CRUa 
(Day -1) 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
±1 
Day 
15 
±1 
Day 
29 
±1 
Day 
50 
±2 
Day 
71 
±3 
Day 
93 
±7 
Day 
106 
±7 
Day 
127b±7 
Hours After Dose 
(for inpatient portion) 
0 
12 
±1 
24 
±2 
48 
±2 
72 
±4 
120 
±4 
168 
±4 
Informed consent 
X 
Inpatient stay at CRU 
X 
→ 
→ 
→ 
→ 
→ 
→ 
X 
Outpatient visit to CRU 
X 
→ 
→ 
→ 
→ 
→ 
→ 
X 
Assessment of eligibility, 
medical/medication historyc 
X 
X 
Physical exam and weight (plus height 
at Screening, only)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review alcohol/caffeine/tobacco, as 
applicable 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review prior or concomitant 
treatments, as applicable 
X 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
X 
Demography 
X 
Review contraception use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious and non-serious AEs 
monitoring 
X 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
X 
Injection site assessmente 
X 
→ 
X 
Supine 12-lead ECG (triplicate) 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
Single, supine BP and PR (triplicate 
pre-dose Day 1, only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eligibility overview for study 
enrollmentg 
X 
X 
Study intervention administration 
X 
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Screening 
Inpatient stay at CRU 
Outpatient FU 
ET/DC 
Day relative to Day 1 
For abbreviations, refer to Appendix 7 
Day -28 
to Day -2 
Admit to 
CRUa 
(Day -1) 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
±1 
Day 
15 
±1 
Day 
29 
±1 
Day 
50 
±2 
Day 
71 
±3 
Day 
93 
±7 
Day 
106 
±7 
Day 
127b±7 
Hours After Dose 
(for inpatient portion) 
0 
12 
±1 
24 
±2 
48 
±2 
72 
±4 
120 
±4 
168 
±4 
Blood samples: 
serum FSH (females 
amenorrheic ≥12 months, only), 
HIV, HBsAg, HBcAb, HCVAb, 
Syphilis test 
X 
Safety laboratory testsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Blood Sample (s): serum ponsegromab 
(PK) 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug test 
X 
X 
COVID-19 test(s)j 
X 
a. 
Participants will admit to CRU at least 12 hours prior to dosing. Admission procedures to be conducted once, unless deemed necessary by investigator 
or sponsor. 
b. FU to approximately 18 weeks postdose planned; FU visits may be adjusted at investigator/sponsor discretion, including to monitor open AE, or based 
on emerging data (see Section 4.4). 
c. 
Medication history will be updated at each visit. 
d. Full PE at Screening or admission; at all other timepoints, limited PE performed for findings during previous exam or new/open AEs, at investigator 
discretion. PE may be conducted at final FU visit, at investigator discretion. Body weight to be measured at all indicated timepoints. 
e. 
Injection site assessment at predose (-30 min to 0 h), and 1 h (±10 min), 6 h (±0.5 h), 12 h (±1 h) and 24 h (±2 h) postdose. Additional assessments at 
investigator discretion and/or until any symptoms resolve. Additional requirements see Section 8.2.2. 
f. 
Baseline ECGs should be triplicate collections at 60 min (±5 min) predose, 30 min (±5 min) predose, and 15 min (±5 min) predose (nine measurements 
in total).Additional requirements on ECGs see Section 8.2.4. 
g. Eligibility overview for study enrollment could be performed after all procedures are completed on Day -1, or before all procedures on Day 1, according 
to site operating practices. 
h. See Appendix 2 for safety laboratory tests in the study. 
i. 
Predose sample collection may be conducted between CRU admission and dose administration on Day 1. 
j. 
The timing and methods of COVID-19 test(s) should follow the requirements from local regulations or the investigator (CRU). 
 
 
 
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2. INTRODUCTION 
Cachexia is a metabolic disorder and comorbidity that occurs with several chronic diseases 
including cancer, heart failure, COPD, and CKD. Cachexia manifests as marked involuntary 
body weight loss, muscle atrophy, and reduced appetite, progressing to significant functional 
impairment and increased risk of death. 
GDF-15 is a stress responsive cytokine secreted by tumor cells, macrophages and damaged 
cells.1-5 In several chronic conditions such as cancer, COPD, and CKD, circulating GDF-15 
concentrations are markedly elevated compared to healthy individuals.6-9 Elevated GDF-15 is 
associated with weight loss/cachexia in cancer10-13 and also heart failure14,15 patients. In 
addition, elevated circulating GDF-15 levels are associated with poor survival in many 
cancers, heart failure, CKD and COPD.16-22 In rodents and non-human primates, GDF-15 
induces anorexia and weight loss23-27 by acting through the GFRAL. Furthermore, increased 
GDF-15 levels are associated with cachexia in mouse tumor models, and neutralization of 
GDF-15 reverses weight loss and improves survival.12 
Ponsegromab is a humanized mAb which binds to the GDF-15 protein and prevents its 
interaction with GFRAL and is currently being developed for the treatment of cachexia in 
cancer patients. Its potential to mitigate muscle mass loss, improve anorexia, and reduce 
fatigue in patients with cancer cachexia is being investigated. In addition to cancer cachexia, 
it has the potential to improve the symptoms and function of patients with heart failure who 
have elevated levels of GDF-15. 
2.1. Study Rationale 
This study is the first clinical study with ponsegromab in the Chinese population. The 
purpose of this study is to evaluate the PK, PD, safety, and tolerability of ponsegromab 
following 100 mg and 400 mg single subcutaneous dose in healthy adult Chinese 
participants. Ponsegromab exhibits target mediated disposition, in addition to non-specific 
catabolism, which is considered to be less susceptible to ethnic factors. Results from this 
study will be used to preliminarily support the ethnic sensitivity assessment between Chinese 
and Westerners, to inform clinical development of ponsegromab in China, to facilitate 
China’s participation in global pivotal studies, and to support China registration of 
ponsegromab. 
2.2. Background 
A summary of relevant, currently available data is provided in this protocol. Additional 
details and further information for this compound may be found in the IB. 
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2.3.2. Benefit Assessment 
Ponsegromab is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate safety, tolerability, PK, and PD data for further 
clinical development. 
2.3.3. Overall Benefit/Risk Conclusion 
Taking into account all available nonclinical and clinical data regarding the reassuring safety 
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and tolerability of ponsegromab to date, and measures to monitor and minimize risk to study 
participants, the overall benefit/risk profile supports further clinical development of 
ponsegromab in healthy adult Chinese participants. 
3. OBJECTIVES AND ENDPOINTS 
 
