A MULTICENTER, OPEN-LABEL, MULTIPLE ASCENDING DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF SUBCUTANEOUS OR INTRAVENOUS PF-06741086 IN SUBJECTS WITH SEVERE HEMOPHILIA
Phase: PHASE2
Conditions: Hemophilia A or B
Sponsor: Pfizer

PF-06741086
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Final Protocol Amendment 4, 02 OCT 2017
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A MULTICENTER, OPEN-LABEL, MULTIPLE ASCENDING DOSE STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, 
PHARMACODYNAMICS, AND EFFICACY OF SUBCUTANEOUS OR 
INTRAVENOUS PF-06741086 IN SUBJECTS WITH SEVERE HEMOPHILIA
Compound:
PF-06741086
Compound Name:
Not applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-001885-27
Protocol Number:
B7841002
Phase:
1b/2
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Document History
Document
Version Date
Summary of Changes
Amendment 4
02 Oct 2017
Title

Removed “AND” from “AND/OR” to 
conform to previous amendment that 
removed a combination subcutaneous 
and intravenous dose.
General Changes Throughout Protocol

Editorial changes to fix titles, headers, 
grammar and typographical errors.
Schedule of Activities

Revised window for Day 2, Day 4, 
Day 30 and Day 33 visits to ± 1 day to 
allow for scheduling flexibility.

Added reference to FVIII and FIX 
inhibitor levels (to allow for inclusion 
of subjects with inhibitors) and CD4 
cell count (editorial change).
Protocol Summary

Added language allowing for the 
inclusion of subjects with inhibitors
against FVIII or FIX.

Added language excluding subjects 
with inhibitors who must use APCC 
(FEIBA) for bypass therapy and 
cannot substitute treatment with FVIIa 
(eptacog alfa [activated]) at 
approximately 90 µg/kg.
Section 1.2.1. Nonclinical Pharmacology 
and Pharmacokinetics

Added a summary of the nonclinical 
combination pharmacology data 
supporting the combination of 
PF-06741086 and FVIIa (eptacog alfa 

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[activated]).
Section 1.2.2. Nonclinical Toxicology

Added a summary of the nonclinical 
toxicology study data supporting 
6 months of treatment with of 
PF-06741086.
Section 1.3.2. Study Rationale

Added language allowing for the 
inclusion of subjects with inhibitors
Section 1.3.4. Summary of Risk/Benefit

Added language allowing for the 
inclusion of subjects with inhibitors
and the use of concomitant bypass 
agent therapy during
PF-06741086 treatment.
Section 2.1. Objectives

Added language allowing for the 
inclusion of subjects with inhibitors 
against FVIII or FIX.
Section 3. Study Design

Updated Figure 1 – Dose Progression 
Scheme to make it easier to 
understand. 
Section 3.1. Planned Number of Subjects

Added language stating that subjects 
with inhibitors will be enrolled into 
cohorts currently open for enrollment.
Section 3.3. Dose Escalation and Stopping 
Rules

Revised language to clarify dose 
progression definition, in order to 

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Summary of Changes
allow for a cohort at a previously 
studied dose to be evaluated if 
necessary.
Section 4.1. Inclusion Criteria
•
Revised Inclusion Criterion #4 to 
remove language prohibiting subjects 
with inhibitors against Factor VIII or 
Factor IX.
•
Added Inclusion Criterion #5 to 
establish criteria for subjects with 
inhibitors to FVIII or FIX.
•
Revised Inclusion Criterion #6 to add 
language on washout requirements for 
bypass agent therapy.
Section 4.2. Exclusion Criteria
•
Removed Exclusion Criterion 
#5 which prohibited subjects with 
inhibitors (≥ 0.6 Bethesda Units [BU])
from eligibility.
•
Revised Exclusion Criterion #6 to 
remove the exclusion of FVIIa
(eptacog alfa [activated]) subjects, and 
revise the exclusion of APCC treated 
subjects to those subjects who cannot 
substitute treatment with factor VIIa 
(at a dose level of approximately 
90 μg/kg) for the duration of the 
study.
Section 4.3. Randomization Criteria
•
Added language on washout 
requirements prior to Day 1 for FVIIa 
bypass agent therapy.
Section 5. Study Treatments
•
 
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Section 5.3.1. Dosage Form(s) and 
Packaging
•
Section 5.7.1. Prohibited Medications
•
Added language on washout 
requirements for bypass agent therapy.
•
Revised language regarding
prohibitions against the use of FVIIa 
bypass therapy, including restricting 
use to approximately 90 μg/kg, and 
added language stating that subjects 
using APCC therapy, who cannot 
switch to FVIIa therapy, are not 
eligible for the study.
Section 5.7.2. Treatment for Acute 
Bleeding Episodes
•
Added language allowing for FVIIa 
bypass therapy at approximately 
90 μg/kg for acute bleeding episodes.
Section 6.1. Screening
•
Added a review of inhibitor history 
and a review of bypass agent therapy 
use to Screening activities.
•
Added reference to CD4 cell count.
Section 6.2.1. Day 1 Visit
•
Added a review of bypass agent 
therapy use to Day 1 activities.
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Section 6.2.2. Day 2 (1 day) and Day 
4 Visit (1 day)

Revised window for Day 2 and Day 4, 
to ± 1 day to allow for scheduling 
flexibility.
Section 6.2.4. Day 30 (1 day) and Day 
33 Visit (1 day)

Revised window for Day 2 and Day 4, 
to ± 1 day to allow for scheduling 
flexibility.
Section 7.1.1 Laboratory Tests

Added reference to FVIII and FIX 
inhibitor levels (to allow for inclusion 
of subjects with inhibitors) and CD4 
cell count (editorial change).
Section 7.2.1. Hemophilic Bleeding 
Episodes

Added language to include the use of 
bypass agent therapy for assessing
bleeding episodes.
Section 7.2.1. Treatment of Bleeding 
Episodes

Added language to include FVIIa 
bypass agent therapy as a treatment of 
bleeding episodes.
Section 9.2.1. Analysis of the Efficacy 
Endpoint

Added language to specifiy analyses 
for inhibitor subjects.
Amendment 3
12 December 2016
Section 3.3. Dose Escalation and Stopping 
Rules

Removed language in dose escalation 

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section that maintained subjectivity in 
stopping rules.  Objective set of criteria 
for stopping rules is now listed in 
Section 3.3.

Added reference to the NIAID DMID 
criteria for adverse event grading for dose 
escalation criteria.  Grade 3 adverse 
events will all qualify as dose-limiting 
toxicities, as specified in Appendix 2.

Deleted statement on analysis of 
thrombotic events by background of 
prothrombotic conditions, as these 
subjects are no longer eligible for the 
study.

Removed all references to investigator 
attribution of causality.

Added objective criterion for 
dose-escalation stopping rules based on 
tolerability.

Added criteria and plans for dose 
modifications for individual subjects with 
our without a dose-limiting toxicity.
Section 4.1. Inclusion Criteria

Revised Inclusion Criterion #2 to state 
that only adult subjects (18 to 65 years of 
age) are eligible for the study.
Section 4.2. Exclusion Criteria

Added Exclusion Criterion #4 to state that 
subjects with pro-thrombotic conditions 
are excluded from the study.
Appendix 2

Changed title of Appendix 2 to “Criteria 
for Dose Limiting Toxicity”

Added severe/Grade3 TEAE criterion as a 

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dose limiting toxicity.

Added reference to the NIAID DMID 
criteria for toxicity grading.
Amendment 2
02 November 2016
General Changes Throughout Protocol

Removed “and/or” clause for routes of 
administration as subjects will not be 
administered via both IV and SC 
routes of administration.

Editorial changes to fix titles, headers, 
grammar and typographical errors.
Protocol Title Page

Added US IND # to protocol.
Protocol Summary

Added requirement for episodic 
(on-demand) treatment for inclusion to 
the study.

Removed option for 
self-administration by subjects for SC 
cohorts and specified visits for SC 
cohorts.

Added text stating that adverse events 
will be graded by the WHO scale.
Schedule of Activities:
Table 1

Footnote (i): deleted reference to an 
IV loading dose and SC doses.  This 
will not be administered in this study.

Footnote (j): deleted reference to 
recording information in the subject 
diary on self-administration.
Table 2

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
Revised table headers to remove 
references to treatment 
self-administration and specify visits 
for SC cohorts.

Footnote (h):  revised text to mimic 
Footnote (j) in Table 1.

Revised inaccurate reference to 
Footnote (g) in the header row of 
Table 2 to the correct Footnote (f).
Section 1.2.1. Nonclinical Pharmacology

Updated exposure multiples based on data 
from completed first-in-human study.
Section 1.3.1.1. Overall Safety

Added a brief statement on the final safety 
data from the B7841001 first-in-human 
study. 
Section 1.3.1.2. Plasma Pharmacokinetics 
of PF-06741086 Following Administration 
of Single IV and SC Doses of PF-06741086

Added a new section to detail final PK 
data from the B7841001 first-in-human 
study.
Section 1.3.1.3. Pharmacodynamics of 
PF-06741086 Following Administration of 
Single IV and SC Doses of PF-06741086

Added a new section to detail final PD 
data from the B7841001 first-in-human 
study.
Section 1.3.3. Dose Rationale

Added a new section (1.3.3.1 Starting 
Dose) to detail justification for the 
300 mg starting dose.

Revised nominal doses planned for 

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Cohorts 2 through 4 added to new 
section (1.3.3.2 Dose Progression).  
Starting dose and route of 
administration for Cohort 1 did not 
change.

Table 4: updated PK projections for 
the revised nominal doses in 
Section 1.3.3.
Section 3. Study Design

Figure 1 was updated to include 
revised nominal doses planned for 
Cohorts 2 through 4.  The title was 
revised from “Dose Escalation 
Scheme” to “Dose Progression 
Scheme” as planned doses may not be 
escalating.

Updated bullet list below Figure 1 to 
include revised nominal doses planned 
for Cohorts 2 through 4.  Removed 
reference to “dose escalating fashion” 
as planned doses may not be 
escalating.
Section 3.2. Study Duration

Removed option for 
self-administration for SC cohorts and 
specified visits for SC cohorts.
Section 3.3. Dose Escalation and Stopping 
Rules

Removed the requirement for “clinical 
significance” from all stopping 
criteria, to make the criteria less 
subjective.

Added text indicating that vessel 
occlusion secondary to venous 
catheter placement may be excluded 
from the stopping criteria.  Also added 

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text that thrombotic adverse events 
will be evaluated based against 
baseline pro-thrombotic risk factors.

Added a stopping criterion for the 
review of all adverse events, without 
regard to organ class or relationship to 
treatment.
Section 4.1. Inclusion Criteria

Inclusion Criterion #5:  criterion was 
revised to state that only patients 
currently treated with episodic 
(on-demand) factor replacement 
therapy are eligible for this study.
Section 4.4. Lifestyle Guidelines

Added text indicating that 
contraception requirements may be 
extended if new data from 
B7841002 warrant such a change.
Section 5.2. Subject Compliance

Removed option for 
self-administration for SC cohorts and 
specified visits for SC cohorts.
Section 5.3.2. Preparation and Dispensing

Removed option for 
self-administration.
Section 5.4.  Administration

Removed option for 
self-administration.
Section 5.5. Investigational Product 
Storage

Removed option for 

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self-administration.

Revised section on temperature 
monitoring to conform to Sponsor 
requirements for active monitoring.
Section 5.6. Investigational Product 
Accountability

Removed option for 
self-administration.
Section 5.7. Concomitant Treatment(s)

Added a requirement for investigator 
to contact the Sponsor medical 
monitor to review concomitant 
treatment in the case of emergency or 
unplanned surgery.
Section 5.7.1. Prohibited Medications

Added text indicating that additional 
washout time may be necessary 
depending on the coagulation factor 
product in use.
Section 6.2.3. Day 8 (1 day), Day 
15 (2 days), Day 22 (2 days) and 
Day 29 (2 days) at Clinic Visits

Removed reference to IV loading dose
as there will not be an IV and SC route 
of administration.

