A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, 2-WAY CROSSOVER STUDY ASSESSING PHARMACOKINETIC COMPARABILITY OF TWO PF-06881894 PRESENTATIONS, ON-BODY INJECTOR AND PREFILLED SYRINGE, IN HEALTHY PARTICIPANTS
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Pfizer

Pegfilgrastim (PF-06881894) 
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Final Protocol, 19 Nov 2021 
PFIZER CONFIDENTIAL
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Title Page
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, 2-WAY CROSSOVER 
STUDY ASSESSING PHARMACOKINETIC COMPARABILITY OF TWO 
PF-06881894 PRESENTATIONS, ON-BODY INJECTOR AND PREFILLED 
SYRINGE, IN HEALTHY PARTICIPANTS
Study Intervention Number:
PF-06881894
Study Intervention Name:
Pegfilgrastim
US IND Number:
EudraCT Number:
N/A
ClinicalTrials.gov ID: 
N/A
Protocol Number:
C1221007
Phase:
1
Brief Title: Pharmacokinetic Comparability Study in Healthy Participants of 
PF-06881894 On-Body Injector Relative to Prefilled Syringe 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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CCI

Pegfilgrastim (PF-06881894) 
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Final Protocol, 19 Nov 2021 
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Document History
Document
Version Date
Original protocol
19 Nov 2021
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Final Protocol, 19 Nov 2021 
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................11
1.3. Schedule of Activities .............................................................................................12
2. INTRODUCTION ...............................................................................................................16
2.1. Study Rationale .......................................................................................................16
2.2. Background .............................................................................................................16
2.2.1. Nonclinical Pharmacology..........................................................................18
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................18
2.2.3. Nonclinical Safety ......................................................................................18
2.2.4. Clinical Overview.......................................................................................19
2.3. Benefit/Risk Assessment.........................................................................................20
2.3.1. Risk Assessment.........................................................................................21
2.3.2. Benefit Assessment.....................................................................................23
2.3.3. Overall Benefit/Risk Conclusion................................................................23
3. OBJECTIVES AND ENDPOINTS.....................................................................................23
4. STUDY DESIGN.................................................................................................................23
4.1. Overall Design.........................................................................................................23
4.2. Scientific Rationale for Study Design.....................................................................24
4.2.1. Reproductive Risk ......................................................................................25
4.2.2. Collection of Retained Research Samples..................................................25
4.3. Justification for Dose ..............................................................................................25
4.4. End of Study Definition ..........................................................................................25
5. STUDY POPULATION......................................................................................................25
5.1. Inclusion Criteria.....................................................................................................26
5.2. Exclusion Criteria....................................................................................................27
5.3. Lifestyle Considerations..........................................................................................30
5.3.1. Meals and Dietary Restrictions...................................................................30
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................30
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5.3.3. Activity .......................................................................................................31
5.3.4. Contraception..............................................................................................31
5.4. Screen Failures ........................................................................................................32
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................32
6.1. Study Intervention(s) Administered........................................................................32
6.1.1. Administration............................................................................................32
6.1.2. Medical Devices .........................................................................................33
6.2. Preparation, Handling, Storage, and Accountability...............................................34
6.2.1. Preparation and Dispensing........................................................................35
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................35
6.3.1. Allocation to Study Intervention ................................................................35
6.4. Study Intervention Compliance...............................................................................35
6.5. Dose Modification...................................................................................................36
6.6. Continued Access to Study Intervention After the End of the Study......................36
6.7. Treatment of Overdose............................................................................................36
6.8. Concomitant Therapy..............................................................................................37
6.8.1. Prior Treatments .........................................................................................37
6.8.2. Permitted During the Study ........................................................................37
6.8.3. Prohibited During the Study.......................................................................38
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................38
7.1. Discontinuation of Study Intervention ....................................................................38
7.1.1. Pregnancy ...................................................................................................39
7.2. Participant Discontinuation/Withdrawal From the Study.......................................39
7.2.1. Withdrawal of Consent...............................................................................40
7.3. Lost to Follow up ....................................................................................................40
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................41
8.1. Efficacy Assessments (Not Applicable)..................................................................42
8.2. Safety Assessments .................................................................................................42
8.2.1. Physical Examinations................................................................................42
8.2.2. Vital Signs ..................................................................................................43
8.2.2.1. BP and PR .................................................................................43
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8.2.2.2. Respiratory Rate........................................................................43
8.2.2.3. Temperature ..............................................................................43
8.2.3. Electrocardiograms and Chest X-ray..........................................................43
8.2.4. Clinical Safety Laboratory Assessments ....................................................44
8.2.5. COVID-19 specific assessments.................................................................45
8.2.6. Pregnancy Testing ......................................................................................45
8.2.7. Assessment ISRs and ASRs........................................................................45
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................46
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......46
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................47
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................47
8.3.2. Method of Detecting AEs and SAEs ..........................................................47
8.3.3. Follow-Up of AEs and SAEs......................................................................47
8.3.4. Regulatory Reporting Requirements for SAEs...........................................48
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................48
8.3.5.1. Exposure During Pregnancy......................................................48
8.3.5.2. Exposure During Breastfeeding ................................................50
8.3.5.3. Occupational Exposure .............................................................50
8.3.6. Cardiovascular and Death Events (Not Applicable)...................................51
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................51
8.3.8. (Not Applicable) .........................................................................................51
8.3.9. Adverse Events of Special Interest.............................................................51
8.3.9.1. Lack of Efficacy........................................................................51
8.3.10. Medical Device Deficiencies....................................................................51
8.3.10.1. Time Period for Detecting Medical Device Deficiencies .......51
8.3.10.2. Follow-Up of Medical Device Deficiencies............................52
8.3.10.3. Prompt Reporting of Device Deficiencies to the Sponsor ......52
8.3.10.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................52
8.3.11. Medication Errors.....................................................................................53
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8.4. Pharmacokinetics ....................................................................................................53
8.5. Genetics...................................................................................................................54
8.5.1. Specified Genetics ......................................................................................54
8.5.2. Retained Research Samples for Genetics ...................................................54
8.6. Biomarkers ..............................................................................................................55
8.6.1. Specified Gene Expression (RNA) Research .............................................55
8.6.2. Specified Protein Research.........................................................................55
8.6.3. Specified Metabolomic Research ...............................................................55
8.6.4. Retained Research Samples for Biomarkers...............................................55
8.7. Immunogenicity Assessments.................................................................................55
8.8. Health Economics ...................................................................................................55
9. STATISTICAL CONSIDERATIONS ................................................................................55
9.1. Statistical Hypotheses .............................................................................................55
9.2. Analysis Sets ...........................................................................................................55
9.3. Statistical Analyses .................................................................................................56
9.3.1. Pharmacokinetic Analysis ..........................................................................56
9.3.2. Safety Analysis ...........................................................................................58
9.3.3. Other Analyse(s).........................................................................................58
9.4. Interim Analyses .....................................................................................................58
9.5. Sample Size Determination.....................................................................................58
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................59
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............59
10.1.1. Regulatory and Ethical Considerations ....................................................59
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................59
10.1.2. Financial Disclosure .................................................................................60
10.1.3. Informed Consent Process ........................................................................60
10.1.4. Data Protection .........................................................................................61
10.1.5. Committees Structure ...............................................................................61
10.1.5.1. Data Monitoring Committee ...................................................61
10.1.6. Dissemination of Clinical Study Data ......................................................61
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10.1.7. Data Quality Assurance ............................................................................63
10.1.8. Source Documents....................................................................................64
10.1.9. Study and Site Start and Closure ..............................................................64
10.1.10. Publication Policy...................................................................................65
10.1.11. Sponsor’s Qualified Medical Personnel .................................................66
10.2. Appendix 2: Clinical Laboratory Tests .................................................................67
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................69
10.3.1. Definition of AE .......................................................................................69
10.3.2. Definition of an SAE ................................................................................70
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................71
10.3.4. Reporting of SAEs....................................................................................75
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................76
10.4.1. Male Participant Reproductive Inclusion Criteria....................................76
10.4.2. Female Participant Reproductive Inclusion Criteria.................................76
10.4.3. Woman of Childbearing Potential ............................................................77
10.4.4. Contraception Methods.............................................................................78
10.5. Appendix 5: Genetics............................................................................................80
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......81
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................83
10.8. Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting in Medical Device Studies .............................................85
10.8.1. Definition of AE and ADE .......................................................................85
10.8.2. Definition of SAE, SADE, and USADE ..................................................85
10.8.3. Definition of Device Deficiency...............................................................86
10.8.4. Recording/Reporting and Follow-Up of Medical Device 
Deficiencies......................................................................................................86
10.8.5. Reporting of SAEs....................................................................................88
10.8.6. Reporting of SADEs.................................................................................88
10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI.......89
10.10. Appendix 10: Abbreviations ...............................................................................90
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11. REFERENCES ..................................................................................................................94
LIST OF TABLES
Table 1.
Schedule of Activities...............................................................................12
Table 2.
PK Sampling Schema – Periods 1 and 2 ..................................................15
Table 3.
Treatment Sequences................................................................................23
Table 4.
Laboratory Tests .......................................................................................67
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: Pharmacokinetic Comparability Study in Healthy Participants of PF-06881894 
On-Body Injector Relative to Prefilled Syringe
Rationale
The PK comparability of PF-06881894 administered by PFS versus by OBI will be assessed 
in a single-dose comparative PK evaluation in healthy participants enrolled at approximately 
4 CRUs. Assessment of PK using a single-dose study design in healthy participants is 
expected to be the most sensitive setting to detect intrinsic differences in PK between the 
OBI and PFS presentations of PF-06881894. 
Objectives and Endpoints
Objectives
Endpoints
Primary:
Primary: 
•
PK comparability
•
To assess the PK comparability of 
PF-06881894 administered by OBI versus 
PFS as a single SC dose.
•
Cmax, AUClast and AUCinf (if data permits).
Secondary: 
Secondary: 
•
To characterize the PK of PF-06881894 OBI 
dosing presentation to PFS dosing presentation
in healthy participants.
•
To assess the safety (including 
immunogenicity) of PF-06881894 OBI dosing 
presentation to PFS dosing presentation in 
healthy participants.
•
Tmax and t½ (if data permits).
•
AEs, including AESIs and device-related AEs;
ISRs and ASRs.
Overall Design
Brief Summary
This will be an open-label, randomized, 2-treatment, 2-period, crossover single-dose study in 
approximately 134 healthy adult participants. Participants will be randomized into 
2 sequences of treatment as described in the following table of Intervention Groups and 
Duration.
Number of Participants
Approximately 134 participants will be enrolled to study intervention, with 67 participants 
assigned to each treatment sequence. Dropouts may be replaced at the discretion of the 
investigator upon consultation with the sponsor.