 
Primary: 
Objectives 
 
 
Primary: 
Endpoints 
• 
To characterize the serum PK of ponsegromab 
following a single SC administered dose in healthy 
adult Chinese participants. 
Secondary: 
• 
To evaluate the safety and tolerability of 
ponsegromab following a single SC administered 
dose in healthy adult Chinese participants. 
• 
Ponsegromab serum PK parameters (unbound and 
total), as data permit: AUCinf, AUClast, Cmax, Tmax, and 
t½. 
Secondary: 
• 
AEs, clinical safety laboratory tests, vital signs (blood 
pressure, pulse rate), physical examinations, and 
12-lead ECGs for approximately 18 weeks post single 
dose. 
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN 
4.1. Overall Design 
This study is an open-label, single dose study to characterize the PK, PD, safety, and 
tolerability of ponsegromab. 
The study will enroll 2 cohorts of approximately 18 healthy adult Chinese participants (N=9 
for each cohort). Participants will receive ponsegromab 100 mg (Cohort 1) or ponsegromab 
400 mg (Cohort 2) on Day 1. 
The total duration of each participation in this study is approximately 22 weeks, including a 
screening period of up to 4 weeks to confirm eligibility, and a follow-up period of 
approximately 18 weeks after the single SC dose. Participants will be admitted to the CRU at 
least 12 hours prior to their planned dose administration time, and will be required to remain 
in the CRU until completion of procedures on Day 8 as described in the SoA. Admission 
procedures are to be conducted once, unless deemed necessary by investigator or sponsor. 
Inpatient stay at CRU can be prolonged for safety monitoring purpose, at the discretion of the 
investigator and sponsor. 
Each participant will receive 1 single SC dose of ponsegromab 100 mg or ponsegromab 
400 mg on Day 1. Participants in 100 mg cohort will be dosed firstly, and will be kept under 
safety monitoring for 8 days at the CRU. Progression to 400 mg will occur if 100 mg is well 
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Studies in healthy
tolerated after reviewing the safety data up to 8 days post-dose. Sentinel dosing may be 
implemented in the 400 mg cohort as judged by the investigator: eg, 2 participants may be 
dosed prior to the remaining participants in Cohort 2. If the dose level is determined to have 
an acceptable safety and tolerability profile up to 8 days post-dose, as judged by the 
investigator for the first 2 sentinel participants, the remaining 7 participants in that cohort 
will be dosed. 
Participants will return for outpatient visits per the SoA. Participants who experience AE 
will continue to be followed to resolution or stabilization of the event as agreed upon by the 
investigator and sponsor. 
Participants who discontinue prior to completion of the study may be replaced, at the 
discretion of the investigator and sponsor. 
4.2. Scientific Rationale for Study Design 
This study is the first clinical study with ponsegromab in the Chinese population. The study 
is designed as open-label, with PK in healthy adult Chinese participants as the primary 
objective. The safety and tolerability, 
will be investigated as secondary 
The intended route of administration of ponsegromab to patients is SC; the same route will 
be tested in this study. 
As is typical for early development studies, and to allow better comparisons in PK, PD, 
safety, and tolerability of ponsegromab between Chinese and non-Chinese, the population 
envisioned for this China Phase 1 study will be similar to that in studies C3651001 and 
C3651002, ie, healthy male and female participants. Female participants will be confirmed 
to be categorized as women of non-childbearing potential as, at the present time, 
embryo-fetal developmental toxicology studies with ponsegromab have not been conducted. 
In male participants, appropriate measures to minimize potential transfer of ponsegromab via 
semen to partners are expected to be followed (see Appendix 4). 
Risks to study participants will be minimized by dose administration in an inpatient setting, 
with careful assessment and on-going review of safety data. After single-dose SC 
administration, there will be a follow-up period of approximately 18 weeks. This duration 
has been chosen based on the PK half-life of ponsegromab observed in the completed clinical 
trials CCI 
 Clinical 
safety laboratory tests (see Section 8.2.5), thorough assessments of vital signs, ECGs, 
physical examinations, and AE monitoring will provide essential data to evaluate the safety 
and tolerability of ponsegromab. 
 
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populations including global Phase 1 study (C3651001), Japan Phase 1 study (C3651002), 
and the current China Phase 1 study (C3651012) are all designed as single dose. Serial PK 
samples will be collected following single dosing to generate PK parameters which allows 
comparison among different ethnic populations. 
 
 
4.3. Justification for Dose 
Participants enrolled will receive a single 100 mg or 400 mg SC dose of ponsegromab on 
 
Specifically, the 400 mg is expected to cover the potential highest clinical dose in subsequent 
 
direct comparison of ponsegromab exposure cross three different populations (Chinese, 
Westerners, and Japanese). 
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 he/she has completed all periods of 
the study, including the procedures at their last follow-up visit. Follow-up visits in addition 
to those in the SoA may be scheduled at investigator discretion, including to monitor open 
AE, or based on emerging data. 
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 
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Phase 2 and Phase 3 studies. CCI 
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taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex: 
1. Participants must be 18 to 55 years of age, inclusive, at the time of signing the ICD. 
• Female participants must be of non childbearing potential (see Section 10.4.3). 
• Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Type of Participant and Disease Characteristics: 
2. Male and female Chinese participants who are overtly healthy as determined by 
medical evaluation including medical history, physical examination, BP and PR 
measurement, 12-lead ECG, and laboratory tests. Chinese participants are defined as 
individuals currently residing in mainland China who were born in China and have 
both parents of Chinese descent. 
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
Weight: 
4. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
Informed Consent: 
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
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allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
2. History of HIV infection, syphilis, hepatitis B, or hepatitis C; positive testing for 
HIV, syphilis, HBsAg, or HCVAb. Hepatitis B vaccination is allowed. 
3. History of allergic or anaphylactic reaction to any therapeutic or diagnostic 
monoclonal antibody or molecules made of components of monoclonal antibodies. 
4. History of recurrent infections or active infection within 28 days of screening. 
5. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
6. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg, contact with positive case, residence, 
or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
Prior/Concomitant Therapy: 
7. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.8 Concomitant Therapy for additional details). 
8. Exposure to live vaccines within 28 days of screening. 
Prior/Concurrent Clinical Study Experience: 
9. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or marketed or investigational monoclonal antibodies within 
3 months or 5 half-lives preceding the first dose of study intervention used in this 
study (whichever is longer). 
Diagnostic Assessments: 
10. A positive urine drug test. 
11. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility. 
12. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, baseline QTcF interval 
>450 msec, or QRS interval >120 msec). If the baseline uncorrected QT interval is 
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>450 msec, this interval should be rate-corrected using the Fridericia method and the 
resulting QTcF should be used for decision making and reporting. If QTcF exceeds 
450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and 
the average of the 3 QTcF or QRS values should be used to determine the 
participant’s eligibility. Computer-interpreted ECGs should be overread by a 
physician experienced in reading ECGs before excluding a participant. 
13. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
• AST or ALT level ≥1.5 × ULN; 
• Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ ULN. 
14. COVID-19 positive. 
Other Exclusions: 
15. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 240 mL beer, 30 mL of 
40% spirit or 90 mL of wine). 
16. Blood donation (excluding plasma donations) of approximately 400 mL or more 
within 60 days prior to dosing. 
17. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
18. 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 
The following guidelines are provided: 
5.3.1. Meals and Dietary Restrictions 
• Participants must abstain from all food and drink (no water restriction) at least 
4 hours prior to any safety laboratory evaluations. 
• An evening snack may be permitted. 
 