Added a bullet to indicate Day 
29 administration of IP for IV cohorts 
only, to conform with the Schedule of 
Activities.
Section 6.2.5. Day 36 (2 days), Day 
43 (2 days) and Day 50 (2 days) at Clinic 
Visits

Removed reference to IV loading dose

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as there will not be an IV and SC route 
of administration.

Removed option for 
self-administration.  Removed 
requirement for collection of 
self-administration on subject diary.
Section 6.2.6. Day 57 (2 days) at Clinic 
Visit

Removed option for 
self-administration.  Removed 
requirement for collection of 
self-administration on subject diary.
Section 6.2.7. Day 64 (2 days), Day 
71 (2 days) and Day 78 (2 days) at Clinic 
Visits

Removed reference to IV loading dose
as there will not be an IV and SC route 
of administration.

Removed option for 
self-administration.  Removed 
requirement for collection of 
self-administration on subject diary.
Section 6.2.8. Day 85 (2 days) at Clinic 
Visit 

Removed option for 
self-administration.  Removed 
requirement for collection of 
self-administration on subject diary.
Section 6.3.1. Day 113 (7 days) at Clinic 
Visit

Removed option for 
self-administration.  Removed 
requirement for collection of 
self-administration on subject diary.

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Section 6.4. Subject Withdrawal

Removed option for 
self-administration.  Removed 
requirement for collection of 
self-administration on subject diary.
Appendix 1

Added Appendix 1 to list thrombotic 
adverse events that would qualify for 
stopping criteria.
Amendment 1
09 September 2016
Protocol Title Page
Added EudraCT # to protocol.
Section 4.1 – Inclusion criteria
Revised inclusion criterion #2 to 
restrict subjects from 12 and 
<18 years of age to cohorts at a dose 
level and route of administration 
previously studied which has not met 
the protocol safety criteria for 
termination of dose escalation.  This 
change was implemented to comply 
with regulatory requests in the EU.
Original protocol
09 April 2016
Not applicable 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................20
LIST OF FIGURES .................................................................................................................20
APPENDICES .........................................................................................................................20
PROTOCOL SUMMARY.......................................................................................................21
SCHEDULE OF ACTIVITIES................................................................................................23
1. INTRODUCTION ...............................................................................................................29
1.1. Mechanism of Action/Indication.............................................................................29
1.2. Background .............................................................................................................29
1.2.1. Nonclinical Pharmacology and Pharmacokinetics .....................................30
1.2.2. Nonclinical Toxicology ..............................................................................31
1.3. Rationale..................................................................................................................33
1.3.1. Clinical Experience with PF-06741086......................................................33
1.3.1.1. Overall Safety............................................................................33
1.3.1.2. Plasma Pharmacokinetics of PF-06741086 Following 
Administration of Single IV and SC Doses of PF-06741086............33
1.3.1.3. Pharmacodynamics of PF-06741086 Following 
Administration of Single IV and SC Doses of PF-06741086............34
1.3.2. Study Rationale...........................................................................................34
1.3.3. Dose Rationale............................................................................................35
1.3.3.1. Starting Dose.............................................................................35
1.3.3.2. Dose Progression.......................................................................36
1.3.4. Summary of Risk/Benefit ...........................................................................37
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................37
2.1. Objectives................................................................................................................37
2.1.1. Key Secondary Objective ...........................................................................37
2.1.2. Secondary Objectives .................................................................................37
2.2. Endpoints.................................................................................................................38
2.2.1. Primary Endpoints - Safety.........................................................................38
2.2.2. Secondary Endpoints ..................................................................................38
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3. STUDY DESIGN.................................................................................................................39
3.1. Planned Number of Subjects...................................................................................41
3.2. Study Duration ........................................................................................................41
3.3. Dose Escalation and Stopping Rules.......................................................................42
4. SUBJECT SELECTION......................................................................................................44
4.1. Inclusion Criteria.....................................................................................................44
4.2. Exclusion Criteria....................................................................................................45
4.3. Randomization Criteria ...........................................................................................46
4.4. Lifestyle Guidelines ................................................................................................47
4.5. Sponsor’s Qualified Medical Personnel..................................................................48
5. STUDY TREATMENTS.....................................................................................................49
5.1. Allocation to Treatment ..........................................................................................49
5.2. Subject Compliance.................................................................................................49
5.3. Investigational Product Supplies.............................................................................49
5.3.1. Dosage Form(s) and Packaging..................................................................49
5.3.2. Preparation and Dispensing........................................................................50
5.4. Administration.........................................................................................................50
5.5. Investigational Product Storage ..............................................................................50
5.6. Investigational Product Accountability...................................................................51
5.6.1. Destruction of Investigational Product Supplies ........................................51
5.7. Concomitant Treatment(s).......................................................................................51
5.7.1. Prohibited Medications...............................................................................52
5.7.2. Treatment(s) for Acute Bleeding Episodes.................................................52
6. STUDY PROCEDURES .....................................................................................................53
6.1. Screening.................................................................................................................53
6.2. Study Period ............................................................................................................55
6.2.1. Day 1 Visit..................................................................................................55
6.2.2. Day 2 (-6 hours/+1 day) and Day 4 (-6 hours/+1 day) PK/PD Blood 
Draws ...............................................................................................................57
6.2.3. Day 8 (1 day), Day 15 (2 days), Day 22 (2 days) and Day 29 (2 
days) Visits.......................................................................................................58
6.2.4. Day 30 (-6 hours/+1 day) and Day 33 (-6 hours/+1 day) PK/PD 
Blood Draws at Clinic Visits ...........................................................................60

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6.2.5. Day 36 (2 days), Day 43 (2 days) and Day 50 (2 days) Visits.............60
6.2.6. Day 57 (2 days) Visit................................................................................61
6.2.7. Day 64 (2 days), Day 71 (2 days) and Day 78 (2 days) Visits.............62
6.2.8. Day 85 (2 days) Visit................................................................................62
6.3. Follow-up Visit/End of Study .................................................................................64
6.3.1. Day 113 (7 days) Visit..............................................................................64
6.4. Subject Withdrawal.................................................................................................65
7. ASSESSMENTS..................................................................................................................67
7.1. Safety.......................................................................................................................68
7.1.1. Laboratory Tests .........................................................................................68
7.1.2. Physical Examinations................................................................................69
7.1.3. Blood Pressure and Pulse Rate ...................................................................69
7.1.4. Respiratory Rate .........................................................................................69
7.1.5. Temperature................................................................................................70
7.1.6. Electrocardiogram.......................................................................................70
7.1.7. Injection and Infusion Site Reactions.........................................................70
7.2. Efficacy ...................................................................................................................71
7.2.1. Hemophilic Bleeding Episodes...................................................................71
7.2.2. Bleeding......................................................................................................71
7.2.3. Types of Bleeding.......................................................................................71
7.2.4. Location of Bleeds......................................................................................72
7.2.5. Treatment of Bleeding Episodes.................................................................72
7.3. Pharmacokinetics (PK)............................................................................................73
7.3.1. Plasma for Analysis of PF-06741086.........................................................73
7.3.2. Shipment of Pharmacokinetic Samples ......................................................73
7.4. Immunogenicity ......................................................................................................73
7.4.1. Immunogenicity Analyses ..........................................................................73
7.4.2. Plasma for Analysis of ADA (Anti-PF-06741086) and NAb.....................74
7.4.3. Shipment of Immunogenicity Samples.......................................................74
7.5. Pharmacodynamics..................................................................................................74
7.5.1. Pharmacodynamic Markers ........................................................................74
7.5.1.1. Samples for TFPI Level ............................................................74

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7.5.1.2. Samples for Thrombin Generation............................................74
7.5.1.3. Samples for Prothrombin Fragment 1 and 2 and D-dimer........75
7.5.1.4. Samples for Dilute Prothrombin Time......................................75
7.5.2. Shipment of Pharmacodynamic Samples ...................................................75
7.7. Blood Volume .........................................................................................................77
7.8. Triggered Requirements..........................................................................................78
8. ADVERSE EVENT REPORTING......................................................................................79
8.1. Adverse Events........................................................................................................79
8.2. Reporting Period .....................................................................................................79
8.3. Definition of an Adverse Event...............................................................................79
8.3.1. Adverse Events of Special Interest.............................................................80
8.4. Medication Errors....................................................................................................80
8.5. Abnormal Test Findings..........................................................................................81
8.6. Hemophilia Events ..................................................................................................81
8.7. Serious Adverse Events...........................................................................................81
8.7.1. Protocol-Specified Serious Adverse Events...............................................82
8.7.2. Potential Cases of Drug-Induced Liver Injury............................................82
8.8. Hospitalization ........................................................................................................83
8.9. Severity Assessment................................................................................................84
8.10. Causality Assessment............................................................................................85
8.11. Exposure During Pregnancy..................................................................................85
8.12. Occupational Exposure .........................................................................................86
8.13. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................87
8.14. Eliciting Adverse Event Information ....................................................................87
8.15. Reporting Requirements........................................................................................87
8.15.1. Serious Adverse Event Reporting Requirements .....................................87
8.15.2. Adverse Events of Special Interest...........................................................88
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8.15.3. Nonserious Adverse Event Reporting Requirements ...............................88
8.15.4. Sponsor’s Reporting Requirements to Regulatory Authorities ................88
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................88
9.1. Sample Size Determination.....................................................................................88
9.2. Efficacy Analysis ....................................................................................................88
9.2.1. Analysis of the Efficacy Endpoint..............................................................88
9.3. Analysis of Pharmacokinetic Endpoints .................................................................89
9.4. Analysis of Pharmacodynamic Endpoints...............................................................89
9.6. Safety Analysis........................................................................................................90
9.6.1. Derivation of Vital Signs Parameters .........................................................90
9.6.2. Electrocardiogram (ECG) Analysis............................................................91
9.7. Interim Analysis ......................................................................................................91
9.8. Data Monitoring Committee ...................................................................................92
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................92
11. DATA HANDLING AND RECORD KEEPING .............................................................92
11.1. Case Report Forms/Electronic Data Record .........................................................92
11.2. Record Retention...................................................................................................93
12. ETHICS..............................................................................................................................93
12.1. Institutional Review Board/Ethics Committee......................................................93
12.2. Ethical Conduct of the Study ................................................................................94
12.3. Subject Information and Consent..........................................................................94
12.4. Subject Recruitment ..............................................................................................95
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................95
13. DEFINITION OF END OF TRIAL...................................................................................95
13.1. End of Trial in a Member State.............................................................................95
13.2. End of Trial in All Other Participating Countries.................................................95
14. SPONSOR DISCONTINUATION CRITERIA ................................................................96
15. PUBLICATION OF STUDY RESULTS..........................................................................96
15.1. Communication of Results by Pfizer ....................................................................96
15.2. Publications by Investigators ................................................................................97
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16. REFERENCES ..................................................................................................................98
LIST OF TABLES
Table 1.
Study Flow Chart – Screening and Treatment Period (Day -34 to Day 29).........23
Table 2.
Study Flowchart – Treatment and Follow-up Period (Day 30 to Day 113) .........27
Table 3.
Descriptive Summary of Plasma PF-06741086 Pharmacokinetic 
Parameters Following Single SC and IV Doses, Study B7841001 ......................34
Table 4.
Estimated PK and Nonclinical Safety Margins for Planned PF-06741086 
Doses.....................................................................................................................36
Table 5.
Laboratory Tests ...................................................................................................68
Table 6.
Blood Volume for SC Cohorts .............................................................................77
Table 7.
Blood Volume for IV Cohorts..............................................................................78
LIST OF FIGURES
Figure 1.
Dose Progression Scheme.....................................................................................40
APPENDICES
Appendix 1. Thrombotic Adverse Events for Stopping Criteria ...........................................102
Appendix 2. Criteria for Dose Limiting Toxicity..................................................................103