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Note: "Enrolled" means a participant's, or his or her legally authorized representative’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
Sequence
Period 1
Washout
Period 2
1 (n=67)
Treatment A
At least 56 days
Treatment B
2 (n=67)
Treatment B
At least 56 days
Treatment A
Treatment A: PF-06881894, OBI, 6 mg administered as a single SC injection 
Treatment B: PF-06881894, PFS, 6 mg administered as a single SC injection
Screening evaluation will occur within 30 days prior to the first dose of study intervention in 
Period 1. Day -1 is defined as the day prior to the first day of dosing (Day 1) in each period. 
Participants will be admitted to the CRU on Day -2, at 36-42 hours prior to Day 1 dosing, 
and will remain confined in the CRU until completion of all study activities on Day 5 during 
each period.  
There will be at least a 56-day washout period between administration of each study 
intervention to ensure the complete elimination of the drug. The total duration of 
participation in the study for each participant, excluding Screening, is approximately 12 
weeks.
On Day -1 of each period, the PF-06881894 OBI will be activated and applied on participants
randomized in the OBI arm. 
On Day 1 of each period, each participant will receive a single SC dose of 6 mg 
PF-06881894 administered by OBI or by PFS based on the randomization code. For those 
doses administered via OBI, removal of the device will occur following completion of the 
infusion.
The same injection site (left or right side of the abdomen) will be used for both OBI and PFS 
for each participant, keeping at least 2 inches (5 cm) away from the belly button. The same 
needle angle (90°) for SC injection will be used for each participant in the OBI and PFS
arms.
Blood samples for PK (3.0 mL) will be collected by either intravenous catheter or 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration 
(Hour 0) and at 0.167 (10 min), 0.5, 1, 3, 6, 12, 16, 24, 48, 72, 96, 120, 144, 168, 192, 216, 
240, 264 and 288 hours post-dose. For the OBI treatment period, PK collection should 
resume 10 min (0.167 hrs) following the start of the injection and continue as shown. This 
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sample collection scheme will adequately characterize the PK of pegfilgrastim following a 
single SC dose. 
Safety will be assessed for all treatments by monitoring AEs and other parameters defined by 
protocol such as vital signs, laboratory assessments, etc.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
The serum concentration time data from Day 1 through Day 13 from individual participants
will be analyzed by non-compartmental methods to determine the PK parameters. The 
primary PK parameters to be estimated will include Cmax, AUClast and AUCinf (if data 
permits). The secondary PK parameters to be estimated will include Tmax, and t½ (if data 
permits). Descriptive statistics for the PK parameters will be provided.  
Ninety percent (90%) CIs for the test to reference ratios (PF-06881894 OBI versus 
PF-06881894 PFS) for Cmax, AUClast and AUCinf will be constructed on a natural log scale 
using ANOVA with treatment, sequence and period as effects. PK similarity for a given test 
to reference comparison will be considered to be demonstrated if the 90% CIs for the test to 
reference ratios of Cmax, AUClast and AUCinf fall within the 80% - 125% BE window.
1.2. Schema
Not applicable.
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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.
Table 1.
Schedule of Activities
Period 1a
Period 2a
Visit 
Identifier/Study 
Day (Visit 
Window)
Screening
b
-5 to -4
-2
-1
1
2
3 4 5 6 7 8 9 10
11
12
13
28 
(+2)  
TCc
-5 to -4
-2
-1
1
2
3 4 5 6 7 8 9 10
11
12
13
28 (+2) or 
Early 
Withdrawald
Informed consent
Xe
CRU confinement
X
X
X
X
X X X
X
X
X
X
X X X
Inclusion/exclusion 
criteria
X
X
Randomizationf
X
OBI activated and 
applied to those 
randomized to this 
arm
X
X
OBI removal after 
injection completed, 
as appropriate
X
X
Medical history 
X
Xg
Medication history
X
Xh
Physical 
examination 
including Spleen 
Assessment
X
X
X
Demography
X
Vital signsi
X
X
X
X X X X X X
X
X
X
X
X
X X X X X X
X
X
X
X
Height and weight
X
Serology testing
X
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Table 1.
Schedule of Activities
Period 1a
Period 2a
Visit 
Identifier/Study 
Day (Visit 
Window)
Screening
b
-5 to -4
-2
-1
1
2
3 4 5 6 7 8 9 10
11
12
13
28 
(+2)  
TCc
-5 to -4
-2
-1
1
2
3 4 5 6 7 8 9 10
11
12
13
28 (+2) or 
Early 
Withdrawald
Contraception 
checkj
X
X
X X X X X
X
X
X
X
X
X X X X X
X
X
X
X
Pregnancy testk
X
X
X
X
FSHl
X
Urine drug 
screening
X
X
X
Urine cotinine 
X
Alcohol screening
X
X
X
Chest X-ray
X
Resting 12-lead 
ECG
X
X
CBC, Platelets, and 
Chemistry Panelm
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
Enzyme/Liver Panel 
only (ALT, AST, 
LDH, ALP, GGT, 
TBili)
Xn
X
X
X
Xn
X
X
X
Study treatment 
administration
X
X
Assessment of ISRs
and ASRso
Xp
X
X
X X X X X X X X
X
X
X
Xp
X
X
X X X X X X X X
X
X
X
PK blood sampling
Xq
X
X X X X X X X X
X
X
X
Xq
X
X X X X X X X X
X
X
X
AE monitoring
To be captured from informed consent through to the Period 2 Day 28 Visit
Concomitant 
medication
To be captured from informed consent through to the Period 2 Day 28 Visit
Retained Research 
Sample for Genetics 
(Prep D1)r
X
COVID-19 testings
X
X
X
COVID-19 
questionnairet
X
X
X
X
X X X X X X X X
X
X
X
X
X
X
X
X
X X X X X X X X
X
X
X
X
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Table 1.
Schedule of Activities
Period 1a
Period 2a
Visit 
Identifier/Study 
Day (Visit 
Window)
Screening
b
-5 to -4
-2
-1
1
2
3 4 5 6 7 8 9 10
11
12
13
28 
(+2)  
TCc
-5 to -4
-2
-1
1
2
3 4 5 6 7 8 9 10
11
12
13
28 (+2) or 
Early 
Withdrawald
a.
Washout period between treatments will be at least 56 days.
b.
Within 30 days prior to first dose of study intervention
c.
Telephone visit.
d.
In the event of early withdrawal, the participant is to return for an Early Withdrawal visit (Treatment Period 2 Day 28 procedures) at least 28 days after the last dose of study intervention, 
otherwise participants will return for their final visit on Period 2 Day 28.
e.
Informed consent must be completed before any study related procedures are performed.
f.
Period 1 only.
g.
Record change(s) in medical history and prior medication since screening (Period 1 only)
h.
Complete history of all prescription and non-prescription drugs, herbal medicines, and dietary and herbal supplements taken within 30 days prior to the planned first dose. History of drug, 
alcohol, and tobacco use will also be collected.
i.
Sitting BP, PR, respiratory rate and tympanic temperature. To be obtained prior to any procedures, eg, blood draws. 
j.
The investigator or his/her designee will discuss with the participant the need to use highly effective contraception consistently and correctly according to contraception guidelines, and 
confirm and document that proper contraception is being used for the participant and their partner as appropriate.
k.
Pregnancy test (with sensitivity of at least 25 mIU/mL), for females of childbearing potential only, at Screening and Day -1 in Periods 1 and 2 and at Period 2 Day 28/Early withdrawal. 
Pregnancy tests may also be repeated as per request of IRB/ ECs or if required by local regulations. Pregnancy test results will be obtained prior to dosing during each period. A negative 
pregnancy result is required before the participant receives study treatment. In the case of a positive β-hCG test, the participant will be withdrawn from the study (Section 8.2.6).
l.
FSH for women < 60 years of age who are amenorrheic for at least 12 consecutive months and not using hormonal contraception or HRT.
m.
This should include eGFR and Cystatin-C.
n.
Collected pre-dose.
o.
Assessment of ASR is only applicable to the period in which administration occurs via OBI.
p.
On Day -1, only participants with OBI applied will need assessment of ISRs and ASRs.
q.
Predose (Hour 0) blood sample collected within 1 hour prior to dose administration. Hour 0 and at 10 min (0.167), 0.5, 1, 3, 6, 12, 16, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264 
and 288 hours post-dose. Also, see PK sampling schema (Table 2) for the listing of hours for each day for sample collection. For the OBI treatment period, PK collection should resume 
10 min (0.167 hrs) following the start of the injection and continue as shown.
r.
Collected pre-dose, and only collected in period 1.
s.
Participants will be tested for SARS-CoV-2 infection by PCR prior to being admitted to the clinic for confinement and a subsequent COVID-19 test will be performed if they develop 
COVID-19 like symptoms. Additional testing may be required by local regulations or by the Principal Investigator.
t.
Check exposure to positive case, residence or travel in area of high incidence and COVID-19 related signs and symptoms.  
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Table 2.
PK Sampling Schema – Periods 1 and 2
Visit Identifier 
Study Day
1
2
3
4
5
6
7
8
9
10
11
12
13
Hours After Dose
0a
0.167
0.5
1
3
6
12
16
24
48
72
96
12
0
144
168
192
216
240 264
288
Study treatment administration
X
PK blood sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Predose (Hour 0) sample collection within 1 hr prior to dose administration. For the PFS treatment period, Hour 0 is the time of SC injection. For the OBI treatment period, 
Hour 0 is the time when the OBI starts the injection; PK collection should resume 10 min (0.167 hrs) following the start of the injection and continue as shown.
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2. INTRODUCTION
PF-06881894 (pegfilgrastim), a US FDA approved biosimilar (Brand name: Nyvepria, 
pegfilgrastim-apgf) to US-approved Neulasta (Amgen, pegfilgrastim), is a colony-stimulating 
factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby 
stimulating proliferation, differentiation, commitment, and end cell functional activation.
The indications for this leukocyte growth factor are to:
•
Decrease the incidence of infection, as manifested by febrile neutropenia, in patients 
with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs 
associated with a clinically significant incidence of febrile neutropenia.
•
Increase survival in patients acutely exposed to myelosuppressive doses of radiation 
(Hematopoietic Subsyndrome of Acute Radiation Syndrome).
2.1. Study Rationale 
The PK comparability of PF-06881894 administered by PFS versus by OBI will be assessed 
in a single-dose comparative PK evaluation in healthy participants. Assessment of PK using a 
single-dose study design in healthy participants is expected to be the most sensitive setting to 
detect intrinsic differences in PK between the OBI and PFS presentations of PF-06881894.  