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• While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal. 
5.3.2. Caffeine, Alcohol, and Tobacco 
• Participants must abstain from alcohol for 24 hours prior to screening, at least 
24 hours prior to admission to the CRU, and 24 hours prior to all outpatient visits. 
Participants are suggested to abstain from alcohol until completion of the final FU 
visit. Participants may undergo an alcohol breath test or blood alcohol test at the 
discretion of the investigator. 
• Participants will abstain from caffeine-containing products for 24 hours prior to all 
outpatient visits (including screening and FU visits), at least 24 hours prior to 
admission and during confinement in the CRU. 
• Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU. 
5.3.3. Activity 
• Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted. 
5.3.4. Contraception 
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 and his or her partner(s) 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 schedule of activities (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 
did not pass the “Eligibility overview for study enrollment” (as shown in the SoA). Screen 
failure data are collected and remain as source and are not reported on the CRF. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
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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. 
For the purposes of this protocol, study intervention refers to ponsegromab. 
6.1. Study Intervention(s) Administered 
Ponsegromab will be provided by Pfizer as liquids in sterile single-use, open-labeled vials at 
the CRU. 
Participants will receive study intervention administered as a subcutaneous injection. All 
dose administration will occur at the study site. 
Ponsegromab will be supplied as individual, single-use vials which are labeled according to 
local regulatory requirements. 
Ponsegromab 100 mg/mL Solution for Injection will be presented as a sterile solution for SC 
administration. Each vial will contain a nominal volume of 1 mL with 100 mg/mL of 
ponsegromab. 
6.1.1. Administration 
Participants will receive study intervention at approximately 0800 hours (±2 hours). The 
administration of SC study intervention must be performed by qualified and trained 
investigator site personnel according to the IP manual. The number of injections and 
injection sites will be recorded. The SC injection(s) area can be the front of the middle thigh, 
anterolateral thigh, abdomen, or outer area of the upper arm. If an arm is used for the SC 
injection, the opposite arm should be used for blood sample collections and BP 
measurements. Multiple injections at the same nominal time should use a unique site for 
each injection, to limit each injection site volume to 1 mL. 
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 
 
 
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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. See the IP manual for storage conditions of the study intervention. 
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. 
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 
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities. 
Ponsegromab will be handled and prepared according to the IP manual that will be provided 
to the site. 
 
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See the IP manual for instructions on how to prepare the study intervention for SC 
administration. Study intervention should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by 
local, and institutional guidance. A second staff member will verify the dispensing. 
All vials will be presented as single-use vials. 
6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Allocation to Study Intervention 
This is an open-label study including 2 independent dose cohorts. Randomization and 
blinding are not applicable. 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. 
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide an allocation schedule to the investigator. The participant will 
receive the study intervention in compliance with the SoA and the protocol instruction. 
6.4. Study Intervention Compliance 
Participants will be dosed at the site. They will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the CRU will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. 
The site will complete the required dosage Preparation Record located in the IP manual. The 
use of the Preparation Record is preferred, but it does not preclude the use of an existing 
appropriate clinical site documentation system. The existing clinical site’s documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose. This may be used in place of the Preparation Record after 
approval from the sponsor and/or designee. 
6.5. Dose Modification 
By design, this study only includes administration of single, SC dose of ponsegromab at 
2 fixed dosage levels (100 mg and 400 mg). As such, dose modifications will not be made 
during the study. 
6.6. Continued Access to Study Intervention After the End of the Study 
No intervention will be provided to study participants at the end of their study participation. 
 
 
 
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CCI 
6.7. Treatment of Overdose 
 
The definition of overdose for this trial is based on the operational aspects of the protocol 
design. Given the nature of this study (ie, SC dose administered in the clinic), and the 
allowed visit window, an overdose will be defined as more than 4 doses of ponsegromab SC 
administered. 
Sponsor 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 and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of ponsegromab (whichever is 
longer). 
3. Document the quantity of the excess dose as well as the time of the overdose in the 
CRF. 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 
5. Obtain a blood sample for PK, CCI 
 analysis approximately 
5-7 days from the date of the last dose of study intervention if requested by the study 
medical monitor (determined on a case-by-case basis). 
6.8. Concomitant Therapy 
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. 
Use of marketed or investigational monoclonal antibodies are prohibited within 3 months or 
5 half-lives (whichever is longer) prior to the first dose of study medication. 
Participants will abstain from all concomitant treatments, except for the treatment of AEs. 
Limited use of nonprescription medications that are not believed to affect participant safety 
or the overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor. 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit. 
 
 
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Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
Since this is a single-dose study, this section is not applicable. 
7.1.1. Potential Cases of Acute Kidney Injury 
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness. 
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr 
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury. 
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants in a given period/treatment arm are noted to have 
2 consecutive SCr results of ≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the 
finding may be considered an adverse drug reaction should be undertaken. 
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 study procedures; 
• Lost to follow-up; 
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• 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. 
The early discontinuation visit applies only to participants who are enrolled and then are 
prematurely withdrawn from the study. Participants should be questioned regarding their 
reason for withdrawal. 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 
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. 
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. 
 
 
 
 
 
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The following actions must be taken if a participant fails to return to the CRU 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. 
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. 
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria. 
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 
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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. 
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(PR and BP) should be collected prior to the insertion of the catheter. 
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 
300 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days. 
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol. 
8.1. Efficacy Assessments 
Not applicable. 
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 Examinations 
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms. 
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
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Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.3.1 to 8.3.3. 
8.2.2. Injection Site Assessment 
Injection site reactions will be assessed according to the SoA. Additional assessments may 
be conducted at investigator discretion and/or until any symptoms resolve. Injection site 
reactions may include but are not limited to: erythema, induration, ecchymosis, pain, and 
pruritus. The size and severity of injection site reactions will be assessed and documented. 
If deemed appropriate by the investigator, a consultation with a dermatologist may be 
performed. Documentation of a reaction may include items such as investigator notes, 
photographs, dermatologist report, and/or clinic notes. 
8.2.3. Vital Signs 
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. 
When triplicate BP and PR are required (on Day 1), they will be obtained approximately 2 to 
4 minutes apart; the average of the triplicate BP and PR measurements collected prior to 
dosing on Day 1 will serve as each participant’s baseline value. 
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times of BP and pulse rate will be permitted, as necessary, to ensure 
appropriate collection of safety data. 
8.2.4. Electrocardiograms 
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTcF intervals and QRS 
complex. The timing of the PK samples should drive the timing of the ECGs. Note that 
ECGs do not need to be recorded at every time a PK sample is collected, but whenever an 
ECG is recorded, a PK sample should be collected at approximately the same time 
(preferably immediately after). Alternative lead placement methodology using torso leads 
(eg, Mason-Likar) should not be used given the potential risk of discrepancies with ECGs 
 
 
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acquired using standard limb lead placement. All scheduled ECGs should be performed after 
the participant has rested quietly for at least 5 minutes in a supine position. 
Triplicate standard 12-lead ECGs will be obtained approximately within 5 minutes. The 
average of the triplicate ECG measurements collected prior to dosing on Day 1 will serve as 
each participant’s baseline value. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) the 
mean value from the triplicate measurements for any postdose QTcF interval is increased by 
≥60 ms from the baseline and is >450 ms; or b) an absolute QT value is ≥500 ms for any 
scheduled ECG. If either of these conditions occurs, then a single ECG measurement must 
be repeated at least hourly until QTcF values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement. 
If a) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or b) 
an absolute QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator); or c) QTcF intervals get progressively longer, 
the participant should undergo continuous ECG monitoring. A cardiologist should be 
consulted if QTcF intervals do not return to less than the criteria listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range. 
ECG values of potential clinical concern are listed in Appendix 6. 
8.2.5. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within the time frame before the final planned follow-up visit 
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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 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury. 
Participants may undergo random urine drug testing at the discretion of the investigator. 
Urine drug testing conducted prior to dosing must be negative for participants to receive 
study intervention. 
8.2.6. COVID-19 specific assessments 
Participants will be tested for SARS-COVID-19 infection prior to being admitted to the 
clinic for confinement or site visit in compliance with the requirements from local 
regulations or the investigator. Additional testing for COVID-19 (e.g. chest radiograph) may 
be required by local regulations or by the investigator. 
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. 
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 (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant 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 
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minimum of the time of the final planned follow-up visit after the 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 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. 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 
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. 
 
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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 or 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 toward 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 
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. 
 