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PROTOCOL SUMMARY
Study B7841002 is a Phase 1b/2, open-label, multiple ascending dose clinical study in 
subjects with severe hemophilia A or B, with or without inhibitors to Factor VIII (FVIII) or 
Factor IX (FIX).  This study is designed to evaluate the safety, tolerability, pharmacokinetics 
(PK), pharmacodynamics (PD) and efficacy of multiple subcutaneous (SC) or intravenous 
(IV) doses of PF-06741086, a monoclonal antibody that targets tissue factor pathway 
inhibitor (TFPI). 
TFPI is an antagonist of the extrinsic coagulation pathway.  PF-06741086, through its 
neutralization of TFPI, is expected to increase coagulation activity.  Study B7841002 will 
assess the effect of PF-06741086 on various measures of coagulation, including the number 
of acute bleeding episodes during a 3-month treatment period as a measure of prophylaxis 
efficacy.  Satisfactory safety, tolerability, PK, PD and efficacy data from this study are 
intended to support the development of PF-06741086 as a monotherapy for prophylactic 
treatment to prevent or reduce the frequency of bleeding episodes in patients with hemophilia 
A or B with or without inhibitors. 
Subjects with severe hemophilia A or B (defined by factor VIII or factor IX activity 1%), 
including subjects with inhibitors to factor VIII or factor IX (positive inhibitor test result
[above the upper limit of normal]), who receive bypass agents as primary treatment for 
bleeding episodes) will be recruited into B7841002.  Subjects with inhibitors who are 
currently treated with activated prothrombin complex concentrate (APCC, eg, FEIBA) and 
cannot substitute treatment with recombinant factor VIIa (rFVIIa, eptacog alfa [activated]) as 
their standard of care for treatment of acute bleeding episodes (at a dose level of 
approximately 90 µg/kg) for the duration of the study are not eligible.  Subjects must be on 
an episodic (on-demand) treatment regimen at the time of study enrollment and also have a 
documented history of at least 6 acute bleeding episodes in the 6 months prior to study 
enrollment.  Subjects must washout from any factor replacement or bypass agent therapy 
prior to screening and prior to study treatment.
Subjects who meet the eligibility criteria will be assigned to a PF-06741086 treatment cohort, 
defined by a specific dose level, dose frequency and route of administration.  Subjects will be 
treated with PF-06741086 for up to 3 months, with a maximum of 5 months expected for 
overall study participation.  Approximately 24 subjects (4 treatment cohorts with 6 subjects 
per cohort) are planned to be treated.  The planned number of subjects, cohorts, dose levels,
dose frequencies and route of administration may change depending on the results from each 
cohort dosed in the study.
Subjects will be required to attend weekly clinic visits during the first month of the study 
(Day 1 to Day 29).  An additional two clinic visits at Day 2 and Day 4 will be required for 
PK/PD blood draws.  Through Day 29 (at a minimum), data will be reviewed to determine if 
PF-06741086 is safe and well tolerated.  Dosing of subjects in any cohort may be stopped if 
the B7841002 protocol-specified stopping criteria are met, or if available data indicate that 
the current dose is not safe and well tolerated.  If available safety, tolerability and PK data 
through Day 29 are permissive for dose escalation, a cohort at a higher dose level (SC or IV 
administration) may be opened for enrollment.  Alternatively, a cohort at a lower dose level 
may be opened if data are supportive.

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Page 22
In addition, if the dose level under review is safe and well tolerated through Day 29, 
treatment will continue for the subjects in that respective cohort during the subsequent
2 months (Day 30 to Day 85).  During this period, clinic visits at Day 30 and Day 33 will be 
required for PK/PD blood draws for all cohorts.  Subjects in the SC cohorts will receive
treatment on Day 36, Day 43, Day 50, Day 57, Day 64, Day 71, Day 78, follow-up on 
Day 85, and end-of-study procedures on Day 113.  Subjects in the IV cohort will return to the 
clinic for treatment on Day 57, follow-up on Day 85, and end-of-study procedures on 
Day 113.  Follow-up beyond Day 113 may be required for any subjects that test positive for 
an anti-drug or neutralizing antibody during the study.
There is no formal statistical hypothesis planned for testing in B7841002.  There is no formal 
sample size calculation informing cohort sample size or overall study sample size.  The 
cohort sample sizes and overall study sample size are based on clinical considerations to 
balance the need to minimize exposure of study subjects to the test article with the need to 
provide adequate safety, tolerability, PK, PD and efficacy data at each dose level and/or route 
of administration.  Additional subjects and/or cohorts may be enrolled in the event that the 
number of dosing cohorts or size of dosing cohorts is increased to fully explore the dose 
range and/or clinical profile at the respective dose levels.
Safety endpoints will include treatment emergent adverse events (graded by the NIAID
DMID severity scale), infusion/injection site reactions, laboratory parameters that may be 
modulated due to coagulopathy (eg, prothrombin time [PT]/INR, activated partial 
thromboplastin time [aPTT], fibrinogen, antithrombin III [ATIII], platelet counts) and 
parameters to screen for possible thrombotic events (eg, cardiac troponin I).  PK and PD 
endpoints include concentrations of PF-06741086 in plasma, non-compartmental PK 
parameters, measures of target binding by PF-06741086 (ie, TFPI level) or downstream 
pharmacological activities of TFPI inhibition (ie, dilute PT, thrombin generation, 
prothrombin fragment 1+2, and D-dimer).  Prophylaxis efficacy will be assessed by 
collecting the number of acute bleeding episodes per subject during the treatment period of 
3 months and determining the annualized bleed rate (ABR) for comparison against historical 
data.  These data will be summarized descriptively for each cohort and the overall study.
Demonstration of safety, tolerability and a PK/PD/efficacy profile that is supportive for 
long-term chronic treatment on an acceptable dosing schedule will allow for progression of 
PF-06741086 to subsequent investigations in patients with severe hemophilia A or B.

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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Table 1.
Study Flow Chart – Screening and Treatment Period (Day -34 to Day 29)
Protocol Activity
Screening
Treatment
Visit Identifier
Screening
Day 1
Day 2
PK/PD Blood 
Draw
Day 4
PK/PD Blood 
Draw
Day 8
Day 15
Day 22
Day 29
Visit window relative to
end of Day 1 IP 
administration
Day -34 to 
Day 0
-6 hours/+1 day
-6 hours/+ 1 day
1 day
2 days
2 days
2 days
Informed consent
X
Medical history 
(including 
hemophiliahistory and 
bleeding episodes over 
past 6 months)
X
Medication history
X
X
Demography, Height
X
Physical examinationa
X
X
X
X
X
X
Weight
X
X
X
Contraception 
instructions/checkb
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
ECGd
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
Hematologye
X
X
X
X
X
X
Factor VIII and Factor IX 
activity
X
X

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B7841002
Final Protocol Amendment 4, 02 OCT 2017
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Table 1.
Study Flow Chart – Screening and Treatment Period (Day -34 to Day 29)
Protocol Activity
Screening
Treatment
Visit Identifier
Screening
Day 1
Day 2
PK/PD Blood 
Draw
Day 4
PK/PD Blood 
Draw
Day 8
Day 15
Day 22
Day 29
Visit window relative to
end of Day 1 IP 
administration
Day -34 to 
Day 0
-6 hours/+1 day
-6 hours/+ 1 day
1 day
2 days
2 days
2 days
Factor VIII and Factor IX 
inhibitor levels (for 
subjects with a 
hemophilia history of 
inhibitor only)
Xk
CD4 cell count
Prothrombin 
20210 mutation testing
X
Factor V Leiden mutation 
testing
X
Lipid profilef
X
Protein C activity/Protein 
S level 
X
Serology: HBs Ag, HBc 
Ab, HCV Ab and HIV
X
Banked biospecimens
(Prep D1)
X
TFPI level
Xg
X
X
X
X
X
X
PT/INR
X
X
X
X
X
X
aPTT
X
X
X
X
X
X
Fibrinogen
X
X
X
X
X
X
Anti-thrombin III 
X
X
X
X
X
X
Thrombin Generation 
(TGA)
Xg
X
X
X
X
X
X
Prothrombin fragment 
1+2 (PF1+2)
Xg
X
X
X
X
X
X
D-dimer
Xg
X
X
X
X
X
X
Dilute prothrombin time 
(dPT)
Xg
X
X
X
X
X
X
Cardiac Troponin I
X
X
X
X
X
PK blood sampling
Xg
X
X
X
X
X
Xg

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Final Protocol Amendment 4, 02 OCT 2017
Page 25
Table 1.
Study Flow Chart – Screening and Treatment Period (Day -34 to Day 29)
Protocol Activity
Screening
Treatment
Visit Identifier
Screening
Day 1
Day 2
PK/PD Blood 
Draw
Day 4
PK/PD Blood 
Draw
Day 8
Day 15
Day 22
Day 29
Visit window relative to
end of Day 1 IP 
administration
Day -34 to 
Day 0
-6 hours/+1 day
-6 hours/+ 1 day
±1 day
±2 days
±2 days
±2 days
Immunogenicity (ADA, 
NAb)
X
X
X
Inclusion/exclusion 
criteria review
X
X
Treatment assignmenth
X
Investigational Product 
administration
X
Xi
Xi
Xi
X
Subject diaryj
X
X
X
X
X
Collect information on
new bleeding episodes 
X
→
→
→
→
→
→
→
Monitoring infusion/ 
injection site reactions
X
→
→
→
→
→
→
Adverse event monitoring
X
→
→
→
→
→
→
→
Concomitant treatments
X
→
→
→
→
→
→
→
Abbreviations: →= ongoing/continuous event; ADA = anti-drug antibodies; aPTT = activated partial thromboplastin time; ECG = electrocardiogram; HBc Ab = hepatitis B core 
antibody; HBs Ag = hepatitis B surface antigen; HCV Ab = hepatitis C antibody; HIV = human immunodeficiency virus; hr = hours; IP = investigational product; 
N/A = not applicable; NAb = neutralizing antibodies; PK = pharmacokinetic; PT/INR = prothrombin time/international normalized ratio; TFPI = tissue factor pathway inhibitor
a.
A full physical examination (PE) will be conducted during Screening.  On and after Day 1 and at the discretion of the Investigator, limited examinations based on signs and 
symptoms will be performed, if clinically indicated to assess changes from baseline/previous visits of any ongoing symptoms.
b.
Instructions will be provided at Screening and at Follow-up/End of Study visit; contraception check will be performed at other visits. A longer duration of contraception 
usage may be required if data from B7841002 warrant this change. 
c.
Vital signs to be assessed include pulse rate, respiratory rate, oral temperature, and supine blood pressure.
d.
Triplicate ECG required at Day 1.  Single ECG required at additional time points unless ECG is abnormal, in which case a triplicate ECG is required.
e.
Differential hematology panel required at Days 1, 29, 85 and 113. 
f.
Subjects must be fasting for 12 hours prior to blood draw.
g.
One sample will be drawn prior to IP administration for both the subcutaneous (SC) and intravenous (IV) routes of administration.  For IV administration only, collect a 
second sample from the arm not used for IV IP administration immediately (0 to 5 minutes) following completion of the IV infusion and line flush.
h.
Treatment assignment may occur at any time prior to dosing once subject has met all eligibility criteria.
i.
IP is administered at these visits for cohorts with SC administration only.
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j.
Subject diary dispensed and/or collected.  Subject diary is reviewed, including information about study compliance bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions. At Day 1, subjects will be provided training with respect to filling out the diary including timing and nature of 
information to be entered.
k.
FVIII and FIX inhibitor levels must be determined by a local laboratory.  A positive inhibitor test result will be above the upper limit of normal for the assay. Inhibitor test 
results from up to 6 months prior to Day 1 may be used to meet this requirement.