2.2. Background 
Neutropenia is a laboratory diagnosis and is defined as the reduction in the absolute number 
of neutrophils in the peripheral blood or circulation. Neutrophils are mature phagocytic 
leukocytes of the granulocyte series; are formed by bone marrow and released into 
circulation; are the predominant component of circulating white cells, and are the 
predominant leukocyte involved in inflammation. Circulating neutrophils actually represent 
only approximately 3% of the body’s total neutrophil numbers, with the vast majority in the 
bone marrow reserve pool and the remainder in the tissue and marginated pool attached to 
vascular endothelial cells.1
Neutropenia is generally characterized as mild, moderate, or severe based on the circulating 
ANC.2,3,4
•
Mild neutropenia: ANC 1000-1500/μL;
•
Moderate neutropenia: ANC 500-1000/μL;
•
Severe neutropenia: ANC <500/μL.
In general, only patients with severe neutropenia have been found to be at risk for major 
pyogenic infections and life-threatening infections, regardless of the underlying etiology of 
the neutropenia, congenital or acquired.2
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Myelosuppressive chemotherapy is an important iatrogenic cause of neutropenia. While 
within a given individual, many chemotherapeutic agents can be associated with neutropenia, 
there are a number of agents that are consistently associated with elevated risk for its 
development. These are consistent with the medical literature as well as national and 
international guidelines for management of CIN.3
Low ANC increases the risk of fevers (febrile neutropenia) and life-threatening infections.5,6
Febrile neutropenia is defined by the CTCAE Version 4.03, categorized as Grades 3 to 5 as 
follows:7
•
Grade 3: ANC <1000/mm3 (=1000/μL) and a single temperature of >38.3°C (101°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.
•
Grade 4: Life-threatening consequences; urgent intervention indicated.
•
Grade 5: Death.
Implications of CIN and febrile neutropenia are manifold and include infection and 
overwhelming sepsis and its associated complications, including death, increased risk for 
hospitalization as well as compromised oncologic outcomes including treatment delays, 
reduction in chemotherapeutic dose, or both. Neutropenia is a common dose-limiting adverse 
effect. As a result, patients can receive suboptimal cancer therapy leading to compromised 
outcomes, including increased morbidity and mortality and decreased survival.5,6,8-11
International guidelines for prevention and management of CIN include the consistent 
recommendation of use of supportive care with myeloid growth factors in patients 
undergoing myelosuppressive chemotherapy with a specified threshold of risk, generally of 
risk for at least 20% of patients receiving the myelosuppressive agent or regimen.2,11,12
Endogenous G-CSF is the primary regulating factor for neutrophils. The G-CSF acts by 
binding to G-CSF receptors located on the cell surface of the whole neutrophil lineage, 
resulting in stimulated proliferation, differentiation, commitment, and end cell functional 
activation. Endogenous G-CSF is known to stimulate proliferation of the mitotic cells, to 
reduce the maturation time of the non-mitotic cells in the bone marrow and to prolong the 
life-span and enhance the function of mature neutrophils. Endogenous G-CSF is produced by 
different cell types including macrophages, monocytes, fibroblasts, stromal cells in bone 
marrow, and endothelial cells. Endogenous G-CSF is triggered by inflammatory agents as 
well as by lipopolysaccharide released from bacteria.13
Recombinant human G-CSFs can vary slightly based on whether it is produced in 
Escherichia coli (filgrastim) or CHO cells (lenograstim). 
The filgrastim protein has an amino acid sequence that is identical to the natural sequence 
predicted from human DNA sequence analysis‚ except for the addition of an N-terminal 
methionine necessary for expression in E coli. Because filgrastim is produced in E coli‚ the 
product is non-glycosylated and thus differs from G-CSF isolated from a human cell or that 
of lenograstim.14,15
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Filgrastim is a water soluble 175 amino acid protein with a molecular weight of 
approximately 19 kD and is obtained from the bacterial fermentation of a strain of E coli
transformed with a genetically engineered plasmid containing the human G-CSF gene. 
G-CSFs, including filgrastim and pegylated filgrastim are leukocyte growth factors that act 
on hematopoietic cells by binding to specific cell surface receptors and stimulating 
proliferation‚ differentiation commitment‚ and some end-cell functional activation. The 
half-life of filgrastim is approximately 210 minutes, while pegylated filgrastim ranges from 
15 to 80 hours after subcutaneous injection.14,16 Based on its circulating half-life, filgrastim 
must be given daily to prevent or treat CIN whereas pegylated filgrastim can be administered 
less frequently; eg, once per chemotherapy cycle.
Protein pegylation is widely utilized to prolong the circulating half-life of biologic agents. 
Pfizer has developed a pegylated G-CSF, referred to as PF-06881894. The proposed 
pegylated recombinant human G-CSF is a covalent conjugate of recombinant methionyl 
G-CSF and a 20 kD mPEG molecule. The mPEG is covalently bound to the N-terminal 
methionyl residue of filgrastim.
For patients at risk of febrile neutropenia as defined by guidelines or individual patient risk, 
per label, G-CSF should not be administered until at least 24 hours after administration of 
cytotoxic chemotherapy. Historically, this meant that the patient would need to return to the 
healthcare clinic the next day after chemotherapy administration for G-CSF injection. The 
current presentation of US FDA approved Pfizer pegfilgrastim biosimilar (Nyvepria) is PFS
for SC delivery. In order to provide an additional option for pegfilgrastim for patients who 
cannot or do not wish to return to the clinic the next day after chemotherapy administration
for their injection, Pfizer has developed an on-body injector—a small, battery-powered, 
electromechanical drug delivery system that is applied to the patient’s skin on the day of 
chemotherapy to deliver a SC dose of PF-06881894 on the next day after chemotherapy. The 
objective of the proposed study is to assess the PK comparability of PF-06881894 
administered by OBI versus PFS as a single SC dose.
2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of PF-06881894 can be found in the current version 
of the IB.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Details of the nonclinical PK and metabolism of PF-06881894 can be found in the current 
version of the IB.
2.2.3. Nonclinical Safety
Details of the nonclinical safety of PF-06881894 can be found in the current version of the 
IB.
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2.2.4. Clinical Overview
PF-06881894 has been evaluated in 3 completed studies, C1221001 (ZIN-130-1505),
C1221002 (ZIN-130-1504), and C1221005. C1221001 was a PD and PK similarity study in 
which PF-06881894 was administered as 6mg/0.6mL PFS SC to healthy participants. This 
study demonstrated the PK/PD comparability of PF-06881894 to US-approved Neulasta 
(pegfilgrastim-US) and EU approved Neulasta (pegfilgrastim-EU). In the evaluable 136 PK 
participants administered with PF-06881894, the arithmetic means (SD) for AUCinf, AUClast,
Cmax, Tmax and t½ were 6,766,153  (4,880,797) h•pg/mL, 6,751,996 (4,882,297) h•pg/mL, 
188,422.1 (112,698.0) pg/mL, 18.61 (5.634) hours, 49.3963 (13.53258) hours, respectively.  
There were no clinically meaningful differences in safety across the PF-06881894, 
pegfilgrastim-US, and pegfilgrastim-EU study interventions, which overall were well-
tolerated in the healthy participants in this study. The safety results were consistent with the 
known safety profile of the reference product.
The C1221005 Phase 1 study assessed the immunogenicity of multiple SC doses of 
PF-06881894 and US-approved Neulasta (pegfilgrastim-US) in healthy volunteers. Results 
from this comparative immunogenicity study met the pre-specified criteria for non-inferiority 
of PF-06881894 vs pegfilgrastim-US with respect to immunogenicity, with no clinically 
meaningful differences in safety between the proposed biosimilar PF-06881894 and 
pegfilgrastim-US reference product.
The safety data from the 2 comparative clinical studies (C1221001 and C1221005) conducted 
in healthy participants support the safety of PF-06881894.
All participants who received at least 1 dose of the study drug (PF-06881894, pegfilgrastim-
US, or pegfilgrastim-EU) were included in the Safety Population. A total of 358 participants 
were exposed to at least 1 dose of PF-06881894 (148 participants in Study C1221001 and 
210 participants in Study C1221005); 356 participants received at least 1 dose of 
pegfilgrastim-US (146 participants in Study C1221001 and 210 participants in Study 
C1221005); 148 participants were exposed to at least 1 dose of pegfilgrastim-EU (Study 
C1221001 only).
Overall, no clinically meaningful differences between the safety profile of PF-06881894 and 
Neulasta were observed in the clinical studies, and results were similar to the established 
safety profile of Neulasta as reflected in the labels.16,17
Overall, the review of the TEAEs showed consistent information in participants administered 
PF-06881894 or pegfilgrastim-US and pegfilgrastim-EU in Studies C1221001 and 
C1221005. Most TEAEs were mild or moderate in severity in Study C1221001 and all 
TEAEs were mild or moderate in severity in Study C1221005. Both pegfilgrastim-US and 
pegfilgrastim-EU had results as anticipated from their known profile. No deaths were 
reported in the 2 comparative studies. Only 4 participants experienced treatment-emergent 
SAEs (3 participants in Study C1221001 and 1 participants in Study C1221005).
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A low number of participants discontinued the studies due to TEAEs (2 participants in Study 
C1221001 [1 due to non-drug-related abortion spontaneous and 1 due to drug-related rash 
generalized] and 2 participants in Study C1221005 [1 due to non-drug-related urinary tract 
infection and 1 due to drug-related angioedema]).
The safety data from the 2 comparative clinical studies conducted in healthy participants 
support comparability of the safety profile of PF-06881894 to Neulasta.
The C1221002 study was the IND-opening study when the plan was for development under a 
351(a) regulatory pathway and was designed to determine the relevant dose for use in the 
required Phase 3 efficacy and safety study. This was a Phase 1-2 study with an adaptive 
design that included assessments of 3 mg/0.3mL, and 6 mg/0.6mL, PF-06881894 PFS, 
administered as SC injection during Cycle 0 (Phase 1, in patients prior to definitive breast 
surgery and without background chemotherapy), and at Cycles 1-4 (Phase 2, in patients after 
definitive breast surgery and treated with TAC chemotherapy). During Cycle 0, 
12 participants received a single dose of 3 mg or 6 mg (6 participants for each dose) of 
PF-06881894; and during Cycles 1-4, 13 participants received multiple doses of 6 mg 
PF-06881894 (1 dose for each of the 4 cycles). In Phase 1, PD (ANC and CD34+) and PK 
results for the 3 mg dose tended to be lower than the results for the 6 mg dose of PF-
06881894 or Neulasta (published data); as a result, 3 mg was not initiated in Phase 2, Cycles 
1-4. Overall, the safety results were consistent with the known safety profile in patients 
treated with Neulasta, with and without myelosuppressive TAC chemotherapy. There were 
no immunogenicity concerns identified for PF-06881894 in the studied populations of breast 
cancer patients with and without chemotherapy.