 
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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 male participant who has been exposed to 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 inhalation or skin contact. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by 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 the time of 
the last follow-up visit. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
 
 
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preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
• Spontaneous abortion including miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
8.3.5.2. Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact. 
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file. 
 
 
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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 
This section is not applicable because efficacy is not expected in the study population. 
8.3.9. Medical Device Deficiencies 
Not applicable. 
8.3.9.1. Time Period for Detecting Medical Device Deficiencies 
Not applicable. 
8.3.9.2. Follow-Up of Medical Device Deficiencies 
Not applicable. 
8.3.9.3. Prompt Reporting of Device Deficiencies to the Sponsor 
Not applicable. 
8.3.9.4. Regulatory Reporting Requirements for Device Deficiencies 
Not applicable. 
 
 
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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. 
8.4. Pharmacokinetics 
Blood samples of approximately 4 mL, to provide approximately 1.5 mL serum, will be 
collected for measurement of serum concentrations of ponsegromab, as specified in the SoA. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples within the protocol-allowed visit window, as defined in the SoA, will not be 
 
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captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF. 
Samples will be used to evaluate the PK of serum unbound and total ponsegromab at all 
times specified in the SoA and will be reported in the CSR, as data permit (see 
Section 9.3.1). Samples collected for analyses of ponsegromab serum concentration may 
also be used to evaluate safety or efficacy aspects related to concerns arising during or after 
the study, or for evaluation of the bioanalytical method. 
Genetic analyses will not be performed on these serum samples. Participant confidentiality 
will be maintained. 
Samples collected for measurement of serum unbound and total concentrations of 
ponsegromab will be analyzed using validated analytical methods in compliance with 
applicable SOPs. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
CCI 
 
 
 
 
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8.6. Genetics 
8.6.1. Specified Genetics 
Genetics (specified analyses) are not evaluated in this study. 
8.7. Biomarkers 
Biomarkers are not evaluated in this study. 
CCI 
 
 
 
 
 
 
 
 
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8.9. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
9.1. Statistical Hypotheses 
There are no statistical hypotheses for this study. 
9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Enrolled 
“Enrolled” means a participant’s agreement to participate in a 
clinical study following completion of the informed consent 
process and screening. Potential participants who are screened 
for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Safety Analysis Set 
All enrolled participants who receive a dose of ponsegromab. 
Participants will be analyzed according to the product they 
actually received. 
PK Concentration 
Analysis Set 
All enrolled participants who receive a dose of ponsegromab 
and in whom at least 1 serum concentration value is reported. 
PK Parameter Analysis 
Set 
All enrolled participants who receive a dose of ponsegromab 
and who have at least 1 of the serum PK parameters of interest 
calculated. 
 
 
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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. Pharmacokinetic Analyses 
9.3.1.1. Derivation of PK Parameters 
Ponsegromab serum PK parameters (total and unbound) will be derived from the 
concentration-time profiles using noncompartmental methods as detailed in Table 1. Actual 
PK sampling times will be used in the derivation of PK parameters. In the case that actual PK 
sampling times are not available, nominal PK sampling times will be used in the derivation 
of PK parameters. 
 
Table 1. 
Serum PK Parameters 
 
Parameter 
Definition 
Method of Determination 
CCI 
Cmax(dn) 
Dose-normalized Cmax 
Cmax/Dose 
Tmax 
Time for Cmax 
Observed directly from data as time of 
first occurrence 
t½a 
Terminal half-life 
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a linear 
regression of the log-linear 
concentration-time curve 
AUClast 
Area under the serum concentration-time 
profile from time zero to the time of the 
last quantifiable concentration (Clast) 
Linear/Log trapezoidal method 
CCI 
 
AUCinfa 
Area under the serum concentration-time 
profile from time zero extrapolated to 
infinite time 
AUClast + (Clast/kel), 
where Clast is the predicted serum 
concentration at the last quantifiable time 
point estimated from the log-linear 
regression analysis 
CCI 
a. 
As data permit. 
 
 
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Description 
CCI 
Participant Analysis 
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9.3.1.2. Statistical Methods for Pharmacokinetic Data 
The serum concentration of ponsegromab (unbound and total) will be listed and descriptively 
summarized by nominal sampling time and cohort. Individual participant and summary 
profiles (mean and median plots) of the serum concentration-time data will be plotted by 
cohort using actual and nominal sampling times respectively. 
The serum PK parameters of ponsegromab (unbound and total) will be listed and 
 
 
 
Additional specifications about the tables, listings, and figures will be outlined in the SAP. 
9.3.2. Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. The safety analyses will be 
presented by cohort. 
AEs, ECGs, BP, PR and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of participants. Any clinical laboratory, 
ECG, BP, and PR abnormalities of potential clinical concern will be described. Safety data 
will be presented in tabular and/or graphical format and summarized descriptively, where 
appropriate. 
Medical history and physical examination collected during the course of the study will be 
considered source data and will not be required to be reported, unless otherwise noted. 
However, any untoward findings identified on physical examinations conducted during the 
active collection period will be captured as AEs, if those findings meet the definition of an 
AE. Data collected at screening that are used for inclusion/exclusion criteria, such as 
laboratory data, ECGs, and vital signs, will be considered source data, and will not be 
required to be reported, unless otherwise noted. 
9.3.2.1. Electrocardiogram Analyses 
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS interval will be summarized by cohort and time. 
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by cohort: 
 
Safety QTcF Assessment 
Degree of Prolongation 
Mild (msec) 
Moderate (msec) 
Severe (msec) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from baseline 
30-60 
>60 
If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
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The PK parameter analysis set will be used. 


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CCI 
observation at that time point. If any of the 3 individual ECG tracings has a QTc value 
>500 msec, but the mean of the triplicates is not >500 msec, the data from the participant’s 
individual tracing will be described in a safety section of the CSR in order to place the 
>500-msec value in appropriate clinical context. However, values from individual tracings 
within triplicate measurements that are >500 msec will not be included in the categorical 
analysis unless the average from the triplicate measurements is also >500 msec. Changes 
from baseline will be defined as the change between the postdose QTc value and the average 
of the predose triplicate values on Day 1. 
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized. 
 
 
 
 
 
 
 
9.4. Interim Analyses 
Interim analysis may be conducted for regulatory communication. 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, facilitating PK/PD modeling, and/or supporting 
regulatory communication and clinical development. 
9.5. Sample Size Determination 
There is no statistical hypothesis for this study, therefore, the study sample size is not based 
on statistical decision rule. 
 
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Approximately 18 participants will be enrolled in this study (N=9 for each cohort) with the 
goal of attaining approximately 16 participants (N=8 for each cohort) evaluable for the 
primary endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant and answer all questions regarding the study. The 
participant should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center. 
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD. 
 
 
 
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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study. 
A copy of the ICD(s) must be provided to the participant. 
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 ID. 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. 
 
 
 
 
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www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
EudraCT 
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov. 
Documents within marketing authorization packages/submissions 
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015. 
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. 
 
 
 
 
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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. 
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/or the 
site 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 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
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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. 
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 study 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. 
 
 
 
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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. 
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. 
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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 SToD system. 
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 
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 2. 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
MCV 
MCH 
MCHC 
Platelet count 
MPV 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN/urea and creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST 
ALT 
Total bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
Urine drug screeningb 
COVID-19 testc 
At screening only: 
FSHd 
HBsAg 
HBcAb 
HCVAb 
HIV 
Syphilis test (TPPA) 
Additional Tests 
(Needed for Hy’s Law) 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
Creatine kinase 
GGT 
PT/INR 
Total bile acids 
Acetaminophen drug 
and/or protein adduct 
levels 
a. 
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase 
b. The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific). 
c. 
The timing and methods of COVID-19 test(s) should follow the requirements from local regulations or 
investigator (CRU). 
d. For confirmation of postmenopausal status only. 
 