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Final Protocol Amendment 4, 02 OCT 2017
Page 27
Table 2.
Study Flowchart – Treatment and Follow-up Period (Day 30 to Day 113)
Protocol Activity
Treatment
Follow-up/End 
of Studyf
Visit Identifier
Day 30
PK/PD
Blood Draw
Day 33
PK/PD
Blood Draw
Day 36
(SC Cohort)
Day 43
(SC Cohort)
Day 50
(SC 
Cohort)
Day 57
Day 64
(SC Cohort)
Day 71
(SC Cohort)
Day 78
(SC Cohort)
Day 85
Day 113
Visit Window
relative to end of 
Day 29 IP 
administration
-6 hours/+ 
1 day
-6 hours/+ 
1 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
±7 days
Physical 
examinationa
X
X
X
Weight
X
X
X
Contraception 
instructions/checkb
X
X
X
Vital Signsc
X
X
X
Urinalysis 
X
X
X
Serum chemistry
X
X
X
Hematologyd
X
X
X
TFPI level
X
X
X
X
X
PT/INR
X
X
X
aPTT
X
X
X
Fibrinogen
X
X
X
Thrombin 
Generation (TGA)
X
X
X
X
X
Prothrombin 
fragment 1+2
(PF1+2)
X
X
X
X
X
D-dimer
X
X
X
X
X
Dilute prothrombin 
time (dPT)
X
X
X
X
X
PK blood sampling
X
X
Xe
X
X
Immunogenicity 
(ADA, NAb)
X
X
Xf
 
Investigational 
Product 
administration
Xg
Xg
Xg
X
Xg
Xg
Xg
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C
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Final Protocol Amendment 4, 02 OCT 2017
Page 28
Table 2.
Study Flowchart – Treatment and Follow-up Period (Day 30 to Day 113)
Protocol Activity
Treatment
Follow-up/End 
of Studyf
Visit Identifier
Day 30
PK/PD
Blood Draw
Day 33
PK/PD
Blood Draw
Day 36
(SC Cohort)
Day 43
(SC Cohort)
Day 50
(SC 
Cohort)
Day 57
Day 64
(SC Cohort)
Day 71
(SC Cohort)
Day 78
(SC Cohort)
Day 85
Day 113
Visit Window
relative to end of 
Day 29 IP 
administration
-6 hours/+ 
1 day
-6 hours/+ 
1 days
2 days
2 days
2 days
2 days
2 days
2 days
2 days
2 days
7 days
Subject diaryh
X
X
X
X
X
X
X
X
X
Collect information 
on new bleeding 
episodes










X
Monitoring 
infusion/ injection 
site reactions










X
Adverse event 
monitoring










X
Concomitant 
treatment










X
Discharge from 
study
X
Abbreviations: = ongoing/continuous event; ADA = anti-drug antibodies; aPTT = activated partial thromboplastin time; ECG = electrocardiogram; HBc Ab = hepatitis B core 
antibody; HBs Ag = hepatitis B surface antigen; HCV Ab = hepatitis C antibody; HIV = human immunodeficiency virus; hr = hours; min = minutes; IP = investigational product; 
N/A = not applicable; NAb = neutralizing antibodies; PK = pharmacokinetic; PT/INR = prothrombin time/international normalized ratio; TFPI = tissue factor pathway inhibitor
a.
On and after Day 1, limited physical examinations based on signs and symptoms will be performed, if clinically indicated, at the discretion of the Investigator, to assess 
changes from baseline/previous visits of any ongoing symptoms.
b.
Instructions provided at Screening and at Follow-up/End of Study visit, contraception check at other visits.  A longer duration of contraception usage may be required if data 
from B7841002 warrant this change. 
c.
Vital signs to be assessed include pulse rate, respiratory rate, oral temperature, and supine blood pressure.
d.
Differential hematology panel required at Days 1, 29, 85 and 113.
e.
One PK sample will be drawn prior to IP administration for both the SC and IV routes of administration.  For IV administration only, collect a second sample from the arm 
not used for IV IP administration immediately (0 to 5 minutes) following completion of the IV infusion and line flush.
f.
Subjects with positive ADA or NAb may be required to attend additional, unscheduled follow-up visits following Day 113.
g.
IP is administered at these visits for cohorts with SC administration only. IP may be administered by investigator site personnel in a home care or ambulatory clinic setting in 
countries where it is approved by the respective competent authority and at sites where it is approved by the respective IRB/EC. 
h.
Subject diary dispensed and/or collected.  Subject diary is reviewed, including information about study compliance, bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions.  At Day 1, subjects will be provided training with respect to filling out the diary including timing and nature of 
information to be entered.

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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06741086 is a human monoclonal immunoglobulin of the G isotype, subclass 1 (IgG1) 
that targets the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI).  PF-06741086 is 
in development as a prophylactic treatment to prevent or reduce the frequency of bleeding 
episodes in individuals with severe hemophilia A or B with or without inhibitors.
Protocol B7841002 is a first-in-patients safety and pharmacology study with PF-06741086.  
This study will provide the initial clinical assessment of the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of PF-06741086 following 
administration of subcutaneous (SC) or intravenous (IV) doses at ascending dose levels.  
Data on bleeding events will be collected to evaluate the therapeutic efficacy of 
PF-06741086.  Study B7841002 will also assess the effect of PF-06741086 on various 
measures of coagulation.  Satisfactory safety, tolerability, PK and PD data from this study are
intended to support the development of PF-06741086 as a prophylactic treatment in 
hemophilia.
1.2. Background 
The current standard of care for treatment of individuals with hemophilia A or B is 
replacement of their deficient clotting factor using factor VIII (FVIII) or factor IX (FIX) 
clotting factor concentrate, respectively.1 This replacement therapy is administered to treat 
or prevent acute bleeding episodes, to provide hemostasis during surgery, invasive 
procedures and the subsequent wound healing period, or to provide routine prophylaxis to 
prevent bleeding episodes.  However, a subset of patients with hemophilia develop 
neutralizing antibodies (inhibitors) directed against FVIII or FIX, reducing the effectiveness 
of factor replacement therapy as a first-in-line therapy for prophylaxis against or treatment of 
hemophilia bleeding episodes.2 For patients who respond to clotting factor replacement, the 
IV administration route and frequency of infusion required for effective prophylaxis 
treatment remains burdensome, and may result in reduced adherence and compromised 
prophylactic efficacy.  As well, venous access for IV administration of clotting factor 
concentrates is limited in the youngest pediatric patients with hemophilia.  In these patients,
indwelling central venous catheters are frequently required to assure venous access with the 
attendant infectious and thrombotic complications.  Thus, an unmet medical need exists for a 
standalone SC or low frequency IV intervention to promote hemostasis and coagulation in 
patients with hemophilia in lieu of coagulation factor replacement therapy.
TFPI is a protease inhibitor which acts as an antagonist of the extrinsic coagulation pathway 
via inhibition of tissue factor-activated coagulation factor VII (FVIIa) and activated 
factor X (FXa).3 TFPI has two isoforms, TFPIand TFPI.  The two isoforms share two of 
the same Kunitz-type domains (K1 and K2), but TFPIlacks the K3 domain.  Isoforms are 
distributed in plasma and on vascular endothelial cell surfaces through 
glycosylphosphatidylinositol anchors.  TFPIis also located in platelets.  Available data 
indicates that a reduced quantity of TFPI in plasma is associated with faster coagulation 
times and increased thrombin generation.4 Individuals with TFPI free antigen at the 
5th percentile and 2nd percentile have an odds ratio for deep vein thrombosis that 

PF-06741086
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Final Protocol Amendment 4, 02 OCT 2017
Page 30
is 2.1- and 2.2-fold that of the general population, respectively, indicating a wide therapeutic 
index is associated with modulation of TFPI activity.5 Additionally, single doses of 
PF-06741086 have been evaluated in a Phase 1 first-in-human study without significant 
adverse effects. These results suggest that TFPI may serve as an acceptable target for a 
pharmaceutical treatment to reduce inhibition of the extrinsic coagulation pathway and
thereby increase clotting activity in patients with bleeding disorders, such as hemophilia. 
1.2.1. Nonclinical Pharmacology and Pharmacokinetics
Analysis at the molecular level demonstrated that PF-06741086 targets an epitope in the 
K2 domain.  Surface Plasmon Resonance (SPR) was used to characterize 
PF-06741086 binding affinity and kinetics of binding to human, cynomolgus monkey, rabbit, 
mouse, and rat TFPI 
.  The 
neutralization of TFPI by PF-06741086 was measured using a number of in vitro functional 
assays.  The analysis included FXa chromogenic activity assays which measure reversal of 
TFPI inhibition of Factor Xa or FXa/FVIIa/TF complex in purified systems.  
PF-06741086 promoted hemostasis in hemophilic plasma from hemophilia A, B, and 
hemophilia inhibitor plasma and in non-hemophilic plasma as measured in thrombin 
generation assays (TGA), and dilute prothrombin time (dPT) assays.  
PF-06741086 inhibitory activity was also demonstrated using thromboelastography (TEG) 
performed on whole non-hemophilic blood.  PF-06741086 also improved the thrombin 
generation response of severe hemophilia plasma dosed with rFVIIa (eptacog alfa 
[activated]).  The efficacy of PF-06741086 was demonstrated in injury models of hemostasis 
using Factor VIII deficient mice (model of hemophilia A) and Factor IX deficient mice 
(model of hemophilia B).  PF-06741086 restored hemostasis in hemophilia mouse injury 
models when administered before and after the onset of a bleeding injury.  The 
pharmacodynamic profile of PF-06741086 is consistent with its TFPI inhibitory activity.
The cumulative pharmacodynamic and potential additive effects of the combined, repeated 
dose administration of PF-06741086 and NovoSeven®RT (rFVIIa) was evaluated in rats in 
a 10-day IV investigative study. 
 
 
 
 
 
 
  
 
 
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Separate safety pharmacology studies were not conducted with PF-06741086, but safety 
pharmacology endpoints evaluating the potential effects of PF-06741086 on the respiratory, 
cardiovascular (CV), and central nervous systems (CNS) were included in the 13-week 
toxicity study in monkeys.
The nonclinical pharmacokinetics (PK) strategy supported the nonclinical pharmacology and 
nonclinical safety evaluation of PF-06741086.  The PK of PF-06741086 was characterized in 
Wistar Han rats, New Zealand White rabbits and cynomolgus monkeys following 
intravenous (IV) and/or subcutaneous (SC) dosing of PF 06741086.  Validated assays were 
used to support the toxicokinetic (TK) and anti-drug antibody (ADA) evaluations in the 
repeat-dose toxicity and toxicokinetic studies in Wistar Han rat and cynomolgus monkeys 
conducted under Good Laboratory Practices (GLP).  The 
pharmacokinetics-pharmacodynamic (PK/PD) relationships for PF-06741086 were 
characterized in cynomolgus monkeys.
Additional information regarding PF-06741086 may be found in the single reference safety 
document (SRSD), which for this study is the Investigator Brochure.
1.2.2. Nonclinical Toxicology
The toxicity of intravenously or subcutaneously administered PF-06741086 was evaluated in 
nonpivotal 
 8-day, repeat-dose studies in rats and monkeys and pivotal (GLP) 
studies in rats and monkeys 
.  The IV and SC 
routes of administration were selected for these studies since they are the intended routes of 
clinical exposure.  Rats and monkeys were chosen as the nonclinical species because 
PF-06741086 binds to TFPI in these species.  The use of rats and monkeys in nonclinical 
toxicology studies is further justified by evidence of pharmacological activity, such as 
decreases in fibrinogen (FIB) and increases in D-dimer, in both species in repeat-dose 
toxicity studies.  Both species demonstrated drug exposure following IV or SC 
administrations and target organ toxicity; therefore the rat was suitable for use as the only 
species for evaluating chronic toxicity.  Other toxicity studies included tissue cross reactivity 
assay, FcR and C1q binding assays, and a cytokine release assay.  Genetic toxicity studies 
were not conducted because they are generally not appropriate for biotechnology-derived 
products.  
 