2.3. Benefit/Risk Assessment
PF-06881894 is not expected to provide any clinical benefit to healthy participants. This 
study is designed primarily to generate PK data for further clinical development. In this 
study, PF-06881894 will be administered at single dose of 6 mg by OBI or by PFS.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06881894 may be found in the IB, which is the SRSD for this 
study. Data from the 2 comparative studies in healthy participants can be found in Section 6 
of the IB.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) PF-06881894 (pegfilgrastim)
Potential risks associated with PF-06881894
include but may not be limited to the following: 
potential allergic reactions; splenomegaly; splenic 
rupture; acute respiratory distress syndrome; 
alveolar haemorrhage; hemoptysis; leukocytosis; 
thrombocytopenia; capillary leak syndrome; 
cytokine release syndrome; cutaneous vasculitis; 
glomerulonephritis. These risks represent AESI for 
PF-06881894 (see Section 8.3.8).
Two SC injections will be administered using a 
PFS and OBI during the study, with a washout 
period of 56 days between doses. For those doses 
administered via the OBI, removal of the device
will occur following completion of the infusion. 
The same injection site (left or right side of the 
abdomen) will be used for both OBI and PFS for 
each participant, keeping at least 2 inches (5 cm) 
away from the belly button.
The potential risks for pegylated G-CSF are
based on safety information of Neulasta, as 
described in the Neulasta (Amgen) Package 
Insert16, and grouped by similar medical 
constructs. The AESIs were further informed 
based on the known extension of the 
pharmacology of the drug as manifested by 
known clinical adverse reactions with G-CSFs.
ISR has been reported previously in the 
completed PF-06881894 studies and can be found 
in Section 6 of the IB.
ISRs were identified during the post-approval use 
of pegfilgrastim products and ASRs (including 
events such as application site hemorrhage, 
application site pain, application site discomfort, 
application site bruise, and application site 
erythema) have been identified during the post 
approval use of the on-body injector for Neulasta.
Eligibility criteria have been selected to ensure 
that only appropriate participants are included in 
the study (see Section 5). AEs and clinical 
laboratory results will be monitored on an 
ongoing basis.
ISR Assessment will be performed daily from day 
-1* to Day 13.  *On Day -1 only participants with 
OBI applied will need assessment of ISRs and 
ASRs (see SoA and Section 8.2.7).
Device related risks:
Allergies to Acrylics: The OBI for PF-06881894
uses acrylic adhesive. For participants who have 
reactions to acrylic adhesives, use of this product 
may result in a significant reaction. Please see IB 
Section 7.11.1.3. Known Drug Class Effects and 
Other Human Experience for information regarding 
allergies to adhesives with the OBI for Neulasta.
Potential Device Failures: In the event of a missed 
or partial dose, study participants should be 
Risks and Adverse Drug Reactions seen in 
Neulasta OBI could also be seen for the OBI used 
in this study.
Missing a dose or receiving a partial dose could 
impact study results.
Exclusion criteria excludes participants with 
known hypersensitivity to acrylic adhesive (see 
Section 5). AEs, ISRs, ASRs and clinical 
laboratory results will be monitored on an 
ongoing basis.  
Confinement will enable increased observation of 
participants, should a reaction occur.
Suspected missed or partial doses due to OBI 
device malfunction should be reported via the 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
instructed to notify the principal investigator. 
Please see IB Section 7.11.1.3. Known Drug Class 
Effects and Other Human Experience for 
information regarding potential device failures with 
the OBI for Neulasta.
Adverse Drug Reactions:
There have been no adverse reactions to the OBI 
for PF-06881894 identified at this time. Please see 
IB Section 7.11.1.3. Known Drug Class Effects and 
Other Human Experience for information regarding 
adverse reactions identified during post approval 
use of the OBI for Neulasta.
Device Medical Complaint form 
(Section 8.3.10.3).
Potential fetal risk
Studies in animals have shown reproductive 
toxicity.
WOCBP who are unwilling or unable to use
highly effective method of contraception as
defined in the study protocol will be excluded
(See Section 5.3.4 and Appendix 4).
Potential risk of secreting into human milk
It is not known whether PF-06881894 is secreted
into human milk.
PF-06881894 should not be administered to
breastfeeding women and exposure during
breastfeeding should be reported to Pfizer Safety 
(See Section 8.3.5.2).
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2.3.2. Benefit Assessment
For healthy participants in this study, no clinical benefit is expected. 
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with PF-06881894 are clinically acceptable.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary:
Primary: 
•
PK comparability
•
To assess the PK comparability of 
PF-06881894 administered by OBI versus 
PFS as a single SC dose.
•
Cmax, AUClast and AUCinf (if data permits).
Secondary: 
Secondary: 
•
To characterize the PK of PF-06881894 OBI 
dosing presentation to PFS dosing presentation 
in healthy participants.
•
To assess the safety (including 
immunogenicity) of PF-06881894 OBI dosing 
presentation to PFS dosing presentation in 
healthy participants.
•
Tmax and t½ (if data permits).
•
AEs, including AESIs and device-related AEs; 
ISRs and ASRs.
4. STUDY DESIGN
4.1. Overall Design
This will be an open-label, randomized, 2-treatment, 2-period, crossover single-dose study in 
approximately 134 healthy adult participants enrolled at approximately 4 CRUs. There will 
be a washout period of at least 56 days between the 2 treatments. The order of treatment
administration will be randomized, with approximately 67 participants assigned to each 
treatment sequence. Dropouts may be replaced at the discretion of the investigator upon 
consultation with the sponsor.
Table 3.
Treatment Sequences
Sequence
Period 1
Washout
Period 2
1 (n=67)
Treatment A
At least 56 days
Treatment B
2 (n=67)
Treatment B
At least 56 days
Treatment A
Treatment A: PF-06881894, OBI, 6 mg administered as a single SC injection 
Treatment B: PF-06881894, PFS, 6 mg administered as a single SC injection
Screening evaluation will occur within 30 days prior to the first dose of study intervention in 
Period 1. Day -1 is defined as the day prior to the first day of dosing (Day 1) in each period.  
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Participants will be admitted to the CRU on Day -2, at 36-42 hours prior to Day 1 dosing, 
and will remain confined in the CRU until completion of all study activities on Day 5 during 
each period.  
There will be at least a 56-day washout period between administration of each study 
intervention to ensure the complete elimination of the drug. The total duration of 
participation in the study for each participant, excluding Screening, is approximately 12 
weeks.
On Day -1 of each period, the PF-06881894 OBI will be activated and applied on participants
randomized in the OBI arm. 
On Day 1 of each period, each participant will receive a single SC dose of 6 mg 
PF-06881894 administered by OBI or by PFS based on the randomization code. For those 
doses administered via the OBI, removal of the device will occur following completion of the 
infusion.
The same injection site (left or right side of the abdomen) will be used for both OBI and PFS 
for each participant, keeping at least 2 inches (5 cm) away from the belly button. The same 
needle angle (90°) for SC injection will be used for each participant in the OBI and PFS 
arms.
Blood samples for PK (3.0 mL) will be collected by either intravenous catheter or 
venipuncture into evacuated collection tubes within 1 hour prior to dose administration 
(Hour 0) and at 0.167 (10 min), 0.5, 1, 3, 6, 12, 16, 24, 48, 72, 96, 120, 144, 168, 192, 216, 
240, 264 and 288 hours post-dose. For the OBI treatment period, PK collection should 
resume 10 min (0.167 hrs) following the start of the injection and continue as shown. This 
sample collection scheme will adequately characterize the PK of pegfilgrastim following a 
single SC dose. 
Safety will be assessed for all treatments by monitoring AEs and other parameters defined in 
Section 8.
4.2. Scientific Rationale for Study Design
PF-06881894 (Nyvepria) is a pegylated recombinant human methionyl G-CSF that is a US 
FDA approved biosimilar to the licensed pegfilgrastim (reference product) approved in US
and EU in 2002 marketed as Neulasta® (Amgen). Pfizer is developing an OBI device, which 
is being designed to have similar features and perform equivalently, where applicable, to the 
Amgen OBI device from the Neulasta Onpro® Kit. Like the Amgen OBI device, the Pfizer 
OBI delivery device is intended to provide increased convenience to patients and improved 
compliance for dose administration at the pre-determined time. PF-06881894 is required to 
be injected no sooner than 24 hours after a patient receives chemotherapy. The Pfizer OBI 
device will be pre-programmed to automatically deliver PF-06881894 approximately 
27 hours after activation. This would eliminate the patient's need for a return visit to a 
hospital or other clinical setting the day after chemotherapy to receive PF-06881894, 
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facilitate the medication administration per the recommended dosing schedule, and provide 
an alternative for patients who do not wish to self-administer or to be administered by a 
caregiver. To demonstrate PK equivalence of PF-06881894 whether delivered using the OBI 
device or the PFS, this single dose study in healthy participants is designed, and is expected 
to be the most sensitive setting to detect intrinsic differences in PK between the OBI and PFS 
presentations of PF-06881894.
4.2.1. Reproductive Risk
There are no or limited amount of data from the use of pegfilgrastim in pregnant women. 
Studies in animals have shown reproductive toxicity. In pregnant rabbits, pegfilgrastim has 
been shown to cause embryo/fetal toxicity (embryo loss) at cumulative doses approximately
4 times the recommended human dose, which were not seen when pregnant rabbits were 
exposed to the recommended human dose. In rat studies, it was shown that pegfilgrastim may 
cross the placenta. Studies in rats indicated that reproductive performance, fertility, oestrous 
cycling, days between pairing and coitus, and intrauterine survival were unaffected by 
pegfilgrastim given subcutaneously. The relevance of these findings for humans is not 
known. See the IB for more details. Pegfilgrastim is not recommended during pregnancy and 
in women of childbearing potential not using contraception. All male participants who are 
able to father children and female participants who are of childbearing potential and are 
sexually active and at risk for pregnancy must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of PF-06881894.  
4.2.2. Collection of Retained Research Samples
Retained research samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
PF-06881894 6 mg administered by OBI or by PFS will be used in this study, and is the 
approved dose of the originator product Neulasta® (Amgen). The safety profile for the 6 mg 
dose is considered acceptable for healthy participants.
4.4. End of Study Definition
The end of the study is defined as the date the last participant completes the Period 2 Day 28
Visit.
A participant is considered to have completed the study if he/she has completed all periods of 
the study, including the Period 2 Day 28 Visit or Early Withdrawal Visit, shown in the SoA.
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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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. Healthy male and/or female participants who, at the time of screening, are between 
the ages of 18 and 65 years, inclusive.  
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants, for the definition of Woman of Childbearing 
Potential (Section 10.4.3), and for contraception methods (Section 10.4.4).
Type of Participant and Disease Characteristics:
2. Participants will include healthy individuals, with healthy being defined as no 
clinically relevant abnormalities identified by a detailed medical history, full physical 
examination, including BP and PR measurement, 12-lead ECG, chest X-ray, or 
clinical laboratory tests.
3. Participants agree to abstain from the use of tobacco- or nicotine-containing products 
for at least 90 days prior to dosing and have a negative urine screen for cotinine at 
Screening.
4. Participants agree to abstain from alcohol consumption for at least 48 hours prior to
Day 1 of dosing in each study period and have a negative screen for alcohol.
5. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
6. BMI between 19 and 30 kg/m2, inclusive, and body weight of not<50 kg or >100 kg.
Informed Consent:
7. 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.
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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, neurologic, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, injuries to subcutaneous tissue 
at the injection site).
3. Any clinically significant, as determined by the investigator, abnormal laboratory 
evaluations, including HIVAb, HBVsAg, HBVcAb, HCVAb and liver function taken 
at Screening. The negative HIVAb status will be confirmed at Screening, and all HIV 
results will be maintained confidentially by the study site.
4. History of malignancy, including current malignancy, with the exception of
adequately treated squamous or basal cell carcinoma of the skin or cervical carcinoma 
in situ within 5 years.
5. Surgery within the 4 months prior to Screening.
6. History of splenic rupture (or participant who is asplenic), pulmonary infiltrate or 
pneumonia, sickle cell disease, chronic neutropenia, thrombocytopenia, or vasculitis.
7. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
8. History of biological growth factor exposure, including but not limited to 
pegfilgrastim, filgrastim and other G-CSFs in the context of treatment, prophylaxis, 
peripheral blood stem cell mobilization, or previous investigational study setting. This 
also includes exclusion for history of interferon, epoetin, and IVIG exposure.
9. Receipt of live vaccination, or exposure to communicable viral diseases such as 
chicken pox, varicella, mumps, measles, or COVID-19 within the 4 weeks prior to 
Screening.
10. Use of any prescription medicine (with the exception of contraceptives) within 7 days 
or at least 5 half-lives, whichever was longer. Use of oral or parenteral anticoagulant 
or antiplatelet agents and corticosteroids should be specifically queried.
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11. Administration of a drug by depot injection (with the exception of depot 
contraception) within 30 days prior to the initial study drug administration or 
5 half-lives of that drug, whichever is longer.
12. Use of over the counter medications, including aspirin and non-steroidal 
anti-inflammatory drugs, or natural preparations (dietary supplement or herbal 
product) within 7 days of the first dose of PF-06881894 or at least 5 half-lives, 
whichever is longer. Vitamins and calcium supplements are allowed (not to exceed 
100% Daily Value). As an exception, acetaminophen/paracetamol may be used at 
doses of ≤1 g/day. Limited use of non-prescription 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.
13. Females using post-menopausal hormone replacement therapy may be eligible to 
participate in this study if they are willing to discontinue therapy at least 28 days prior 
to the first dose of study treatment and remain off hormonal therapy for the duration 
of the study. Hormonal contraceptives that meet the requirements of this study are 
allowed to be used in participants who are WOCBP.
Prior/Concurrent Clinical Study Experience:
14. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of study intervention (whichever 
is longer) prior to study entry and/or during study participation. If a participant 
receives a vaccine or other medical product for the prevention or treatment of 
COVID-19 authorized under an Emergency Use Authorization, this would not be 
considered an investigational medical product.
Diagnostic Assessments:
15. Hematologic laboratory abnormalities at screening or the Day -5 to Day -4 visit
including leukocytosis (defined as total leukocytes >11,000/μL), leukopenia (defined 
as total leukocytes <4000/μL), neutropenia (defined as ANC <1500/μL) or 
thrombocytopenia (defined as platelet count of <150,000/μL).
16. A positive urine drug test.
17. A positive SARS-CoV-2 infection determined by PCR at screening or Day -5 to 
Day -4, or determined by a positive COVID-19 antigen test (if performed as part of 
an investigator site policy). 
18. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of 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.
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19. Screening supine 12-lead ECG demonstrating QTc >450 msec or a QRS interval 
>120 msec. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be 
repeated two more times and the average of the three QTc or QRS values should be 
used to determine the participant’s eligibility. 
20. Participants with the following abnormalities in clinical laboratory tests at screening
or the Day -5 to Day -4 visit, as assessed by the study specific laboratory will be 
confirmed by a single repeat test, if deemed necessary. Then the investigator (in 
consultation with the medical monitor) will determine if the laboratory abnormality is 
clinically significant and sufficient to exclude the participant from the study. 
•
Lack of adequate hepatic reserve, defined by AST/SGOT or ALT/SGPT 
≥1.5 × ULN of the reference laboratory;
•
TBili ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have a 
direct bilirubin measured and would be eligible for this study provided the direct 
bilirubin is ≤ULN.
•
Lack of renal reserve, defined by serum creatinine of ≥1.2 × ULN for reference 
laboratory or eGFR of ≤ 80 mL/minute; or known history of glomerulonephritis.
Other Exclusions:
21. Drug sensitivity, allergic reaction to, or known hypersensitivity/idiosyncratic reaction 
to E coli -derived proteins, pegfilgrastim, filgrastim, other G-CSFs or any component 
of the product or known hypersensitivity to pegylated products or acrylic adhesives. 
Participants with the rare heredity problem of fructose intolerance are excluded due to 
the excipient sorbitol.
22. History of regular alcohol consumption exceeding 7 drinks/week for females or 
14 drinks/week for males (1 drink = 5 ounces [150 mL] of wine or 12 ounces 
[360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months of Screening.
23. History of sensitivity to heparin or heparin-induced thrombocytopenia.
24. Pregnant female participants, breastfeeding female participants, and male participants 
able to father children and female participants of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in 
this protocol for the duration of the study and for at least 28 days after the last dose of 
study intervention.
25. Blood donation (including plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing OR had a transfusion of any blood product within 
90 days prior to Screening.
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26. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.  Male participants with pregnant partners are not to be 
enrolled in the study, even if the participant is willing to comply with the 
contraception lifestyle requirements and use a highly effective method of 
contraception consistently and correctly for the duration of the study and for at least 
28 days after the last dose of study intervention.
27. 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 (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the 
pre-dose pharmacokinetic sample. Water is permitted until 1 hour prior to study 
intervention administration.  
•
Water may be consumed without restriction beginning 1 hour after completion of 
dosing. Non-caffeinated drinks may be consumed with meals and the evening snack.
•
Lunch will be provided approximately 4 hours after completion of dosing.
•
Dinner will be provided approximately 9 to 10 hours after completion of dosing.
•
An evening snack may be permitted.
•
While confined, the 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 will abstain from alcohol for 48 hours prior to Day 1 of dosing and 
continue abstaining from alcohol until collection of the final pharmacokinetic sample 
of each study period. Participants may undergo an alcohol breath test or blood alcohol 
test at the discretion of the investigator.
•
Caffeine-containing products are permitted, however participants should abstain 
within 2 hours of vital sign/ECG measurements.  
•
Participants will abstain from the use of tobacco- or nicotine-containing products 
during the study.  
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5.3.3. Activity
•
Participants will avoid getting body lotions, creams, oils or cleaning agents near the 
OBI as these products may loosen the adhesive; participants will keep the on-body 
injector dry for the last 3 hours prior to the dose delivery start; participants will be 
careful not to bump the OBI or knock the OBI off of their body. Refer to the complete
OBI Instructions for Use and the IP Manual.
•
Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 72 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted.
•
Participants will also be instructed to maintain their usual level of activity during the 
study when they are not in the study unit, with the exception that participants should 
refrain from collision sports as defined below and from professional or highly 
competitive university team contact sports such as basketball or soccer during the 
study period.
In collision sports (eg, boxing, ice hockey, rugby, [American] football, lacrosse, roller 
derby, and rodeo), athletes purposely hit or collide with each other or with inanimate 
objects (including the ground) with great force. In contact sports (eg, basketball and 
soccer), athletes routinely make contact with each other or inanimate objects but 
usually with less force than in collision sports. 
•
Exposure to communicable viral diseases such as COVID-19, varicella, mumps, or 
measles should be avoided during the study period. If such exposure occurs, it should 
be reported to the investigator.
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 from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception) considering that their risk for pregnancy may have changed since 
the last visit. In addition, the investigator or designee will instruct the participant to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the participant or partner.
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5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to pegfilgrastim-apgf administered 
by PFS or PF-06881894 administered by OBI.
6.1. Study Intervention(s) Administered
The OBI is to be used with the reference product PF-06881894 PFS 6 mg/0.6 mL solution for 
injection, 0.63 mL. The OBI and the PFS for OBI will be contained within the same kit.
PF-06881894 PFS 6 mg/0.6 mL solution for injection, 0.63 mL to be used with OBI –
Treatment A (Test Product), contains 0.63 mL to deliver 6 mg/0.6 mL subcutaneously with 
OBI.
Pegfilgrastim-apgf PFS 6 mg/0.6 mL solution for injection, 0.6 mL SC injection - Treatment 
B (Reference Product).
The pegfilgrastim PFS and OBI kits (containing OBI device and PFS for OBI) will be 
labeled according to local regulatory requirements and provided to the clinical site for 
dispensing. 
Pivotal BA/BE study PFS and OBI kits will be supplied to the clinical site in single dose 
labeled containers (in sufficient number to allow unopened containers to be kept as retains).
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive study intervention
at approximately 0800 hours (plus or minus 2 hours). Investigator site personnel will 
administer study intervention during each period. Administer study intervention according to 
the IP manual and the OBI Instructions for Use.
The pegfilgrastim-apgf PFS will be administered on Day 1 of Treatment Period 1 or Period 2
based on participant’s randomization.  The OBI will be applied on Day -1 of Treatment 
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Period 1 or Period 2, and PF-06881894 will be administered by the OBI on the following day 
(Day 1). 
A qualified staff member will dispense the study intervention via unique numbers on carton 
containing pegfilgrastim-apgf PFS 6 mg/0.6 mL solution for injection, 0.6mL; and/or
PF-06881894 PFS for OBI 6 mg/0.6 mL solution for injection, 0.63mL packaged with OBI 
device.
The site should be instructed to maintain the product in the cartons provided, and the cartons
should not be opened until the study intervention is to be administered. The following 
activities should be recorded by a member of the study site staff for each OBI applied during 
the study:
Date/time the OBI is activated – to activate the OBI both activation buttons should be 
pressed and held for 3 seconds, a double-beep will be heard, and then the buttons will flash 
amber for approximately 10 seconds and then flash green. Subsequent actions should occur 
as described in the OBI Instructions for Use. Study site staff should avoid delay in the 
insertion of the soft cannula.
Date/time of the start of injection via OBI – approximately 27 hours after activation the OBI
will produce a series of triple beeps, and dose delivery will begin approximately 2 minutes
later.  The OBI will produce a double beep to indicate the dose is beginning, and the green 
light will flash (this time should be recorded as the start of injection). The dose takes 
approximately 30 minutes to complete.
Date/time of the end of injection via OBI – when the dose delivery is complete a long beep 
will sound, and the status light will be solid green and then turn off.
Please reference the OBI Instructions for Use for complete instructions.
OBI device malfunction should be reported via the Device Medical Complaint form 
(Section 8.3.10.3).