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. 
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
 
 
 
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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. 
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. 
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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. 
* 
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. 
• 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. 
 
 
 
 
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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/SAEs associated 
with exposure during 
pregnancy or breastfeeding 
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)* 
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF. 
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE).** 
Environmental or 
None. Exposure to a study 
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.*** 
occupational exposure 
non-participant is not 
to the product under 
collected on the CRF. 
study to a non- 
participant (not 
involving EDP or EDB). 


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• 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. 
 
 
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. 
 
 
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• 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. 
 
 
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. 
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• 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. 
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 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 18 weeks after the last dose of study intervention, 
which corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom may 
break or leak when having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4). 
10.4.2. Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not a WOCBP (see definitions below in 
Section 10.4.3). 
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. 
 
 
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Women in the following categories are not considered WOCBP: 
1. 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. 
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. 
2. 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 old 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. 
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). 
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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; 
• Intravaginal; 
• Transdermal; 
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. 
In addition, one of the following effective barrier methods must also be used when 
option 6 or 7 are chosen above: 
• Male or female condom with or without spermicide; 
• Cervical cap, diaphragm, or sponge with spermicide; 
• 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: 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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10.6. Appendix 6: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• New PR interval prolongation >280 msec. 
• New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from 
baseline. 
• New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm. 
• New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 msec. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset left bundle branch block (QRS >120 msec). 
• New-onset right bundle branch block (QRS >120 msec). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 
• In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 
 
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• Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to 
<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR 
>100 bpm (such as torsades de pointes)). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heart block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>30 seconds’ duration). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
• Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion. 
• Ventricular fibrillation/flutter. 
• At the discretion of the investigator, any arrhythmia classified as an adverse 
experience. 
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.7. Appendix 7: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
Abs 
absolute 
ADA 
antidrug antibodies 
ADCC 
antibody dependent cell-mediated cytotoxicity 
ADL 
activity of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC168H 
area under the curve from the time of dose administration up to 
168 hours 
AUCinf 
area under the serum concentration time profile from time zero 
extrapolated to infinite time 
CCI 
AUClast 
area under the serum concentration time profile from time zero to 
the time of the last quantifiable concentration (Clast) 
CCI 
AV 
atrioventricular 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
C1q 
complement component 1q 
Cav 
average concentration 
CDC 
complement-dependent cytotoxicity 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD 
chronic kidney disease 
CL 
clearance 
CCI 
Clast 
last quantifiable concentration 
Cmax 
maximum observed concentration 
CCI 
CO2 
carbon dioxide (bicarbonate) 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
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Abbreviation 
Term 
CSR 
clinical study report 
CT 
clinical trial 
CYP 
Cytochrome P450 
DC 
discontinuation 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
CCI 
DNA 
deoxyribonucleic acid 
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 
Emax 
maximum effect 
ET 
early termination 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
Fcγ 
fragment crystallizable gamma 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
FU 
follow-up 
GCP 
Good Clinical Practice 
GDF-15 
growth differentiation factor 15 
GDNF 
glial cell-derived neurotrophic factor 
GFRAL 
glial cell-derived neurotrophic factor (GDNF) family receptor α 
like 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IB 
investigator brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
ID 
identification 
IgG1 
immunoglobulin G1 
IND 
investigational new drug application 
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Abbreviation 
Term 
INR 
international normalized ratio 
IP 
investigational product 
IPAL 
Investigational Product Accountability Log 
IRB 
institutional review board 
IV 
intravenous 
kel 
terminal phase rate constant 
LFT 
liver function test 
mAb 
monoclonal antibody 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MPV 
mean platelet volume 
N 
number 
N/A 
not applicable 
NAb 
neutralizing antibodies 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PE 
physical exam 
pH 
potential of hydrogen 
PK 
pharmacokinetic(s) 
POC 
proof of concept 
PR 
pulse rate 
PT 
prothrombin time 
PVC 
premature ventricular contraction 
Q 
distributive clearance 
Q3W 
administered every 3 weeks 
QT 
Q wave interval 
QTcF 
corrected QT (Fridericia method) 
qual 
qualitative 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS 
Severe Acute Respiratory Syndrome 
SC 
subcutaneous 
SCr 
serum creatinine 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SToD 
Study Team on Demand 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
TBili 
total bilirubin 
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Abbreviation 
Term 
TEAE 
treatment-emergent adverse event 
TGFβ 
transforming growth factor beta 
THC 
tetrahydrocannabinol 
Tmax 
time for Cmax 
TPPA 
Treponema pallidum particle agglutination test 
ULN 
upper limit of normal 
US 
United States 
CCI 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11. REFERENCES 
1. 
Ponnaluri VK, Vadlapatla RK, Vavilala DT, et al., Hypoxia induced expression of 
histone lysine demethylases: implications in oxygen-dependent retinal neovascular 
diseases. Biochem Biophys Res Commun. 2011;415(2):373-7. 
2. 
Krieg AJ, Rankin EB, Chan D, et al., Regulation of the histone demethylase JMJD1A 
by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor 
growth. Mol Cell Biol 2010;30(1):344-53. 
3. 
Albertoni M, Shaw PH, Nozaki M, et al., Anoxia induces macrophage inhibitory 
cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. Oncogene 
2002;21(27):4212-9. 
4. 
Akiyama M, Okano K, Fukada Y, et al., Macrophage inhibitory cytokine MIC-1 is 
upregulated by short-wavelength light in cultured normal human dermal fibroblasts. 
FEBS Lett 2009;583(5):933-7. 
5. 
Bottner M, Suter-Crazzolara C, Schober A, et al., Expression of a novel member of the 
TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting 
cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res 1999;297(1):103-10. 
6. 
Wang X, Li Y, Tian H, et al., Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a 
novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma. BMC Cancer 
2014;14:578. 
7. 
Welsh JB, Sapinoso LM, Kern SG, et al., Large-scale delineation of secreted protein 
biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci USA 
2003;100(6):3410-5. 
8. 
Breit SN, Carrero JJ, Tsai VW, et al., Macrophage inhibitory cytokine-1 (MIC- 
1/GDF15) and mortality in end-stage renal disease. Nephrol Dial Transplant 
2012;27(1):70-5. 
9. 
Patel MS, Lee J, Baz M, et al., Growth differentiation factor-15 is associated with 
muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in 
vivo. J Cachexia Sarcopenia Muscle 2016;7(4):436-48. 
10. Lu ZH, Yang L, Yu JW, et al., Weight loss correlates with macrophage inhibitory 
cytokine-1 expression and might influence outcome in patients with advanced 
esophageal squamous cell carcinoma. Asian Pac J Cancer Prev 2014;15(15):6047-52. 
11. Lerner L, Hayes TG, Tao N, et al., Plasma growth differentiation factor 15 is associated 
with weight loss and mortality in cancer patients. J Cachexia Sarcopenia Muscle 
2015;6(4):317-24. 
 