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PF-06741086 was administered to rats and monkeys by intravenous (IV) and subcutaneous 
(SC) injection, in studies up to 26 weeks in duration
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  The potential 
target organs identified in these studies was the coagulation cascade based on changes in 
D-dimer, PT, APTT and fibrinogen, with no clinical signs or microscopic evidence of 
bleeding or adverse thrombi/emboli formation.  However, there were other effects on ALB, 
GLOB, ALB:GLOB and total protein values of rats and monkeys, the SC injection site of 
rats, and ADA’s were observed in rats.  Consistent with ICH S6 guidance, PF-06741086 was 
not evaluated in genotoxicity studies because it is not expected that this large molecule would 
interact directly with DNA or other chromosomal material.
Additional information regarding PF-06741086 may be found in the single reference safety 
document (SRSD), which for this study is the Investigator Brochure. 
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1.3. Rationale 
1.3.1. Clinical Experience with PF-06741086
1.3.1.1. Overall Safety
To date, a single clinical study has been completed with PF-06741086.  The clinical 
development of PF-06741086 began in September 2015 with B7841001: a Phase 1, 
first-in-human (FIH) single ascending dose (SAD) study in healthy subjects.  Male subjects 
between the ages of 18 and 55 with no known risk factors for thrombosis were eligible for 
this study.  Subjects were enrolled sequentially into cohorts ordered by 
PF-06741086 maximum single-dose concentration and randomized to receive a single SC or 
IV dose of PF-06741086 or placebo. Data on safety, tolerability, PK, PD and 
immunogenicity were collected during clinic confinement (7 days) and outpatient follow-up 
(up to 84 days).
All doses of PF-06741086 were well-tolerated in study B7841001.  There were no serious 
adverse events (SAEs).  There were no severe treatment emergent adverse events (TEAEs).  
There were no reported infusion or injection site reactions following administration with 
PF-06741086.
Additional clinical information regarding PF-06741086 including data from study 
B7841001 may be found in the Investigators Brochure.
1.3.1.2. Plasma Pharmacokinetics of PF-06741086 Following Administration of Single 
IV and SC Doses of PF-06741086
A summary of PK parameters following single dose SC administration of PF-06741086 at 
30, 100, and 300 mg and single dose IV infusion over 1 hour at 150 and 440 mg is presented 
in Table 3.
Peak plasma concentration (Cmax) was reached at 1 hour, ie, first sample collection at the end 
of infusion, following IV administration and 48 to 108 h following SC administration.  Under 
the same dosing route, exposures (particularly AUC) appeared to increase greater than 
proportionally with dose, which suggests that PF-06741086 may undergo target-mediated 
drug disposition.  As dose increases, mean terminal half-life of PF-06741086 increased from 
33.3 h (100 mg SC) to 79.5 h (440 mg IV) in non-Japanese subjects.

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Table 3.
Descriptive Summary of Plasma PF-06741086 Pharmacokinetic Parameters 
Following Single SC and IV Doses, Study B7841001
Parameter Summary Statistics by PF-06741086 Treatment Group
Parameter 
(units)
30 mg 
SC
100 mg SC
300 mg SC
300 mg SC 
Japanese
150 mg IV
440 mg IV
N, n
4, 0
6, 4
6, 3
4, 2b
6, 6
6, 5
AUCinf
(ng.hr/mL)
NC
257700 (34)
2799000 (83)
4955000
(4240000-5670000)
2608000 (16)
14380000 (19)
AUClast
(ng.hr/mL)
0
81890 (391)
3120000 (68)
3551000 (28)
2346000 (14)
14290000 (21)
Cmax (ng/mL)
0
1183 (287)
16490 (63)
18500 (25)
45640 (5)
152800 (12)
Tmax (hr)
NR
48.0 (48.0-72.0) 72.0 (48.0-144) 108 (72.0-144)
1.07 (1.05-2.00) 1.54 (1.08-2.00)
t½ (hr)
NC
33.30 ± 5.39
65.77 ± 18.00
98.35 (74.7-122)
43.58 ± 4.95
79.46 ± 17.71
N = Number of subjects contributing to the summary statistics; n = number of subjects for t½ and AUCinf. 
NC=Not Calculated.
NR = Not reported: summary statistics are not presented for n<3.
a Geometric mean (geometric %CV) for all except:  median (range) for Tmax; arithmetic mean ±SD for t½.
b Median and range presented since N=2.
1.3.1.3. Pharmacodynamics of PF-06741086 Following Administration of Single IV and 
SC Doses of PF-06741086
Pharmacologic effects reflective of coagulation pathway activation, which includes dPT, 
PF1+2, D-dimer, as well as the TGA parameters of lag time and peak thrombin generation, 
were monitored in study B7841001. Total plasma TFPI level was also measured to reflect 
target binding.
Preliminary PD data following single dose SC administration of PF-06741086 at 30, 100, and 
300 mg and single dose IV infusion over 1 hour at 150 and 440 mg suggested that 
treatment-related changes were observed for all PD endpoints and generally the response was 
exposure-dependent.  Pharmacologic effects on total TFPI as well as a number of PD 
biomarkers (eg, PF1+2, TGA lag time and thrombin generation, and D-dimer) persist 
>7 days following administration a single 300 mg SC dose of PF-06741086. To support the 
planned weekly dosing following SC administration, area under the effect curve for change 
from baseline values (ie, 0H on Day 1) from Days 1-7 for each PD endpoint was calculated. 
While changes were observed at all dose levels for some PD endpoints (eg, TGA lag time 
and TGA thrombin generation), others were only observed at a higher dose level (eg, 
D-dimer, PF1+2 and dPT at 100 mg and above, and total TFPI at 150 mg and above). 
Maximum or near maximum effect occurred most frequently following a single dose of 
300 mg SC based on these AUC values. 
1.3.2. Study Rationale
The clinical investigation of PF-06741086 will continue with study B7841002, an open-label, 
Phase 1b/2, multiple ascending dose (MAD) study in severe hemophilia A or B subjects, 
including subjects with inhibitors to factor VIII or factor IX.  The clinical risk/benefit profile 
for this population is considered appropriate for the evaluation of safety, tolerability, PK, PD, 
and efficacy of multiple doses of PF-06741086.  Frequency of bleeding episodes (of study 
subjects during treatment with PF-06741086) will be compared against the frequency of 
bleeding episodes in an external control group as a measure of therapeutic efficacy.

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The primary objective of study B7841002 is to evaluate the safety and tolerability of multiple 
ascending doses of PF-06741086 administered by the SC or IV route.  Secondary objectives
include evaluating the PK and PD properties of PF-06741086, as well as assessing clinical 
efficacy based on the frequency of bleeding episodes.  Selection of the PD endpoints and 
sampling schedule are based on results from non-clinical studies and the Phase 1 FIH study 
results.  They will reflect either target binding by PF-06741086 (ie, TFPI level) or 
downstream pharmacologic effects of TFPI inhibition (ie, dPT, TGA, PF1+2 and D-dimer).  
Thrombosis is a potential risk for inhibition of TFPI, and PF-06741086 is expected to 
significantly inhibit TFPI, particularly at the highest dose levels.  To minimize this risk,
hemophilia patients with a known history of thrombotic, ischemic or coronary artery disease, 
or known pro-thrombotic conditions (eg, Protein C deficiency) will be excluded from this 
study.  Safety monitoring will include laboratory parameters that may be modulated due to 
coagulopathy (eg, [PT]/INR, aPTT, fibrinogen, ATIII and platelet counts) and parameters to 
screen for possible thrombotic events (eg, cardiac troponin I).  Laboratory endpoints to detect 
excessive modulation of the coagulation pathway will be monitored during the period of peak 
drug exposure, until at least 28 days have passed since the final administration.
Potential risks for treatment with PF-06741086 are thrombi or emboli.  Depending on 
location and severity, thrombi or emboli may be life threatening or fatal.  An additional 
potential risk for treatment with PF-06741086 is ADA-induced hypersensitivity. 
Demonstration of safety, tolerability and a PK/PD profile that is supportive for chronic 
treatment on an acceptable dosing schedule will permit progression to subsequent 
investigations in patients with severe hemophilia.
1.3.3. Dose Rationale
1.3.3.1. Starting Dose
The starting dose for this study is 300 mg PF-06741086 SC once weekly (QW). The safety, 
PK, and PD results from study B7841001 (Section 1.3.1) were used to establish the starting
dose in this study. 
All dose levels (30-300 mg for SC, 150 and 440 mg for IV) evaluated in study 
B7841001 were safe and well-tolerated in healthy adult subjects; as such, the maximum 
tolerated dose (MTD) was not identified.  In addition, as the primary target organ for 
pharmacologic effect of PF-06741086 in non-clinical toxicity studies was the coagulation 
cascade, the MTD in subjects with hemophilia would likely be higher than the MTD in 
healthy subjects with intact coagulation systems. 
The efficacious dose of PF-06741086 was defined to have a trough concentration in the range 
of that conferring approximately 90% to 99% of maximum effect in the PD biomarker assay 
(EC90 to EC99).  This was selected as an approximately similar range indicated modulation of 
the in vivo biomarkers of PF1+2 and D-dimer reported with concizumab (a different 
anti-TFPI antibody) in healthy subjects and subjects with hemophilia.6   Based on data from 
study B7841001, population PK/PD analyses of PD biomarker (ie, dPT, TGA peak thrombin,
and PF1+2) data was conducted using nonlinear mixed-effects modeling with NONMEM 
(version 7.3).  EC90 estimated from the peak thrombin, dPT and PF1+2 models 

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were 0.765, 2.84, and 35.4 μg/mL, respectively.  While the EC90 of dPT is similar to that
derived from a study in normal cynomolgus monkeys, ie, 2.25 μg/mL, the upper end of the 
wide range of EC90 derived from the three biomarkers (dPT, peak thrombin, and PF1+2) 
from B7841001 was also considered when the starting dose was selected to maximize the 
chance of achieving efficacy in hemophilia A and hemophilia B subjects.  The predicted 
Ctrough,ss is 67.3 μg/mL following 300 mg weekly SC dosing of PF-06741086.
At the starting dose of 300 mg weekly SC in the current study, the steady state (SS)
exposures (Cmax and AUC168) are predicted to be more than 150-fold lower than the PK 
stopping limits (Section 3.3).  The predicted steady state (SS) exposures (Cmax and AUC168) 
at the starting dose are also lower than what were observed following single doses of 440 mg 
IV, the highest dose level evaluated in study B7841001. 
1.3.3.2. Dose Progression
The dose progression in the study will be guided by observed safety, PK (including predicted 
exposures at subsequent dose levels), PD and/or efficacy.  Regimens between the starting and 
highest doses will be selected with the intent to bracket the expected clinically efficacious 
exposure range in humans and to provide safety coverage for the expected clinically relevant 
dose range. PF-06741086 dose levels and/or regimen(s) may be modified after the first dose 
such that they can be administered at a higher or lower dose, by a different route (SC or IV), 
frequency (weekly or monthly), and with or without a loading dose, based on emerging data. 
However, they will not exceed the PK exposure or dose limitations for dose escalation 
(Section 3.3). The highest dose for SC dosing will also be determined by the total number of 
injections that can be safely administered in hemophilia patients.
Table 4 illustrates current predictions of the human PK based on data from Study 
B7841001 and the safety margins for the planned dose progression scheme. Nominal 
PF-06741086 doses planned are 300 mg SC QW, 150 mg SC QW (with a 300 mg SC loading 
dose), 450 mg SC QW, and 1000 mg IV QM.
Table 4.
Estimated PK and Nonclinical Safety Margins for Planned 
PF-06741086 Doses
PF-06741086
Dose (mg)
Route 
(Frequency)
Estimated Cmax,ss
[ng/mL]
(fold NOAEL 
margin)
Estimated 
Ctrough,ss
[ng/mL]
Estimated AUC168,ss
[ng*hr/mL]
(fold NOAEL 
margin)
300
SC (QW)
77000
66400
12300000
300 Loading
150
SC (single)
SC (QW)
21000
15700
3220000
450
SC (QW)
134000 (208)
117000
21500000
1000
IV (QM)
313000
8980
26600000
Abbreviations: AUC168,ss = Area under the PF-06741086 concentration time curve from dosing to 168 hours after dosing 
at steady state; Cmax,ss = Maximum observed PF-06741086 concentration at steady-state; NOAEL = no observed adverse 
effect level in the most sensitive species; QM = once monthly; QW = once weekly
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1.3.4. Summary of Risk/Benefit
Based on the potential risks, subjects will be monitored for treatment emergent events using 
the following parameters: serum chemistry, hematology, urinalysis, and coagulation assay 
laboratory values; vital signs; physical examinations; Electrocardiogram (ECG) parameters; 
and adverse events.  Monitoring for antibody immune response will use a tiered testing 
strategy including measurement of ADA to PF-06741086 and further characterization of any 
positive antibody immune responses such as testing for neutralizing antibody.  Additionally, 
subjects will be monitored for breakthrough bleeding events and any clinically-relevant 
effects that may impact hemostasis.
Safety was demonstrated at all tested single dose levels in the B7841001 FIH study.  There 
did not appear to be any dose-related trends in the frequency of treatment emergent adverse 
events.  Possible risks from treatment with PF-06741086 include the potential for 
thromboembolic and ischemic events, hypersensitivity reactions (including local 
injection/infusion site reactions), and antibody immune response with formation of anti-drug 
antibodies.  However, it is expected that the potential risk of a thromboembolic or ischemic 
event in subjects with hemophilia will be lower than in healthy subjects due to the effects of 
FVIII or FIX deficiency. 
The potential therapeutic efficacy of prophylaxis with PF-06741086 may be reflected in a 
reduced frequency of bleeding episodes versus the natural history of bleeding episodes for 
subjects using FVIII or FIX replacement therapy, or bypass agent therapy, for on demand 
treatment of bleeding episodes.  Further, it is assumed that any occurrence of neutralizing 
antibodies against PF-06741086 will have no impact on prophylactic or episodic 
(on-demand) treatment with FVIII or FIX replacement or bypass agent therapy.  These 
anticipated benefits may justify the potential risks of treatment with PF-06741086 for 
subjects with hemophilia A or B without inhibitors currently receiving factor replacement 
therapy, and subjects with inhibitors currently receiving bypass agent therapy.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
To determine the safety and tolerability of multiple doses of PF-06741086 administered to 
severe hemophilia A and B subjects with and without inhibitors against FVIII and FIX.
2.1.1. Key Secondary Objective

To assess the clinical efficacy of repeat dosing of PF-06741086.
2.1.2. Secondary Objectives

To characterize the PK profile of PF-06741086.