6.1.2. Medical Devices
1. The manufactured medical devices provided for use in this study are the PFS that is 
used to administer pegfilgrastim-apgf and the OBI that administers the PF-06881894.  
2. Instructions for medical device use are provided in the IP manual and OBI 
Instructions for Use.
3. All medical device deficiencies (including malfunction, use error, and inadequate 
labeling) shall be documented and reported by the investigator throughout the study 
(see Section 8.3.10) and appropriately managed by the sponsor.
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6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. 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.
7. 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.
8. All pivotal BA/BE retained PFS and OBI kits should be stored by the investigator site 
or with a third-party vendor. Sample retention is the responsibility of the entity 
performing the BA or BE study.
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9. OBI devices utilized during the study will need to be stored in their original 
packaging at the investigator site and subsequently returned to the sponsor or 
designee.  
10. Any PFS or OBI involved in a product complaint should be quarantined in its original 
packaging, and the site staff should wait for further instruction.
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, or 
participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities.
See the IP manual and OBI Instructions for Use for instructions on how to prepare the study 
intervention for 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, state, and institutional guidance. A second staff member will verify the 
dispensing.
The PFS and PFS for OBI are single use. 
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
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 a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.4. Study Intervention Compliance
When participants are 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 clinic 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 
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study intervention. Study site personnel will examine each PFS and OBI device used for a 
participant to see whether the study intervention was administered.  
For the OBI treatment period, once the OBI medicine port has been filled, study site 
personnel will inspect the PFS to ensure the contents are empty, then inspect the fill indicator 
to ensure the yellow line aligns with the “full” icon on the fill indicator (solid drop). If this is 
not the case, the OBI should not be used; a new OBI kit should be utilized. Following dose 
delivery and removal of the OBI, study site personnel will check that the OBI is empty; the 
yellow line will align with the “empty” indicator (empty drop). Please reference the OBI 
Instructions for Use for complete instructions. 
For the PFS treatment period, study site personnel will inspect the PFS to ensure the contents 
are empty following administration of the PFS.
Suspected missed or partial doses due to OBI device malfunction should be reported via the 
Device Medical Complaint form (Section 8.3.10.3).  
For treatment of overdose please reference Section 6.7.
The site will complete the required dosage Preparation Record if instructed to do so 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
Dose modification for PF-06881894 is not allowed.
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.
6.7. Treatment of Overdose
The maximum amount of PF-06881894 that can be safely administered has not been 
determined. As per Nyvepria Package Insert, Overdosage of pegfilgrastim products may 
result in leukocytosis and bone pain. In the event of overdose, the patient should be 
monitored for adverse reactions.
For this study, any dose of PF-06881894 greater than 6 mg within a 24-hour time period will 
be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
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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 PF-06881894 (whichever 
is longer).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 14 days from the date of the last dose 
of study intervention if requested by the medical monitor (determined on a 
case-by-case basis).
6.8. Concomitant Therapy
6.8.1. Prior Treatments
Previous medication must be discontinued. Prescription medicine (with the exception of 
contraceptives) and over the counter medication, including aspirin and non-steroidal 
anti-inflammatory drugs, or natural preparations (dietary supplement or herbal product) must 
be discontinued at least 7 days (or 5 half-lives, whichever is longer) prior to the first dose of 
study intervention. Use of oral or parenteral anticoagulant or antiplatelet agents and 
corticosteroids should be specifically queried. Vitamins and calcium supplements are 
allowed and not to exceed 100% Daily Value. Drug by depot injection (with exception of 
depot contraception) must be discontinued within 30 days prior to the first dose of study 
intervention or 5 half-lives of that drug, whichever is longer.
Participants who have had treatment with another investigational drug within 30 days (or as 
determined by the local requirement) or 5 half-lives prior to the first dose of study 
intervention will not be accepted into the study. All previous medications (prescription and 
non-prescription drugs) taken within 7 days (or 5 half-lives, whichever is longer) prior to 
Randomization (drug by depot injection within 30 days or 5 half-lives, whichever is longer) 
will be documented on the source document and recorded on the eCRFs.
Receipt of live vaccination within the 4 weeks prior to screening is prohibited.
6.8.2. Permitted During the Study
Concomitant therapy refers to therapies used during the investigational period, eg during or 
after study drug dosing. The Investigator or designee will refrain from prescribing new 
medications during the study, unless clinically indicated for the treatment of AEs/SAEs. Use 
of multivitamins and calcium supplements are allowed and not to exceed 100% Daily Value. 
Limited use of non-prescription 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 
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discussion with and approval by the Sponsor. Restrictions on prior and concomitant 
medication are described in Section 5.2.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
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.
Treatments taken within 30 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.
6.8.3. Prohibited During the Study
If medication is required for medical treatment during the study (after study intervention
administration), the participant may be discontinued at the discretion of the Investigator or 
Sponsor.
If administration of any medication becomes necessary after the administration of study 
intervention through the end of the study, the name of the medication, dosage information 
including dose and frequency, date(s) of administration including start and end dates, and 
reason for use must be recorded in the source documents, and the eCRFs completed as 
appropriate.
Females taking post-menopausal hormone replacement therapy may be eligible to participate 
in this study if they are willing to discontinue therapy at least 28 days prior to the first dose 
of study intervention and remain off hormonal therapy for the duration of the study.
Receipt of live vaccination is prohibited during the study period.
No other prohibition for concomitant treatments are required for this study, as there have 
been no formal drug interaction studies between pegfilgrastim and other drugs performed
(Section 10.9).
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: AE, Physician 
Decision, Pregnancy, Protocol Deviation, No Longer meets an eligibility criteria, Study 
Terminated By Sponsor, Lost To Follow-Up, Medication Error without Associated AE, 
Death, Withdrawal By Subject, Refused further study procedures, and Other.
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If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
Note that discontinuation of study intervention does not represent withdrawal from the study.
If study intervention is permanently discontinued, the participant will remain in the study to 
be evaluated for 28 days after the last dose of study intervention. See the SoA for data to be 
collected at the time of discontinuation of study intervention and follow-up for any further 
evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.1.1. Pregnancy 
In the case of a positive confirmed pregnancy, the participant will be withdrawn from 
administration of study intervention. Please also see Section 8.2.6 Pregnancy Testing and 
Section 8.3.5.1 Exposure During Pregnancy.
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;
•
Death;
•
Study terminated by sponsor;
•
AE;
•
Medication Error without Associated AE
•
Physician Decision;
•
Pregnancy;
•
Protocol Deviation;
•
No longer meets an eligibility criteria;
•
Withdrawal by Subject;
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•
Other
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. See the SoA for assessments to be collected at the time of study 
discontinuation.
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.
The following actions must be taken if a participant fails to attend 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 
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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 30 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 30 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 
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.
ECGs should be obtained prior to vital signs.  ECGs and vital signs should be obtained as 
close as possible to scheduled time and prior to blood specimen collection. If an IV catheter 
is utilized for blood sample collections, ECGs and vital sign assessments (PR, BP, respiratory 
rate and tympanic temperature) should be collected prior to the insertion of the catheter.  
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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
240 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.
There may be instances when copies of medical records pertaining to follow-up for an 
abnormal result or AE are requested by Pfizer. In this case, all participant identifiers, with the 
exception of the participant number, must be redacted on the copies of medical records 
before submission to Pfizer.
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, spleen, lymph nodes, and gastrointestinal, 
musculoskeletal, and neurological systems. 
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 calibrated 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. 
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.
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8.2.2. Vital Signs
Vital signs (BP, PR, respiratory rate and tympanic temperature) will be measured at times 
specified in the SoA. Additional collection times or changes to collection times of vital signs 
will be permitted, as necessary, to ensure appropriate collection of safety data. 
8.2.2.1. BP and PR
Sitting BP will be measured with the participant’s arm supported at the level of the heart, 
with feet flat on the floor and back supported, 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.
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 PR is acceptable; however, when done 
manually, PR 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 PR should be 
obtained prior to the nominal time of the blood collection.
Additional collection times of BP and PR will be permitted, as necessary, to ensure 
appropriate collection of safety data.
8.2.2.2. Respiratory Rate
Assessment of respiratory rate should include the following general approach: Measure the 
respiratory rate after at least 5 minutes at rest. Observe the rise and fall of the subject’s chest 
and count the number of respirations for 1 full minute. One respiration consists of 1 complete 
rise and fall of the chest or the inhalation and exhalation of air. Observe the rhythm, ease, and 
strength of the respiration. Accurately document the respiratory rate.
8.2.2.3. Temperature
Temperature will be measured by a tympanic thermometer.
8.2.3. Electrocardiograms and Chest X-ray
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 QTc intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant
has rested quietly for at least 10 minutes in a supine position. Whenever possible, ECGs 
should not be collected within 3 hours after food or beverage consumption. Any 
abnormalities noted should be documented in the source document as clinically significant or 
clinically non-significant.
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 
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same positions each time in order to achieve precise ECG recordings. If there is a new 
occurrence of ECG abnormalities during the study that is judged to be clinically significant 
by the investigator, the investigator should report the event as AE and follow-up ECG should 
be conducted as appropriate. If a machine-read QTc value is prolonged, 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 7.
A posterior and lateral chest radiograph will be obtained at Screening and will be read by 
qualified site personnel.
8.2.4. 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 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
Minimum requirement for drug screening includes: cocaine, THC, opiates/opioids, 
barbiturates, benzodiazepines and amphetamines.
Participants may undergo random urine drug testing at the discretion of the investigator.
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
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8.2.5. COVID-19 specific assessments
A COVID-19 questionnaire should be completed at times listed in the SoA for each 
participant to check for exposure to a positive case, residence or travel in area of high 
incidence and COVID-19 related signs and symptoms. Participants will be tested for 
SARS-CoV-2 infection by PCR prior to being admitted to the clinic for confinement and a 
subsequent COVID-19 test will be performed if they develop COVID-19 like symptoms. 
Additional testing may be required by local regulations or by the Principal Investigator. Sites 
should follow their individual site practice guidelines for COVID-19 testing for symptomatic 
participants. If a test result is inconclusive or indeterminate at any visit, a repeat should be 
performed to gain a result of positive or negative.
If a participant has COVID-19 during the study, this should be reported as an AE or SAE and 
appropriate medical intervention provided.  It is recommended that the investigator discuss 
temporary or permanent discontinuation of study intervention with the study medical 
monitor.
8.2.6. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention. Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded if the serum pregnancy result is positive. In the case 
of a positive confirmed pregnancy, the subject will be withdrawn from administration of 
study intervention.
If a participant requiring pregnancy testing cannot visit a local laboratory, a home urine 
pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant 
to perform the test at home, if compliant with local regulatory requirements. The pregnancy 
test outcome should be documented in the participant’s source documents/medical records 
and relevant data recorded on the CRF. Confirm that the participant is adhering to the 
contraception method(s) required in the protocol.