 
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12. Lerner L, Tao J, Liu Q, et al. MAP3K11/GDF15 axis is a critical driver of cancer 
cachexia. J Cachexia Sarcopenia Muscle 2016;7(4):467-82. 
13. Lerner L, Gyuris J, Nicoletti R, et al., Growth differentiating factor-15 (GDF-15): A 
potential biomarker and therapeutic target for cancer-associated weight loss. Oncol Lett 
2016;12(5):4219-4223. 
14. Gyuris J and Lerner L, Patent WO/2015/196142 Treatment of congestive heart failure 
and other cardiac dysfunction using a gdf15 modulator 2015: United States. 
15. Kempf T, von Haehling S, Peter T, et al., Prognostic utility of growth differentiation 
factor-15 in patients with chronic heart failure. J Am Coll Cardiol 2007;50(11):1054-60. 
16. Brown DA, Ward RL, Buckhaults P, et al., MIC-1 serum level and genotype: 
associations with progress and prognosis of colorectal carcinoma. Clin Cancer Res 
2003;9(7)(Jul):2642-50. 
17. Brown DA, Lindmark F, Stattin P, et al., Macrophage inhibitory cytokine 1: a new 
prognostic marker in prostate cancer. Clin Cancer Res 2009;15(21):6658-64. 
18. Blanco-Calvo M, Tarrio N, Reboredo M, et al., Circulating levels of GDF15, MMP7 
and miR-200c as a poor prognostic signature in gastric cancer. Future Oncol 
2014;10(7):1187-202. 
19. Anand IS, Kempf T, Rector TS, et al., Serial measurement of growth-differentiation 
factor-15 in heart failure: relation to disease severity and prognosis in the Valsartan 
Heart Failure Trial. Circulation 2010;122(14):1387-95. 
20. Rohatgi A, Patel P, Das SR, et al., Association of growth differentiation factor-15 with 
coronary atherosclerosis and mortality in a young, multiethnic population: observations 
from the Dallas Heart Study. Clin Chem 2012;58(1):172-82. 
21. Nair V, Robinson-Cohen C, Smith MR, et al., Growth Differentiation Factor-15 and 
Risk of CKD Progression. J Am Soc Nephrol 2017;28(7):2233-40. 
22. Martinez CH, Freeman CM, Nelson JD, et al., GDF-15 plasma levels in chronic 
obstructive pulmonary disease are associated with subclinical coronary artery disease. 
Respir Res 2017;18(1)(02):42. 
23. Johnen H, Lin S, Kuffner T, et al., Tumor-induced anorexia and weight loss are 
mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med 2007;13(11):1333-40. 
24. Mullican SE, Lin-Schmidt X, Chin CN, et al., GFRAL is the receptor for GDF15 and 
the ligand promotes weight loss in mice and nonhuman primates. Nat Med 
2017;23(10):1150-7. 
 
 
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25. Emmerson PJ, Wang F, Du Y, et al., The metabolic effects of GDF15 are mediated by 
the orphan receptor GFRAL. Nat Med 2017;23(10):1215-1219. 
26. Yang L, Chang CC, Sun Z, et al., GFRAL is the receptor for GDF15 and is required for 
the anti-obesity effects of the ligand. Nat Med 2017;23(10):1158-66. 
27. Hsu JY, Crawley S, Chen M, et al., Non-homeostatic body weight regulation through a 
brainstem-restricted receptor for GDF15. Nature 2017;550(7675)(10):255-259. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
Protocol C3651012 (PF-06946860) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 of 17 
 
 
 
 
 
 
 
Protocol C3651012 
 
 
 
 
A PHASE 1, OPEN-LABEL, SINGLE DOSE STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY, AND 
TOLERABILITY OF PONSEGROMAB ADMINISTERED SUBCUTANEOUSLY IN 
HEALTHY ADULT CHINESE PARTICIPANTS 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
Version: 
1 
Date: 
18 May 2022 


Protocol C3651012 (PF-06946860) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 2 of 17 
 
 
TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................... 3 
APPENDICES ........................................................................................................................... 3 
1. VERSION HISTORY ........................................................................................................... 4 
2. INTRODUCTION ................................................................................................................. 4 
2.1. Modifications to the Analysis Plan Described in the Protocol .................................. 4 
2.2. Study Objectives, Endpoints, and Estimands ............................................................ 4 
2.3. Study Design ............................................................................................................. 5 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS .................................................................................................................. 5 
3.1. Primary Endpoint(s) .................................................................................................. 6 
3.2. Secondary Endpoint(s) .............................................................................................. 6 
CCI 
 
3.4. Baseline Variables ..................................................................................................... 7 
3.5. Safety Endpoints ........................................................................................................ 7 
3.5.1. Adverse Events ............................................................................................. 7 
3.5.2. Laboratory Data ............................................................................................. 7 
3.5.3. Vital Signs Data ............................................................................................ 7 
3.5.4. ECG Results .................................................................................................. 8 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................... 8 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................... 9 
5.1. Hypotheses and Decision Rules ................................................................................. 9 
5.2. General Methods ........................................................................................................ 9 
5.3. Methods to Manage Missing Data ............................................................................. 9 
5.3.1. Safety Data .................................................................................................... 9 
5.3.2. Pharmacokinetic CCI 
 ................................. 9 
6. ANALYSES AND SUMMARIES ....................................................................................... 10 
6.1. Primary Endpoint(s) ................................................................................................. 10 
6.2. Secondary Endpoint(s) ............................................................................................. 11 


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6.4. Subset Analyses ....................................................................................................... 13 
6.5. Baseline and Other Summaries and Analyses .......................................................... 13 
6.5.1. Baseline Summaries .................................................................................... 13 
6.5.2. Study Conduct and Participant Disposition ................................................. 14 
6.5.3. Concomitant Medications and Nondrug Treatments ................................... 14 
6.6. Safety Summaries and Analyses .............................................................................. 14 
6.6.1. Adverse Events ........................................................................................... 14 
6.6.2. Laboratory Data ........................................................................................... 14 
6.6.3. Vital Signs ................................................................................................... 14 
6.6.4. Electrocardiograms ...................................................................................... 14 
7. INTERIM ANALYSES ....................................................................................................... 15 
7.1. Introduction .............................................................................................................. 15 
7.2. Interim Analyses and Summaries ............................................................................ 15 
8. REFERENCES ..................................................................................................................... 15 
9. APPENDICES ...................................................................................................................... 16 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ................................................................................. 4 
Table 2. 
Ponsegromab Serum PK Parameters (unbound and total) .......................... 6 
Table 3. 
PK Parameters to be Summarized Descriptively ...................................... 10 
 
 
APPENDICES 
Appendix 1. Categorical Classes for ECG and Vital Signs Endpoints ..................................... 16 
Appendix 2. List of Abbreviations ........................................................................................... 17 


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1. VERSION HISTORY 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated Protocol Amendment 
Rationale 
Specific Changes 
1 18 May 2022 
Original 22 Apr 2022 
N/A 
N/A 
 
2. INTRODUCTION 
The purpose of this study is to evaluate the pharmacokinetics (PK), CCI 
 
safety, and tolerability of ponsegromab following 100 mg and 400 mg single subcutaneous 
(SC) dose in healthy adult Chinese participants. Results from this study will be used to 
inform clinical development of ponsegromab in China, to facilitate China’s participation in 
global pivotal studies, and to support China registration of ponsegromab. 
This statistical analysis plan (SAP) provides the detailed methodology for summaries and 
statistical analyses of the data to be collected in Study C3651012. This document may 
modify the plans outlined in the protocol; however, any major modifications of the primary 
endpoints definitions or their analyses will also be reflected in a protocol amendment. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
Not applicable. 
2.2. Study Objectives, Endpoints, and Estimands 
There are no estimands for this study. 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To characterize the serum PK of ponsegromab 
following a single SC administered dose in 
healthy adult Chinese participants. 
• 
Ponsegromab serum PK parameters (unbound 
and total), as data permit: AUCinf, AUClast, 
Cmax, Tmax, and t½. 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of 
ponsegromab following a single SC 
administered dose in healthy adult Chinese 
participants. 
• 
Adverse events (AE), clinical safety 
laboratory tests, vital signs (blood pressure, 
pulse rate), physical examinations, and 
12-lead ECGs for approximately 18 weeks 
post single dose. 