To characterize the PD profile of PF-06741086.

To characterize the immunogenicity of PF-06741086.

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2.2. Endpoints 
2.2.1. Primary Endpoints - Safety
•
Frequency, severity and causal relationship of treatment emergent adverse events 
(AEs) (treatment emergent adverse events [TEAEs]) and withdrawals due to TEAEs; 
Day 1 up to Day 113.
•
Frequency and magnitude of abnormal laboratory findings (including hematology, 
PT/INR, aPTT, chemistry, urinalysis, fibrinogen, ATIII activity and cardiac 
troponin I); Day 1 up to Day 113.
•
Changes from baseline in vital sign (blood pressure, pulse rate, temperature and 
respiration rate) measurements 12-lead electrocardiogram (ECG) parameters and 
physical examination; Day 1 up to Day 113.
•
Frequency, severity and causal relationship of infusion and injection site reactions; 
Day 1 up to Day 113.
2.2.2. Secondary Endpoints 
•
Efficacy:
•
Frequency and annualized rate of bleeding episodes; Day 1 up to Day 85.
•
Pharmacokinetics:
•
Plasma PF-06741086 concentrations (Day 1 up to Day 113) and 
noncompartmental parameters will be calculated as determined by a validated 
assay:
•
Single-dose.
•
Day 1 to Day 7 (QW): Cmax, Tmax, AUClast, C168h.
•
Day 1 to Day 28 (QM): Cmax, Tmax, AUClast, C672h.
•
Multiple-dose Day 29 to Day 36 (QW) or Day 29 to Day 57 (QM) Cmax,ss, 
Tmax,ss, AUCτ, Vss (for IV administration only), CL (for IV administration 
only) or CL/F (for SC administration only), and Cmin.
•
Pharmacodynamics:
•
Total TFPI; Day 1 up to Day 113.
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•
Thrombin generation (including lag time, peak thrombin generation and 
endogenous thrombin generation potential); Day 1 up to Day 113.
•
Prothrombin fragment 1+2; Day 1 up to Day 113.
•
D-dimer; Day 1 up to Day 113.
•
Dilute prothrombin time; Day 1 up to Day 113.
•
Immunogenicity:
•
Frequency of anti-drug antibody (ADA) and neutralizing antibody (NAb) 
production against PF-06741086; Day 1 up to Day 113.  Only positive ADA 
samples and the corresponding baseline sample will be tested in the NAb assay.
 
 
 
 
3. STUDY DESIGN
B7841002 will be an open-label investigation of the safety, tolerability, PK, PD, and efficacy
of multiple SC or IV doses of PF-06741086 in males with hemophilia A or B, with or 
without inhibitors to FVIII or FIX.  The subjects, investigator, site personnel, and Sponsor
will not be blinded to the treatment assignment. 
Subjects with severe hemophilia A or B (defined by factor VIII or factor IX activity ≤1%), 
including subjects with inhibitors to factor VIII or factor IX (positive inhibitor test result 
[above the upper limit of normal]), who receive bypass agents as primary treatment for 
bleeding episodes) will be recruited into B7841002.  Subjects with inhibitors who are 
currently treated with activated prothrombin complex concentrate (APCC, eg, FEIBA) and 
cannot substitute treatment with recombinant factor VIIa (rFVIIa, eptacog alfa [activated]) as 
their standard of care for treatment of acute bleeding episodes (at a dose level of 
approximately 90 μg/kg) for the duration of the study are not eligible.  Subjects must be on 
an episodic (on-demand) treatment regimen at the time of study enrollment and also have a 
documented history of at least 6 acute bleeding episodes in the 6 months prior to study 
enrollment.  Subjects must washout from any factor replacement or bypass agent therapy 
prior to screening and prior to study treatment.
The following schematic is meant to demonstrate the planned dose progression scenario:
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Figure 1.
Dose Progression Scheme
SC or IV multiple dose cohorts will be enrolled starting at the 300 mg SC dose.  Subjects will 
be enrolled and assigned to treatment as follows. 

Cohort 1 (n=6): 300 mg PF-06741086 SC QW (n=6).

Cohort 2 (n=6): 300 mg SC loading dose, 150 mg PF-06741086 SC QW (n=6).

Cohort 3 (n=6): 450 mg PF-06741086 SC QW (n=6).

Cohort 4 (n=6): 1000 mg PF-06741086 IV QM (n=6).
Doses, frequency and route(s) of administration after the first dose may be modified based on 
review of available data.  Additional subjects or cohorts may be added for reasons described 
in Section 3.1.
Safety endpoints will include TEAEs (graded by the NIAID DMID severity scale), 
infusion/injection site reactions, laboratory parameters that may be modulated due to 
coagulopathy (eg, PT/INR, activated aPTT, fibrinogen, ATIII, platelet counts) and 
parameters to screen for possible thrombotic events (eg, cardiac troponin I).  PK and PD 
endpoints include concentrations of PF-06741086 in plasma, non-compartmental PK 
parameters, measures of target binding by PF-06741086 (ie, TFPI level) or downstream 
pharmacological activities of TFPI inhibition (ie, dPT, thrombin generation, PF1+2, and 
D-dimer). 

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3.1. Planned Number of Subjects
Approximately 24 subjects are planned for enrollment at approximately 20 study sites.  
Subjects who are withdrawn for reasons other than safety may be replaced at the discretion of 
the Sponsor.  Subjects with inhibitors to FVIII or FIX will only be enrolled into a cohort with 
a dose level and regimen that was previously assessed as safe and well tolerated in subjects 
without inhibitors.  Additional subjects and/or cohorts may be enrolled in the event that the 
number of dosing cohorts or size of dosing cohorts is increased to fully define the dose range
and/or clinical profile at the respective dose levels.
3.2. Study Duration
Subjects will be screened within 35 days prior to administration of the investigational 
product to confirm that they meet the subject eligibility criteria for the study.  At the 
Day 1 clinic visit, eligibility criteria will be confirmed.  Subjects will begin dosing on Day 1.  
Subjects will be required to return to the clinic (eg, study site) for PK/PD sample collection
on Day 2 and Day 4.  Subjects will then be required to attend weekly clinic visits on Day 8, 
Day 15, Day 22, and Day 29.  For subjects with once weekly (QW) dosing frequency, 
investigational product will be administered at these visits as well. 
Following Day 29, provided that safety was confirmed for the cohort and no stopping criteria 
were met, all subjects in each cohort will return to the clinic for PK/PD sample collection on 
Day 30 and Day 33.  Subjects in the SC cohorts will receive treatment on Day 36, Day 43, 
Day 50, Day 57, Day 64, Day 71, Day 78, follow-up on Day 85, and end-of-study procedures 
on Day 113.  For the Day 36, 43, 50, 64, 71 and 78 SC treatments, in countries where 
approved by respective competent authorities and at sites where it is approved by the 
respective IRB/EC, SC treatment with investigational product may be administered by 
investigator site personnel in a home care or ambulatory clinic setting.  Subjects in the IV 
cohort will receive treatment on Day 57, follow-up on Day 85, and end-of-study procedures 
on Day 113.
Subjects with positive ADA or NAb results may be requested to return for additional 
follow-up visits after Day 113.
Subjects who experience a treatment-related adverse event (including lab abnormalities) at 
any time point will continue to be followed through resolution or stabilization of the event as 
agreed upon by the investigator and Sponsor. 
The maximum total duration of the study for a single subject, from initial screening to final 
follow-up, will be approximately 5 months.
During the study data will be reviewed on an ongoing basis to determine if PF-06741086 is 
safe and tolerated.  Dosing of subjects in any cohort may be stopped if the 
B7841002 protocol-specified stopping criteria are met (Section 3.3).  If available data are 
permissive for dose progression, subjects will be recruited into the next cohort in the study 
and dosed at the next dose level of PF-06741086. 

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3.3. Dose Escalation and Stopping Rules
Dose escalation stopping rules will be used to determine whether the maximum tolerated 
dose has been attained. 
Dose escalation will not occur if 2 or more dose-limiting toxicities are met within a dosing 
cohort of 6 subjects.  Dose escalation may occur if ≤1 dose limiting toxicity is observed 
within a dosing cohort of 6 subjects.  Dose limiting toxicities are defined as:

Treatment emergent laboratory abnormality as specified in Appendix 2;

Treatment emergent vital sign abnormality as specified in Appendix 2;

Treatment emergent ECG abnormality as specified in Appendix 2;

Treatment emergent severe or ≥ Grade 3 adverse event, as graded by the NIAID
DMID criteria for severity unless incontrovertibly due to extraneous causes.
Additional rules governing dose escalation are as follows:

Dosing at the current dose level (or higher dose levels) will be suspended for any 
treatment emergent thrombotic event (see Appendix 1 for qualifying AEs) in a subject 
receiving PF-06741086 to permit characterization of the respective event and 
communication to regulatory agencies where required.  Vessel occlusion related to 
the insertion or presence of a central venous catheter may be excluded from this 
criterion after review of the AE with the respective investigator to assess causality 
and/or clinical significance.

All treatment emergent adverse events, regardless of system organ class, 
severity/grade, causality, and/or attribution to treatment with PF-06741086 are
assessed and it is determined by the Sponsor that the limit of safety and/or tolerability 
has been reached.

Dose escalation will be paused for any treatment emergent serious adverse event 
(SAE) that occurs in a subject receiving PF-06741086 until causality is fully assessed 
by the Sponsor.  Dose escalation will cease if the SAE is determined to be either 
drug-related or unknown, and may resume if the SAE is determined to be not 
drug-related by the Sponsor.

If, based on the observed data, the group geometric mean Cmax or area under the curve 
(AUC168) (based on total concentration with either the first dose or at steady-state) of 
the next planned regimen is projected to exceed the exposure limits (AUC168 of 
1,940,000 g•h/mL and Cmax of 27,800 g/mL), that dose will not be explored.  
Modified doses may be explored if they are not expected to exceed these PK stopping 
criteria. 

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In addition, tolerability criteria for dose escalation are:

For SC cohorts: no more than 2 subjects in a dosing cohort of 6 subjects experience at 
least moderate severity injection site reactions.