8.2.7. Assessment ISRs and ASRs
Examinations for ISRs and ASR must occur at timepoints specified according to the SoA. If 
a participant develops an ISR or ASR, it must be documented at each subsequent time point 
in the SoA until resolution. In addition, ISRs and ASRs may also be captured during AE 
monitoring to document those reactions that may occur outside the scheduled assessments. 
All ISRs and ASRs will be reported as AEs.
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Reactions may include but are not limited to: erythema, induration, ecchymosis, pain, and 
pruritus. The severity of each ISR and ASR will be assessed and documented. If deemed 
appropriate by the investigator, a consultation with a dermatologist will be performed. 
Documentation may include a dermatologist report, clinic notes and photographs.
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Appendix 8. Device deficiencies are covered in Section 8.3.10.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant 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 
minimum of 28 calendar days after the last administration of the study intervention.  
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
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If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
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.
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 
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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.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 
•
A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.
•
A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.
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•
A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP:  
•
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by skin contact.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by 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 28 days after 
the last dose of study intervention.
•
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
•
Spontaneous abortion including miscarriage and missed abortion;
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•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 
•
A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.
•
A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
participant’s care. 
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The investigator must report 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
8.3.8. (Not Applicable)
8.3.9. Adverse Events of Special Interest
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes.
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.3.1 through 8.3.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
All AEs shall be assessed by the investigator or his/her designee during the administration of 
the drug to identify immediate reactions and any reaction reported within at least 28 days 
after last dose to include potential acute and delayed immunogenic reactions.
8.3.9.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.10. Medical Device Deficiencies
Medical devices are being provided for use in this study for the purposes of administration.
In order to fulfill regulatory reporting obligations worldwide, the investigator is responsible 
for the detection and documentation of events meeting the definitions of device deficiency
that occur during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 8.
Note: AEs and/or SAEs that are associated with a medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Sections 8.3.1 through 8.3.4 and 
Appendix 3 of the protocol.
8.3.10.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
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Importantly, reportable device deficiencies are not limited to problems with the device itself 
but also include incorrect or improper use of the device and even intentional misuse, etc.
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such deficiency is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Appendix 8.
8.3.10.2. Follow-Up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the investigator.
8.3.10.3. Prompt Reporting of Device Deficiencies to the Sponsor
When a device deficiency occurs: 
1. The investigator notifies the sponsor by email within 1 business day of determining 
that the incident meets the protocol definition of a medical device deficiency.  
2. The device deficiency must be recorded on the Medical Device Complaint Form.
3. If an AE (either serious or non-serious) associated with the device deficiency occurs, 
then the AE must be entered into the AE section of the CRF.
4. If an SAE associated with the device deficiency is brought to the attention of the 
investigator, the investigator must immediately notify Pfizer Safety of the SAE (see 
Section 8.3.1.1). All relevant details related to the role of the device in the event must 
be included in the CT SAE Report Form as outlined in Sections 8.3.1.1 and 8.3.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
The manufactured medical devices provided for use in this study are the PFS that is used to 
administer pegfilgrastim-apgf and the OBI that administers the PF-06881894 (Section 6.1.2).
8.3.10.4. Regulatory Reporting Requirements for Device Deficiencies
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
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The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
8.3.11. 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 3 mL, to provide a minimum of 1.5 mL serum, will be 
collected for measurement of serum concentrations of PF-06881894 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.
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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 up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples will be used to evaluate the PK of PF-06881894. Samples collected for analyses of
PF-06881894 concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study, for metabolite identification and/or evaluation of 
the bioanalytical method, or for other internal exploratory purposes.
Genetic analyses will not be performed on these serum samples. Participant confidentiality 
will be maintained.
Samples collected for measurement of serum concentrations of PF-06881894 will be 
analyzed using a validated analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.5. Genetics
8.5.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.5.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
banked samples.
See Section 10.5 Appendix 5 for information regarding genetic research. Details on processes 
for collection and shipment of these samples can be found in lab manual and other supporting 
documentation.
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8.6. Biomarkers
Biomarkers are not evaluated in this study.
8.6.1. Specified Gene Expression (RNA) Research
Specified gene expression (RNA) research is not included in this study.
8.6.2. Specified Protein Research
Specified protein research is not included in this study.
8.6.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.6.4. Retained Research Samples for Biomarkers
Banked biospecimens for biomarkers is not included in this study.
8.7. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the 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
The null hypothesis is PF-06881894 OBI is not equivalent to PF-06881894 PFS. 
Pharmacokinetic equivalence will be assessed by constructing the 90% CIs for the GMR 
(test/reference) for Cmax, AUClast and AUCinf. When the 90% CIs are completely contained 
within the acceptance limits of 80%‑125%, the null hypothesis is rejected.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
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Participant Analysis Set
Description
PK population
The PK population is defined as all participants 
randomized who are treated and have valid PK 
parameters in at least 1 treatment period.
Participants will be analyzed according to the 
treatment they are randomized to receive.
This will be the primary population to assess PK 
equivalence.
Participants with device failures/malfunctions that
could potentially impact drug delivery may not be 
included in the PK population analysis. Details 
will be described in the SAP.
Full Analysis Set
All participants who are randomized and take at 
least 1 dose of study intervention. Participants 
will be analyzed according to the treatment they 
were to receive based on randomization. 
Sensitivity analysis of PK parameters will be 
performed using the full analysis set.
Safety population
All participants who are randomized and take at 
least 1 dose of study intervention. Participants 
will be analyzed according to the treatment they 
actually receive based on randomization.
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 Analysis
Participants who receive at least 1 dose of study intervention and have sufficient valid data to 
calculate the primary PK parameters (Cmax, AUClast and AUCinf) will be included in the PK 
population. The PK population will be the primary analysis set for the primary PK analyses. 
PK comparability determination of the 2 treatments will be made on the PK population.
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PK parameters following single dose administration will be derived from the concentration 
time profiles by noncompartmental analysis as follows:
Parametera
Definition
Method of Determination
AUClast
Area under the serum drug 
concentration-time profile from 
time 0 to the last quantifiable 
concentration (Clast)
Linear-log trapezoidal method
AUCinfb
Area under the serum 
concentration-time profile from 
time 0 extrapolated to infinite 
time
AUClast + (Clast*/kel)
where Clast* is the predicted 
serum concentration at the last 
quantifiable time point estimated 
from the log-linear regression 
analysis
Cmax
Maximum serum concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as 
time of first occurrence
t½b
Terminal serum elimination 
half-life
Loge(2)/kel, where kel is the 
terminal phase rate constant 
calculated by linear regression of 
the log-linear concentration-time 
curve. Only those data points 
judged to describe the terminal 
log-linear decline will be used in 
the regression
a.
Actual PK sampling times will be used in the derivation of PK parameters
b.
If data permits.
The serum concentration time data from Day 1 through Day 13 from individual participants
will be analyzed by non-compartmental methods to determine the PK parameters. The 
primary PK parameters to be estimated will include Cmax, AUClast and AUCinf (if data 
permits). The secondary PK parameters to be estimated will include Tmax, and t½ (if data 
permits). Descriptive statistics for the PK parameters will be provided.  
Supporting data from the estimation of t½ and AUCinf will be listed: terminal phase rate 
constant (kel); goodness of fit statistic from the log-linear regression (r2); the percent of 
AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of time points 
used in the estimation of kel. 
Ninety percent (90%) CIs for the test to reference ratios (PF-06881894 OBI versus 
PF-06881894 PFS) for Cmax, AUClast and AUCinf will be constructed on a natural log scale 
using ANOVA with treatment, sequence and period as effects. PK similarity for a given test 
to reference comparison will be considered to be demonstrated if the 90% CIs for the test to 
reference ratios of Cmax, AUClast and AUCinf fall within the 80% - 125% BE window.
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9.3.2. Safety Analysis
All safety analyses will be performed on the safety population.
AEs including AESIs and device related AEs, ISRs, and ASRs, ECGs, vital signs, 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.
The following data summary tables will be generated to evaluate immunogenicity-related 
safety events for all participants:
•
Number and percentage of participants with ISR and ASR; 
•
Number and percentage of participants that meet Sampson’s Criteria
•
Number and percentage of participants who experienced hypersensitivity-related AEs 
(including anaphylactic reactions) using the relevant SMQs.
Physical examination (including spleen) and neurologic examination information, as 
applicable, 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 and/or neurologic examinations conducted after the administration of 
the first dose of study intervention will be captured as an AE, if those findings meet the 
definition of an AE. In addition to summaries of AEs by treatment that include all AEs, 
device-related AEs, AESIs, ISRs, and ASRs will also be summarized by treatment.  
9.3.3. Other Analyse(s)
Pharmacogenomic data from Retained Research Samples may be collected during or after the 
trial and retained for future analyses; the results of such analyses are not planned to be 
included in the CSR.
9.4. Interim Analyses
No formal interim analysis is planned for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment. 
9.5. Sample Size Determination
The study is powered for assessment of the primary PK parameters Cmax, AUClast and AUCinf. 
Assuming a within-participant coefficient of variation of 39% (based on Study C1221001) 
and a true ratio of 1.05, and an equivalence range of 80 to 125% of the test/reference mean 
ratio for Cmax, AUClast and AUCinf, a total of 134 enrolled participants will be required to 
demonstrate PK equivalence with 100 evaluable participants at approximately 90% power.
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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 
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 clinical 
monitoring plan, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study -site closure at any time upon notification to the sponsor
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 study portal.
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an 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 4.
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
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)
ALT, AST, LDH, GGT,
TBili
ALP
Uric acid
Albumin
Total protein
Cystatin-C and eGFR
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte 
esterase
Urobilinogen
Urine bilirubin
Microscopy and 
Culturea
Protein:creatinine 
ratio if urine is 
positive for
protein
FSHb
Urine drug 
screeningc
β-hCGd
Alcohol 
screeninge
Urine 
cotininef
Serologyf
(anti-HIVAb, 
anti-HCVAb, 
HBVsAg, 
HBVcAb) 
Screening 
only
SARS-CoV-2 
PCR
Enzyme/Liver Panel
ALT, AST,
ALP, LDH, GGT, TBili
Additional Tests (Needed for Hy’s law
assessment; 
See Appendix 6 of the protocol for additional 
information.):
AST, ALT (repeat)
TBili (repeat)
Albumin (repeat)
ALP (repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or
protein adduct levels
a.
Only if UTI suspected or urine result is positive for blood, protein, nitrites or leukocyte esterase.
b.
At Screening only, in females <60 years of age who are amenorrheic for at least 12 consecutive months and not 
using hormonal contraception or HRT. 
c.
At Screening and the Day -5 to Day -4 visit in Periods 1 and 2 and at the discretion of the investigator.  
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Table 4.
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
d.
Serum or urine β-hCG for females of childbearing potential.
e.