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2.3. Study Design 
This is an open-label, single dose study to characterize the PK, CCI safety, and tolerability of 
ponsegromab following 100 mg or 400 mg single SC dose in healthy adult Chinese 
participants. 
The study will enroll 2 cohorts of approximately 18 healthy adult Chinese participants (N=9 
for each cohort). 
Participants who meet eligibility criteria at baseline will receive a single SC dose of 
ponsegromab at 100 mg (Cohort 1) or 400 mg (Cohort 2) on Day 1. Participants in the 100 
mg cohort will be dosed firstly, and will be kept under safety monitoring for 8 days at the 
clinical research unit (CRU). Progression to 400 mg will occur only if 100 mg is well 
tolerated after reviewing the safety data up to 8 days post-dose as judged by the investigator. 
Sentinel dosing may be implemented in the 400 mg cohort as judged by the investigator: eg, 
2 participants may be dosed prior to the remaining participants in Cohort 2. If the dose level 
is determined to have an acceptable safety and tolerability profile up to 8 days post-dose, as 
judged by the investigator for the first 2 sentinel participants, the remaining 7 participants in 
that cohort will be dosed. The total duration of each participation in this study is 
approximately 22 weeks, including a screening period of up to 4 weeks to confirm eligibility 
and a follow-up period of approximately 18 weeks after the single SC dose. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
As listed in Section 2.2 the primary and the other endpoints are related to ponsegromab 
serum PK and are described herein. 
Samples for the PK analysis of ponsegromab will be taken according to the schedule of 
activities (SoA) given in the protocol. 
Objectives 
Endpoints 
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Ponsegromab serum PK parameters (unbound and total) will be derived (if data permit) from 
the concentration-time profiles using standard non-compartmental methods as detailed in 
Table 2. Actual PK sampling times will be used in the derivation of ponsegromab serum PK 
parameters (unbound and total). In the case that actual PK sampling times are not available, 
nominal PK sampling times will be used. 
 
Table 2. 
Ponsegromab Serum PK Parameters (unbound and total) 
 
Parameter 
Definition 
Method of Determination 
Cmax 
Maximum serum concentration 
Observed directly from data 
CCI 
Tmax 
Time for Cmax 
Observed directly from data as time of 
first occurrence 
t½a 
Terminal half-life 
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a linear 
regression of the log-linear 
concentration-time curve 
AUClast 
Area under the serum concentration-time 
profile from time zero to the time of the 
last quantifiable concentration (Clast) 
Linear/Log trapezoidal method 
CCI 
AUCinfa 
Area under the serum concentration-time 
profile from time zero extrapolated to 
infinite time 
AUClast + (Clast/kel), 
where Clast is the predicted serum 
concentration at the last quantifiable time 
point estimated from the log-linear 
regression analysis 
CCI 
a. 
As data permit. 
 
3.1. Primary Endpoint(s) 
The primary endpoints are below ponsegromab serum PK parameters (unbound and total): 
• AUCinf, AUClast, Cmax, Tmax, and t½. 
3.2. Secondary Endpoint(s) 
The secondary endpoints include safety endpoints, which are described in Section 3.5. 
 
 
 


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3.4. Baseline Variables 
There are no baseline variables to be used as covariates or stratification factors in this study. 
Baseline values are those collected on Day 1 prior to dosing, or the last pre-dose 
measurement collected on Day -1. 
3.5. Safety Endpoints 
3.5.1. Adverse Events 
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. All events that start on or after the first 
dosing day and time/start time, if collected, but before the end of the study will be flagged as 
TEAEs. The algorithm will not consider any events that started prior to the first dose date. 
3.5.2. Laboratory Data 
Safety laboratory tests will be performed as described in the protocol. Baseline is defined as 
the last pre-dose measurement collected on Day -1. 
To determine if there are any clinically significant laboratory abnormalities, the hematology, 
chemistry, urinalysis and coagulation tests will be assessed against the criteria specified in 
Clinical Data Interchange Standards Consortium (CDISC) standard. The assessment will not 
take into account whether each participant’s baseline test result is within or outside the 
laboratory reference range for the particular laboratory parameter. 
3.5.3. Vital Signs Data 
Supine blood pressure (BP) and pulse rate (PR) will be taken at times detailed in the SoA 
given in the protocol. When triplicate BP and PR are required, the average of the triplicate 
BP and PR measurements collected prior to dosing on Day 1 will serve as baseline. Change 
from baseline in supine BP and PR will be determined. 


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3.5.4. ECG Results 
Supine triplicate 12-lead ECGs will be obtained at each assessment time indicated in the SoA 
given in the protocol. For each ECG parameter, the average of the triplicate readings 
collected at each assessment time will be used to represent a single observation. Baseline will 
be defined as the last pre-dose recordings on Day 1. Change from baseline in QT interval, 
heart rate, QTcF interval, PR interval, and QRS interval will be determined. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
For purposes of analysis, the following analysis sets are defined: 
 
Participant 
Analysis Set 
Description 
Applicable Analysis 
(for additional 
information refer to 
section 6) 
Enrolled 
“Enrolled” means a participant’s agreement 
to participate in a clinical study following 
completion of the informed consent process 
and screening. Potential participants who are 
screened for the purpose of determining 
eligibility for the study, but do not participate 
in the study, are not considered enrolled, 
unless otherwise specified by the protocol. A 
participant will be considered enrolled if the 
informed consent is not withdrawn prior to 
participating in any study activity after 
screening. 
Safety Analysis 
All enrolled participants who receive a dose of 
Secondary endpoints 
Set 
ponsegromab. Participants will be analyzed 
(section 6.2) 
according to the product they actually received. 
PK 
All enrolled participants who receive a dose of 
Primary endpoints 
Concentration 
ponsegromab and in whom at least 1 serum 
(section 6.1) 
Analysis Set 
concentration value is reported. 
PK Parameter 
All enrolled participants who receive a dose of 
Primary endpoints 
Analysis Set 
ponsegromab and who have at least 1 of the 
serum PK parameters of interest calculated. 
(section 6.1) CCI 


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Participant 
Analysis Set 
Description 
Applicable Analysis 
(for additional 
information refer to 
section 6) 
CCI 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
There are no statistical hypotheses for this study. 
5.2. General Methods 
All data will be descriptively summarized. 
Binary and categorical variables will be presented using summary statistics: number of 
observations and percentages. 
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, standard deviation (SD), coefficient of variation (cv%), median, minimum, 
maximum, geometric mean and geometric cv%. 
5.3. Methods to Manage Missing Data 
5.3.1. Safety Data 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
5.3.2. Pharmacokinetic CCI 
 Data 
Concentrations Below the Limit of Quantification 
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. 
In allCCI data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to the LLQ. 
In listings, BLQ values will be reported as “<LLQ”, where LLQ will be replaced with the 
value for the lower limit of quantification (LLQ). 