For IV cohorts: no more than 2 subjects in a dosing cohort of 6 subjects experience at 
least moderate severity infusion/injection site reactions.
Progression to a higher dose level or regimen not assessed as safe and well tolerated in a 
previous cohort will follow the Sponsor’s review of the available safety, PK, PD, and bleed 
rate data through study Day 29 (at a minimum) in 100% (ie, 6 of 6) of subjects in the current
cohort.  Accumulated safety, PK, PD, bleed rate and immunogenicity data from previous 
cohorts will also be reviewed.  Progression to the next cohort will occur if the current dose 
level is well tolerated and after satisfactory review of these data. 
For doses with projected Cmax/AUC levels not previously achieved in humans, sequential 
dosing will be implemented for the first 3 subjects at the respective dose level.  Following 
initial dosing for each of the first 3 subjects, available safety and laboratory data through 
72 hours post-dose will be monitored.  Subsequent dosing for the cohort shall not commence 
until satisfactory review of these data is complete.
If at any time during cohort enrollment data suggest that stopping rules may have been met 
then dosing will be suspended.  A formal review of available data by the Sponsor study team 
will determine whether stopping rule criteria have been met.
Dose Modifications
Any subject who experiences a dose limiting toxicity (per Appendix 2) will be discontinued 
from treatment with the investigational product and will be followed for adverse event 
monitoring until resolution of the respective toxicity and elimination of study drug or the end 
of the study (Day 113) and resolution or stabilization of the respective toxicity, whichever 
occurs first. In addition, subjects who have not experienced dose limiting toxicities but are 
currently receiving a dose that met the dose limiting toxicities criteria for termination of dose 
escalation as defined in Section 3.3 will be removed from the current dose level and dropped 
to the next lowest exposure level.
Subjects who have not experienced a dose-limiting toxicity may also require dose 
modifications.  Criteria for modifications of dosing in an individual subject are as follows:

Moderate severity infusion/injection site reactions at more than 2 consecutive visits 
(eg, Day 22, Day 29, and Day 36);

Treatment emergent adverse event(s) that increases in severity/grade, without 
resolution, (eg, Mild to Moderate and continuing) after repeat administration of 
PF-06741086;

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
Treatment emergent adverse event(s) of any severity with more than 2 occurrences 
following repeat administration of PF-06741086.
Any subject who meets the above criteria during treatment with PF-06741086 will be 
removed from the current dose level and dropped to the next lowest exposure level, unless 
the event(s) are incontrovertibly due to extraneous causes or are incontrovertibly 
complications of hemophilia (see Section 8.6 for qualifying events).
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative/parent(s)/legal guardian) has been 
informed of all pertinent aspects of the study.
2. Males 18 and <65 years of age.
3. Body Mass Index (BMI) 17.5 and 30.5 kg/m2 and total body weight 50 and 
100 kg. 
4. Diagnosis of severe hemophilia A or B (Factor VIII or Factor IX activity 1%).
5. Subjects enrolled as Factor VIII or Factor IX inhibitor patients must have a positive 
inhibitor test result (above the upper limit of normal) at the local laboratory and must 
receive a bypass agent as primary treatment for bleeding episodes.  A positive 
inhibitor test result will be above the upper limit of normal for the assay. Inhibitor 
test results from up to 6 months prior to Day 1 may be used to meet this requirement.
6. Patients with an episodic (on-demand) treatment regimen prior to Screening, who are 
willing and able to washout from Factor VIII (for at least 72 hours) or Factor IX (for 
at least 96 hours) replacement therapy, or bypass agent therapy (for rFVIIa and 
APCC: at least 72 hours), prior to Screening laboratory assessments of factor activity 
and have no plans to institute prophylactic factor treatment during the study period.

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7. Had at least 6 acute bleeding episodes (spontaneous/traumatic) during the 6-month 
period prior to Screening.  Surgical bleeding episodes do not apply to this criterion.
8. If receiving therapy for human immunodeficiency virus (HIV) or active hepatitis 
infection, have stable disease and be on a stable regimen at the time of study entry 
(ie, stable dosing for at least 3 months before consent). 
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
10. If with partners currently pregnant or if able to father children, agree to use a highly 
effective method of contraception throughout the study and for least 28 days after the 
last dose of investigational product. 
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Females.
2. Known coronary artery, thrombotic, or ischemic disease.
3. Known hemostatic defect other than hemophilia A or B.
4. ATIII, Protein C, or Protein S deficiency, Factor V Leiden, Prothrombin 
20210 mutation, or other known pro-thrombotic condition
5. Currently receiving treatment for acute bleeding episodes with APCC (eg, Factor 
Eight Inhibitor Bypass Agent [FEIBA]) and cannot substitute treatment with rFVIIa 
at a dose level of approximately 90 µg/kg for the duration of the study.
6. Regular, concomitant therapy with immunomodulating drugs (eg, intravenous 
immunoglobulin [IVIG], and routine systemic corticosteroids).
7. Abnormal renal or hepatic function as defined by the following laboratory results at 
Screening:

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 
>3 times the upper limit of normal (ULN).

Total bilirubin level >2 mg/dL (>35 mol/L).

Serum albumin < the lower limit of normal (LLN).

Serum creatinine level >1.25 times the ULN.

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8. Abnormal hematology values as defined by the following laboratory results at 
Screening: 

Platelet count <100,000/L.

Fibrinogen level < LLN.

Hemoglobin level <10 gm/dL.
9. Abnormal coagulation activity as defined by the following laboratory results at 
Screening:

Prothrombin time (PT) >1.25 times the ULN.
10. CD4 cell count 200/L.
11. Known hypersensitivity or allergic reaction to hamster protein.
12. Known sensitivity to heparin or heparin-induced thrombocytopenia.
13. Investigational site staff members directly involved in the conduct of the study and 
their family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees directly involved in the conduct of the study.
14. Participation in other studies involving investigational drug(s) within 30 days (or as 
determined by the local requirement, whichever is longer) or 5 half-lives prior to 
study entry and/or during study participation.
15. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study.
16. With partners currently pregnant or able to father children 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 
investigational product. 
17. Had major surgery, as judged by the investigator, within 3 months prior to the study 
or have elective surgery planned during the study.
4.3. Randomization Criteria 
This study is not a randomized trial, but allocation to treatment will follow procedures 
similar to randomization (which may be referred to as enrollment).

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All subjects will be given PF-06741086.  Subjects will be assigned a randomization number
provided they have satisfied all eligibility criteria and the following enrollment criteria:
1. Subjects must washout from Factor VIII (for at least 72 hours) or Factor IX (for at 
least 96 hours) replacement therapy and from treatment with any other intravenous 
hemostatic agent (for at least 72 hours) prior to the Day 1 visit laboratory testing for 
clotting factor activity level.  Subjects cannot be enrolled or treated with 
investigational product if they have received treatment for an acute bleeding episode 
with Factor VIII or Factor IX replacement therapy within 72 hours or 96 hours,
respectively, or rFVIIa or APCC (eg: FEIBA) bypass agent therapy within 72 hours,
of the Day 1 visit.  If factor replacement or bypass agent therapy is required to treat a 
bleeding episode during the Screening period, then the subject may return for the 
Day 1 visit after completing the required washout period and remain eligible for study 
participation.  See Section 6.1 for further Screening procedure guidance.
4.4. Lifestyle Guidelines
All male subjects who are able to father children and, in the opinion of the investigator, are 
sexually active and at risk for pregnancy with their partners must agree to 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 investigational product.  A longer duration of 
contraception usage may be required if data from B7841002 warrant this change.  The 
investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and his 
partner from the permitted list of contraception methods (see below) and instruct the subject 
in its consistent and correct use.  Subjects need to affirm that they meet the criteria for correct 
use of at least 1 of the selected methods of contraception.  The investigator or his/her 
designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the Schedule of Activities and document such 
conversation in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (ie, oral, inserted, injected, implanted, transdermal) provided the subject’s 
partner plans to remain on the same treatment throughout the entire study and has 
been using that hormonal contraceptive for an adequate period of time to ensure 
effectiveness.
2. Correctly placed intrauterine device (IUD) or intrauterine system (IUS).

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3. Male condom WITH a spermicide (ie, foam, gel, film, cream, or suppository). For 
countries where spermicide is not available or condom plus spermicide is not 
accepted as highly effective contraception, this option is not appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Female partner who meets the criteria for non-childbearing potential, as described 
below:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum follicle 
stimulating hormone (FSH) level confirming the post-menopausal state.
All other female partners (including females with tubal ligations) will be considered 
to be of childbearing potential.
All sexually active male subjects must agree to prevent potential transfer of and 
exposure to drug through semen to their partners by using a condom consistently and 
correctly, beginning with the first dose of investigational product and continuing 
through discharge from the study.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.

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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33).
Study Treatment
Route of Administration
Protocol Term
PF-06741086, Solution for Injection, 
100 mg/mL
subcutaneous (SC)
investigational product (IP)
PF-06741086, Solution for Injection, 
100 mg/mL
intravenous (IV)
investigational product (IP)
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system.  The site personnel (study coordinator or specified 
designee) will be required to enter or select information including but not limited to the 
user’s identification (ID) and password, the protocol number, the subject number and the date 
of birth of the subject. The site personnel will then be provided with a treatment assignment 
and dispensable unit (DU) or container number when drug is being supplied via the IRT
system.  The IRT system will provide a confirmation report containing the subject number 
and DU or container number assigned. The confirmation report must be stored in the site’s 
files.
There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues. The study specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system.
5.2. Subject Compliance
Subjects assigned to SC cohorts will receive weekly treatment administration Day 1 to 
Day 78 (see Section 3.2).  Subjects assigned to the IV cohort will receive monthly treatment 
administration from Day 1 to Day 57. 
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
PF-06741086 Solution for Injection, 100 mg/mL
, will be supplied by Pfizer as 
a good manufacturing practice (GMP) manufactured, sterile liquid solution for injection 
packaged in a 6 mL glass vial sealed with a stopper and an aluminum seal (nominal fill 
volume of 1.0 mL).
CCI
CCI
CCI

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These products will be supplied to sites as open label packaged supplies for subsequent unit 
dosing.
5.3.2. Preparation and Dispensing
See the Investigational Product Manual (IPM) for instructions on how to prepare the 
investigational product for administration. 
Investigational product should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance.
Each vial is for single-use only.  Vials are for use in a single patient for a single dose.
5.4. Administration
Investigator site personnel will administer investigational product according to the 
Investigational Product Manual (IPM).  When dosing is by IV infusion, the IV infusion will 
be on the opposite arm from PK sampling. 
For subjects receiving SC injection(s), the number of injections and injection sites will be 
recorded.  The preferred body locations of the SC injection(s) are the front of the middle of 
the thigh, including anterolateral, or outer area of the upper arm. If an arm is used for the SC 
injection, the opposite arm should be used for the PK/PD blood sample collections, if 
possible. Multiple injections should use a unique site for each injection where possible, to 
limit the injection site volume to 1 mL (ie, 1 mL in arm, 1 mL in thigh for a 2 mL, 2 injection 
doses).  When feasible, if multiple injections are required, the simultaneous use of both arms 
(eg, 1 mL in left arm and 1 mL in right arm) should be avoided.
5.5. Investigational Product Storage
See the IPM for complete information on storage, handling and stability of investigational 
drug product.
The investigator or an approved representative (eg, pharmacist) will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  See the IPM for storage conditions of the product.
Storage conditions stated in the single reference safety document (SRSD) (eg, investigator’s
brochure [IB]) will be superseded by the storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active evaluation for 

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excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations. The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
Sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the Sponsor approves the use of the investigational 
product after the temperature excursion. Use of the investigational product prior to Sponsor
approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
5.6. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.
5.6.1. Destruction of Investigational Product Supplies 
The Sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by the 
Sponsor, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)

Subjects will abstain from all prohibited concomitant medications, except for the 
treatment of adverse events or acute bleeding episodes as described in
Section 5.7.1 of this protocol. 

All concomitant treatments taken during the study must be recorded with indication, 
and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatments at each clinic visit.

For emergency or unplanned surgical interventions, investigators must contact the 
Sponsor’s medical monitor as soon as possible to review concomitant treatments and 
any impact on subject participation. 