At Screening and Day -1 in Periods 1 and 2 and at the discretion of the investigator.
f.
At Screening.
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:
g. Results in death
h. 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.
i.
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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j.
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.
k. Is a congenital anomaly/birth defect
l.
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.
m. 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.
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
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF.
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE). **
Environmental or 
occupational exposure 
to the product under 
study to a non-
participant (not 
involving EDP or EDB).
None.  Exposure to a study 
non-participant is not 
collected on the CRF.
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE 
Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational 
exposure are reported to Pfizer Safety using the CT SAE Report Form. 
•
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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•
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 28 days 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
•
Vasectomy:
o
Considered a highly effective contraceptive method provided 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.
OR
•
Must agree to use contraception/barrier as detailed below:
•
Agree to use a male condom 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 pregnant or breastfeeding, and at 
least 1 of the following conditions applies:
•
Is not a WOCBP (see definitions below in Section 10.4.3);
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), as described below, during the intervention period and for at 
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least 28 days after the last dose of study intervention, which corresponds to the time 
needed to eliminate any reproductive safety risk of the study intervention(s). If a 
highly effective method that is user dependent is chosen, a second effective method of 
contraception, as described below, must also be used. The investigator should 
evaluate the effectiveness of the contraceptive method in relationship to the first dose 
of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. 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. 
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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).
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;
•
Injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation.
•
Oral;
•
Injectable.
8. Sexual abstinence.
•
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
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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: Genetics
Use/Analysis of DNA
•
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.
•
The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.
•
The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to PF-06881894 or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.
•
The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.
•
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
•
The samples will be retained as indicated:
•
Retained samples will be stored indefinitely or for another period as per local 
requirements.  
•
Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses.  
•
Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:
•
Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.
•
For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
•
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).
•
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
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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10.8. Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs, and Device Deficiencies: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting in 
Medical Device Studies
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this appendix are in accordance with ISO 14155
and the European MDR 2017/745 for clinical device research (if applicable). 
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6 for the list of sponsor medical 
devices).
10.8.1. Definition of AE and ADE
AE and ADE Definition 
•
An AE is defined in Appendix 3 (Section 10.3.1).
•
An ADE is defined as an AE related to the use of an investigational medical 
device. This definition includes any AEs resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as 
any event resulting from use error or from intentional misuse of the 
investigational medical device.
10.8.2. Definition of SAE, SADE, and USADE
SAE Definition:
•
An SAE is defined in Appendix 3 (Section 10.3.2).
SADE Definition
•
An SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of an SAE.
•
Any device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less 
fortunate.
USADE Definition
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•
A USADE is a serious adverse device effect that by its nature, incidence, 
severity, or outcome has not been identified in the current version of the risk 
analysis management file.
10.8.3. Definition of Device Deficiency
Device Deficiency Definition
•
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device 
deficiencies include malfunctions, use errors, and inadequate information 
supplied by the manufacturer.
10.8.4. Recording/Reporting and Follow-Up of Medical Device Deficiencies
Device Deficiency Recording
•
When a device deficiency occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.
•
The investigator will then record all relevant device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal 
clinical practice and will also capture the required information on the Medical 
Device Complaint Form.
•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of following the reporting process 
described in the Medical Device Complaint Form.
•
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.
•
If the investigator determines that the medical device deficiency may have 
injured the participant (ie, the medical device deficiency is associated with an AE 
or SAE), then the investigator will attempt to establish a diagnosis of the event 
based on signs, symptoms, and/or other clinical information. Whenever possible, 
the diagnosis will be documented in the participant’s medical record and 
recorded as the AE or SAE rather than the individual signs/symptoms. 
Requirements for recording and reporting an AE or SAE are provided in 
Appendix 3 (Section 10.3.3).
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•
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.
•
A remedial action is any action other than routine maintenance or servicing 
of a medical device where such action is necessary to prevent recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence.
Assessment of Causality Occurring in Conjunction With a Medical Device 
Deficiency
•
If an AE or SAE has occurred in conjunction with a medical device deficiency, 
the investigator must assess the relationship between each occurrence of the AE 
or SAE and the medical device deficiency. The investigator will use clinical 
judgment to determine the relationship.
•
A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
•
The investigator will also consult the IB in his/her assessment.
•
For each device deficiency, the investigator must document in the medical notes 
that he/she has reviewed the device deficiency and has provided an assessment of 
causality.
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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Follow-Up of Medical Device Deficiency
•
The investigator is obligated to perform or arrange for the conduct of
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the device 
deficiency as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.
•
New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint Form.
•
New or updated information regarding any SAE that was potentially associated 
with the medical device deficiency will be submitted to Pfizer Safety on the CT 
SAE Report Form within 24 hours of receipt of the information, according to the 
requirements provided in Appendix 3.
10.8.5. Reporting of SAEs
Reporting of an SAE to Pfizer Safety must be performed according to the processes 
described in Appendix 3 (Section 10.3.4).
10.8.6. Reporting of SADEs
SADE Reporting to Pfizer Safety 
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs (ie, a SADE) that must fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.
•
Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.
•
The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.
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10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI  
No formal drug interaction studies between pegfilgrastim and other drugs have been 
performed. 
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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
abs
absolute
ADE
adverse device effect
ADL
activity/activities of daily living
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
ASR
application site reaction
AST
aspartate aminotransferase
AUCextrap%
AUC extrapolated as a percentage of AUCinf 
AUCinf
area under the serum concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the serum drug concentration time profile from time 
0 to the last quantifiable concentration 
AV
atrioventricular
β-hCG
β-human chorionic gonadotropin
ΒΑ 
bioavailability 
BE
bioequivalence
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CI
confidence interval
CIN
chemotherapy-induced neutropenia
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Clast
last quantifiable concentration
Cmax
maximum serum concentration
CO2
carbon dioxide
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
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Abbreviation
Term
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Event
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
EC
ethics committee
ECC
Emergency Contact Card
ECG
electrocardiogram
eCRF
electronic case report form
E coli
Escherichia coli
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyl transferase
GMR
geometric mean ratio
HBVcAb
hepatitis B virus core antibody
HBVsAg
hepatitis B virus surface antigen
HCVAb
hepatitis C virus antibody
HIV
human immunodeficiency virus
HIVAb
human immunodeficiency virus antibody
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
ISO
International Organization for Standardization
ISR
injection site reaction
IV
Intravenous(ly)
IVIG
intravenous immunoglobulin
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Abbreviation
Term
kD
kilodalton
kel
terminal phase rate constant
LDH
lactate dehydrogenase
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
medical device regulation
MedDRA
Medical Dictionary for Drug Regulatory Activities
mPEG
monomethoxypolyethylene glycol
N/A
not applicable
OBI
on-body injector
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PFS
prefilled syringe
PK
pharmacokinetic
PR
pulse rate
PT
prothrombin time
PVC
premature ventricular contraction
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
RBC
red blood cell
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous(ly)
SD
standard deviation
SGOT
serum glutamic oxaloacetic transminase
SGPT
serum glutamic pyruvic transminase
SMQ
standardized MedDRA query
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
terminal serum elimination half life
TAC
taxotere, adriamycin, and cyclophosphamide
TBili
total bilirubin
TC
telephone call
TEAE
treatment-emergent adverse event
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Abbreviation
Term
THC
tetrahydrocannabinol
Tmax
time for Cmax
ULN
upper limit of normal
US
Unites States
USADE
unanticipated serious adverse device effect
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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11. REFERENCES
1.
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https://www.cancertherapyadvisor.com/home/decision-support-in-
medicine/pediatrics/management-of-neutropenia/. Accessed on 11 November 2021.
2.
Boxer LA. How to approach neutropenia. Hematology/the Education Program of the 
American Society of Hematology American Society of Hematology Education 
Program. 2012;2012:174-82.
3.
Flowers CR, Karten C. Communicating safe outpatient management of fever and 
neutropenia. Journal of oncology practice/American Society of Clinical Oncology. 
2013;9(4):207-10.
4.
Newburger PE, Dale DC. Evaluation and management of patients with isolated 
neutropenia. Seminars in hematology. 2013;50(3):198-206.
5.
Culakova E, Thota R, Poniewierski MS, Kuderer NM, Wogu AF, Dale DC, et al. 
Patterns of chemotherapy-associated toxicity and supportive care in US oncology 
practice: a nationwide prospective cohort study. Cancer medicine. 2014;3(2):434-44.
6.
Shayne M, Culakova E, Poniewierski MS, Dale DC, Crawford J, Wogu AF, et al. Risk 
factors for in-hospital mortality and prolonged length of stay in older patients with solid 
tumor malignancies. Journal of geriatric oncology. 2013;4(4):310-8.
7.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: 
May 28, 2009 (v4.03: June 14, 2010). U.S. Department of Health and Human Services, 
National Institutes of Health, National Cancer Institute. Available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. Accessed 07 April 2017.
8.
Lyman GH, Michels SL, Reynolds MW, Barron R, Tomic KS, Yu J. Risk of mortality 
in patients with cancer who experience febrile neutropenia. Cancer. 
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9.
Crawford J, Dale DC, Kuderer NM, Culakova E, Poniewierski MS, Wolff D, et al. Risk 
and timing of neutropenic events in adult cancer patients receiving chemotherapy: the 
results of a prospective nationwide study of oncology practice. Journal of the National 
Comprehensive Cancer Network: JNCCN. 2008;6(2):109-18.
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Gunalp M, Koyunoglu M, Gurler S, Koca A, Yesilkaya I, Oner E, et al. Independent 
factors for prediction of poor outcomes in patients with febrile neutropenia. Medical 
science monitor: international medical journal of experimental and clinical research. 
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11.
Mhaskar R, Clark OA, Lyman G, Engel Ayer Botrel T, Morganti Paladini L, 
Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile 
neutropenia. The Cochrane database of systematic reviews. 2014;10:CD003039.
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NCCN Clinical Practice Guidelines on Oncology (NCCN guidelines®), Myeloid 
Growth Factors. Version 1, 2018. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. Accessed on 
25 July 2018.
13.
Quartino AL, Karlsson MO, Lindman H, Friberg LE. Characterization of endogenous 
G-CSF and the inverse correlation to chemotherapy-induced neutropenia in patients 
with breast cancer using population modeling. Pharmaceutical research. 
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Neupogen® (filgrastim), United States Prescribing Information. June 2018. Amgen Inc.
Available: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103353s5194lbl.pdf
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GRANOCYTE (lenograstim), UK SmPC, March, 2018, Chugai Pharma UK Limited.
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Neulasta® (pegfilgrastim), United States Prescribing Information. April 2018. Amgen 
Inc. Available: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-
amgencom/
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Neulasta® (pegfilgrastim) SmPC. April 2019. Amgen Inc. Available: 
https://www.ema.europa.eu/en/documents/product-information/neulastaepar-product-
information_en.pdf. Accessed 25 Apr 2019. 
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