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Deviations, Missing Concentrations and Anomalous Values 
For PK CCI  summary tables, plots of mean profiles and plots of median profiles, 
summary statistics will be calculated setting concentrations to missing if one of the following 
cases is true: 
1. A concentration has been collected as ND (i.e., not done) or NS (i.e., no sample); 
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
Pharmacokinetic CCI 
 Parameters 
Actual PKCCI sampling times will be used in the derivation of PKCCI parameters. 
If a PKCCI parameter cannot be derived from a participant’s concentration data, the 
parameter will be coded as NC (i.e., not calculated). (Note that NC values will not be 
generated beyond the day that a participant discontinues.) 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements. 
If an individual participant has a known biased estimate of a PKCCI parameter (e.g., due to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics. For PK parameter calculations, the sponsor standard rules will be applied. 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoint(s) 
The ponsegromab serum PK parameters (unbound and total) detailed in Section 3.1 will be 
listed and descriptively summarized by cohort based on the PK parameter analysis set (as 
defined in Section 4). Missing values will be handled as detailed in Section 5.3.2. Each 
summary will include the set of summary statistics as specified in Table 3. 
 
Table 3. 
PK Parameters to be Summarized Descriptively 
 
Parameter 
Summary Statistics 
Cmax,CCI 
AUClast, CCI 
AUCinf, CCI 
 
N, arithmetic mean, median, cv%, SD, minimum, 
maximum, geometric mean and geometric cv%. 
Tmax 
N, median, minimum, maximum. 


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Table 3. 
PK Parameters to be Summarized Descriptively 
 
Parameter 
Summary Statistics 
t½ 
N, arithmetic mean, median, SD, minimum, 
maximum. 
 
CCI 
the estimation of t½ will be listed where applicable. 
 
Supporting data from 
The serum ponsegromab concentrations (total and unbound) will be presented within the PK 
concentration analysis set (as defined in Section 4) and will include: 
• 
a listing of all concentrations sorted by cohort, participant ID, study day, and nominal 
time post-dose. The concentration listing will also include the actual times. Deviations 
from the nominal time will be given in a separate listing. 
• 
a summary of concentrations by cohort, study day, and nominal time post-dose, where 
the set of statistics will include number of observations, mean, median, SD, cv%, 
minimum, maximum and the number of concentrations above the LLQ. 
• 
median concentration-time plots (on both linear and semi-log scales) against nominal 
time post-dose by cohort (all cohorts on the same plot per scale, based on the summary 
of concentrations by cohort and time post-dose). 
• 
mean concentration-time plots (on both linear and semi-log scales) against nominal time 
post-dose by cohort (all cohorts on the same plot per scale, based on the summary of 
concentrations by cohort and time post-dose).individual concentration-time plots by 
cohort (on both linear and semi-log scales) against actual time post-dose. 
• 
individual concentration-time plots (on both linear and semi-log scales) against actual 
time post-dose by cohort. 
 
The scale used for the x-axis (time) of these plots will be decided on review of the data, and 
will depend on how long ponsegromab concentrations are quantifiable. 
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual plots by time, the actual PK sampling time will be used. For 
pre-dose, the actual PK sampling time will be set to 0 hour. 
6.2. Secondary Endpoint(s) 
The details of safety analyses are described in Section 6.6. 


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6.4. Subset Analyses 
No subset analyses will be performed. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
Demographic and baseline characteristics collected prior to the first dosing will be 
summarized following CDISC standard. 
CCI 


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6.5.2. Study Conduct and Participant Disposition 
Participant evaluation groups will show participant disposition. Frequency counts and 
percentages will be supplied for participant discontinuation(s). Data will be reported in 
accordance with CDISC standard. 
6.5.3. Concomitant Medications and Nondrug Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be reported according to 
CDISC standard. 
6.6. Safety Summaries and Analyses 
Standard summary tables and listings will be generated in accordance with CDISC standard 
within safety analysis set (as defined in Section 4). 
6.6.1. Adverse Events 
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be listed and summarized by cohort. 
6.6.2. Laboratory Data 
Laboratory data will be listed and summarized by cohort. Baseline is as defined in Section 
3.5.2. 
Incidence of laboratory test (including hematological, clinical chemistry, coagulation test) 
abnormalities (without regard to baseline abnormality, with normal baseline and abnormal 
baseline, respectively) will be reported by cohort. 
6.6.3. Vital Signs 
Absolute values and changes from baseline in supine BP and PR will be summarized by 
cohort and study day. Tables will be paged by parameter. Baseline is as defined in Section 
3.5.3. 
Minimum and/or maximum absolute values and changes from baseline for supine BP and PR 
will also be summarized by cohort using categories as defined in Appendix 1. Numbers and 
percentages of participants meeting the categorical criteria will be provided. All planned and 
unplanned post-dose time points will be counted in these categorical summaries. 
6.6.4. Electrocardiograms 
Absolute values and changes from baseline in QT interval, heart rate, QTcF interval, PR 
interval, and QRS complex will be summarized descriptively by cohort and time. Tables will 
be paged by parameter. Baseline is as defined in Section 3.5.4. 
Maximum and/or minimum absolute values and changes from baseline for ECG endpoints 
(QTcF interval, PR interval and QRS complex) will also be summarized by cohort using 


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categories as defined in Appendix 1. Numbers and percentages of participants meeting the 
categorical criteria will be provided. All planned and unplanned post-dose time points will be 
counted in these categorical summaries. 
Listings of participants with any single post-dose value >500 msec will also be produced for 
QTcF. 
7. INTERIM ANALYSES 
7.1. Introduction 
Interim analysis may be conducted for regulatory communication. 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, facilitating PKCCI modeling, and/or supporting 
regulatory communication and clinical development. 
7.2. Interim Analyses and Summaries 
If an interim analysis is to be proceeded, analyses and summaries planned in this SAP may 
be conducted to support regulatory communication. 
8. REFERENCES 
None. 


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9. APPENDICES 
Appendix 1. Categorical Classes for ECG and Vital Signs Endpoints 
 
Categories for ECG Endpoints 
 
QTcF (msec) 
450< max. ≤480 
480< max. ≤500 
max. >500 
QTcF (msec) increase 
from baseline 
30< max. ≤60 
max. >60 
PR (ms) 
max. ≥300 
PR (ms) increase from 
baseline 
baseline >200 and max. 
≥25% increase 
baseline ≤200 and 
max. ≥50% increase 
QRS (ms) 
max. ≥140 
QRS (ms) increase from 
baseline 
≥50% increase 
 
 
Categories for Vital Signs Endpoints 
 
Systolic BP (mm Hg) 
min. <90 
Systolic BP (mm Hg) change from baseline 
max. decrease ≥30 
max. increase ≥30 
Diastolic BP (mm Hg) 
min. <50 
Diastolic BP (mm Hg) change from baseline 
max. decrease ≥20 
max. increase ≥20 
Pulse rate (bpm) 
min. <40 
max. >120 


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Appendix 2. List of Abbreviations 
 
Abbreviation 
Term 
CCI 
AE 
adverse event 
AUC 
area under the curve 
AUCinf 
area under the concentration-time curve from time 0 to infinity 
AUClast 
Area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
bpm 
beats per minute 
CDISC 
Clinical Data Interchange Standards Consortium 
CCI 
Cmax 
maximum observed concentration 
CRU 
clinical research unit 
CV 
coefficient of variation 
CCI 
ECG 
electrocardiogram 
kel 
first-order elimination rate constant 
LLQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
millisecond 
CCI 
 
NC 
not calculated 
ND 
not done 
NS 
no sample 
N/A 
not applicable 
CCI 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
QTcF 
corrected QT 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SoA 
schedule of activities 
t1/2 
terminal elimination half life 
TEAE 
treatment-emergent adverse event 
Tmax 
time for Cmax 
CCI