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
Treatments taken within 28 days prior to informed consent being signed will be 
documented as a prior treatment.  Treatments taken from date of signed informed 
consent will be documented as concomitant treatments.
5.7.1. Prohibited Medications
Factor VIII (within 72 hours) or Factor IX replacement therapy (within 96 hours), or bypass 
agent therapy (FVIIa or APCC: within 72 hours), before Screening is prohibited.  Depending 
on the coagulation factor product in use, additional wash out time may be required prior to 
the screening assessments to achieve a factor activity level 1%.  If a subject experiences an 
acute bleeding episode during this washout period requiring treatment with a Factor VIII or 
IX replacement therapy, or bypass agent therapy, the subject is to be stabilized utilizing this 
regimen and a new washout period should be initiated.  The regimen used to treat the episode 
should be recorded as a prior medication.
Factor VIII (within 72 hours) or Factor IX replacement therapy (within 96 hours), or bypass 
agent therapy (for FVIIa or APCC: at least 72 hours), before Day 1 treatment is also 
prohibited. If a subject experiences an acute bleeding episode during this washout period 
requiring treatment with a Factor VIII or IX replacement therapy, or bypass agent therapy,
the subject is to be stabilized utilizing this regimen and a new washout period should be 
initiated.  The regimen used to treat the episode should be recorded as a concomitant 
medication.  All acute bleeding episodes between Screening and Day 1 must be recorded.
Treatment with rFVIIa at a dose level greater than approximately 90 µg/kg is prohibited 
throughout the study.  If a subject receiving investigational product is subsequently 
administered a rFVIIa dose greater than approximately 90 µg/kg, the investigator must 
immediately contact the Sponsor’s medical monitor to discuss the case to determine if the 
respective subject should continue to receive IP, remain in the study, or be withdrawn 
immediately.
Treatment with APCC (eg, FEIBA) is prohibited throughout the study.  Subjects 
receiving such therapy, who cannot substitute treatment with rFVIIa, at the 90 µg/kg per dose
are not to be enrolled into this study.  Subjects who are treated with investigational product
who are subsequently administered APCC therapy must be withdrawn from treatment with 
investigational product immediately.  These subjects should be followed at all remaining 
clinic visits up to Day 113 to monitor for adverse events and any additional safety concerns.
The use of immunomodulatory medications (eg, Intravenous Immunoglobulin (IVIG), 
routine systemic corticosteroids) is prohibited during the study.
The use of antifibrinolytic agents or medications known to influence platelet function 
(eg, aspirin or certain non-steroidal anti-inflammatory drugs) within 5 days before initial 
study drug administration through Day 113 is prohibited.
5.7.2. Treatment(s) for Acute Bleeding Episodes
If a subject experiences an acute bleeding episode at any point throughout the study, the 
subject is to be stabilized utilizing the subject’s standard hemostatic treatment regimen

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(which may include Factor VIII or Factor IX replacement therapy, or rFVIIa bypass agent 
therapy at approximately 90 µg/kg per dose).  Pausing or withdrawal of treatment with 
investigational product is not required in the event of a breakthrough bleed, but may be 
considered at the discretion of the investigator.  See Section 7.2.5 for additional information.
6. STUDY PROCEDURES 
6.1. Screening
Subjects will be screened within 35 days prior to administration of the investigational 
product to confirm that they meet the subject selection criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) will obtain informed consent from each 
subject in accordance with the procedures described in the Subject Information and Consent
section. 
All screening procedures must be repeated for any subject who failed initial screening 
procedures and is re-screening into the study, with the exception of the following labs related 
to genetic mutation screening or pharmacogenomics samples:

Prothrombin 20210 mutation testing;

Factor V Leiden mutation testing;

Banked biospecimens;

Factor VIII and Factor IX activity;

Factor VIII or Factor IX inhibitor (this test is only required for subjects with a 
hemophilia history of inhibitors).
The following procedures will be completed during Screening:

Obtain written informed consent;

Review Inclusion and Exclusion criteria;

Obtain medical history, including hemophilia history and inhibitor history, and collect 
the number of bleeding episodes over the past 6 months;

Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken since the start of Screening;

Review use of Factor VIII or Factor IX replacement therapy, or bypass agent therapy,
to ensure subject meets washout criteria prior to Screening;

Collect demography and height;

Collect weight;

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
Provide instructions regarding study contraception requirements;

Obtain pulse rate, respiratory rate, oral temperature, and supine blood pressure;

Conduct full physical examination (PE).  On and after Day 1 and at the discretion of 
the investigator, limited physical examinations based on signs and symptoms will be 
performed, if clinically indicated, to assess changes from baseline/previous visits of 
any ongoing symptoms;

Collect single 12-lead ECG.  If ECG is abnormal, collect triplicate ECG.

Collect blood specimens for the following for analysis at a local laboratory, if 
necessary:

Factor VIII or Factor IX inhibitor (this test is only required for subjects with a 
hemophilia history of inhibitors). Inhibitor test results from up to 6 months prior 
to Day 1 may be used to meet this requirement.

Following at least a 4-hour fast (and at least a 12-hour fast prior to lipid panel), 
collect blood and urine specimens for the following for shipment to the study central
laboratory:

Urinalysis; 

Serum chemistry;

Hematology;

Factor VIII and Factor IX activity;

CD4 cell count;

Prothrombin 20210 mutation testing;

Factor V Leiden mutation testing; 

Lipid panel;

Protein C activity/Protein S level;

Serology (HBs Ag, HBc Ab, HCV Ab, and HIV);

PT/INR;

aPTT;

Fibrinogen;

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
ATIII.
To prepare for study participation, subjects will be instructed on the use of the Lifestyle 
Guidelines and Concomitant Treatment(s) sections of the protocol.
6.2. Study Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.

ECGs: obtain prior to vital signs and prior to blood specimen collection;

Blood pressure/pulse rate: prior to blood specimen collection;

Pharmacokinetic blood specimens: samples collected in sodium citrate tubes should 
not be the initial tube of blood collected;

Other procedures.
When an IV catheter is utilized for blood sample collections, ECGs and vital signs (pulse
rate, respiratory rate, blood pressure and oral temperature) assessments should be collected 
prior to the insertion of the catheter.
6.2.1. Day 1 Visit
Prior to dosing on Day 1 the following procedures will be completed:

Assess baseline symptoms/AEs including interval since Screening;

Review changes in subject’s concomitant treatment information since Screening;

Review use of Factor VIII or Factor IX replacement therapy, or rFVIIa bypass agent 
therapy to ensure subject meets washout criteria prior to Day 1;

Review changes in the subject’s medical history including medication history since 
Screening;

Collect information on new bleeding episodes;

Review Inclusion and Exclusion criteria;

Conduct a limited physical examination at the discretion of the investigator, if 
clinically indicated, to assess changes since Screening of any ongoing symptoms;

Collect weight;

Confirm proper contraception is being used;

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•
Obtain pulse rate, respiratory rate, oral temperature, and supine blood pressure;
•
Collect triplicate 12-lead ECG. 
•
Collect blood and urine specimens for the following for shipment to the study central
laboratory:
•
Urinalysis;
•
Serum chemistry;
•
Hematology with differential panel;
•
Factor VIII and Factor IX activity;
•
Banked biospecimens;
•
TFPI level;
•
PT/INR;
•
aPTT;
•
Fibrinogen;
•
ATIII;
•
TGA;
•
PF1+2;
•
D-dimer;
•
dPT;
•
Cardiac Troponin I; 
•
PK blood sampling;
•
Immunogenicity (ADA, NAb);
•
Treatment assignment any time prior to dosing once subject has met all eligibility 
criteria;
C
C

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
After all pre-dose procedures have been completed, administer the investigational 
product (see STUDY TREATMENTS and Administration Sections). 
After dosing, the following procedures will be completed:

IV cohorts only: Collect blood samples from the arm not used for IV IP 
administration immediately following completion of the IV line flush after 
completion of the IV infusion.  These blood samples are for shipment to the study 
central laboratory:

TFPI level;

TGA;

PF1+2;

D-dimer;

dPT;

PK blood sampling.

Monitor infusion/injection site reactions.

Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel?”

Issue subject diary and provide training with respect to completing the diary including 
timing and nature of information to be entered.
6.2.2. Day 2 (-6 hours/+1 day) and Day 4 (-6 hours/+1 day) PK/PD Blood Draws 
The following procedures will be completed 24 (-6/+24) and 72 (-6/+24) hours following 
investigational product administration on Day 1:

Obtain information regarding the use of concomitant treatment and the occurrence of 
adverse events;

Collect information on new bleeding episodes;

Monitor infusion/injection site reactions;

Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel?” 

Collect blood samples for the following for shipment to the study central laboratory:

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
TFPI level;

TGA;

PF1+2;

D-dimer;

dPT;

PK blood sampling.
6.2.3. Day 8 (1 day), Day 15 (2 days), Day 22 (2 days) and Day 29 (2 days) Visits
The following procedures will be completed:

Obtain information regarding the use of concomitant treatment and the occurrence of 
adverse events;

Collect information on new bleeding episodes;

Conduct a limited physical examination at the discretion of the investigator, if 
clinically indicated, to assess changes from baseline/previous visits of any ongoing 
symptoms;

Collect weight (Day 29 only);

Confirm proper contraception is being used;

Collect the subject’s diary and review with the subject/caregiver, including 
information about study compliance, bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions.  Dispense new subject diary;

Collect single 12-lead ECG.  If ECG is abnormal, collect triplicate ECG;

Obtain pulse rate, respiratory rate, oral temperature, and supine blood pressure;

Collect urine for urinalysis for shipment to the study central laboratory.

Collect blood samples for the following for shipment to the study central laboratory:

Serum chemistry;

Hematology (with differential panel on Day 29 only);

TFPI level;

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•
PT/INR;
•
aPTT;
•
Fibrinogen;
•
ATIII;
•
TGA;
•
PF1+2;
•
D-dimer;
•
dPT;
•
Cardiac Troponin I; 
•
PK blood sampling;
•
Immunogenicity (ADA, NAb) (Days 15 and 29 only);
•
Cohorts with SC administration: After all pre-dose procedures have been 
completed, administer the investigational product (see STUDY TREATMENTS and 
Administration Sections) (Days 8, 15, 22 and 29). 
•
Cohorts with IV administration:  After all pre-dose procedures have been 
completed, administer the investigational product (see STUDY TREATMENTS and 
Administration Sections) (Day 29 only)
After dosing, the following procedures will be completed:
•
IV cohorts only (Day 29 only): Collect blood samples from the arm not used for 
IV IP administration immediately following completion of the IV line flush after 
completion of the IV infusion.  These blood samples are for shipment to the study 
central laboratory;
•
Monitor infusion/injection site reactions;
•
Assess symptoms by spontaneous reporting of adverse events and by asking the
subjects to respond to a non-leading question such as “How do you feel?”
C
C

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6.2.4. Day 30 (-6 hours/+1 day) and Day 33 (-6 hours/+1 day) PK/PD Blood Draws at 
Clinic Visits
The following procedures will be completed 24 (-6/+24) and 96 (-6/+24) hours following 
investigational product administration on Day 29:

Obtain information regarding the use of concomitant treatment and the occurrence of 
adverse events;

Collect information on new bleeding episodes;

Monitor infusion/injection site reactions;

Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel?” 

Collect blood samples for the following for shipment to the study central laboratory:

TFPI level;

TGA;

PF1+2;

D-dimer;

dPT;

PK blood sampling.
6.2.5. Day 36 (2 days), Day 43 (2 days) and Day 50 (2 days) Visits
The following procedures will be completed:

Cohorts with SC administration: administer the investigational product (see
STUDY TREATMENTS and Administration Sections);

Collect information on new bleeding episodes;

Monitor infusion/injection site reactions;  

Collect the subject’s diary and review with the subject/caregiver, including 
information about study compliance, bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions.  Dispense new subject diary;

Report information regarding the use of concomitant treatment and the occurrence of 
adverse events.

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6.2.6. Day 57 (2 days) Visit
The following procedures will be completed:

Obtain information regarding the use of concomitant treatment and the occurrence of 
adverse events;

Collect information on new bleeding episodes;

Conduct a limited physical examination at the discretion of the investigator, if 
clinically indicated, to assess changes from baseline/previous visits of any ongoing 
symptoms;

Confirm proper contraception is being used;

Collect the subject’s diary and review with the subject/caregiver, including 
information about study compliance, bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions.  Dispense new subject diary;

Collect weight;

Obtain pulse rate, respiratory rate, oral temperature, and supine blood pressure;

Collect urine for urinalysis for shipment to the study central laboratory.

Collect blood samples for the following for shipment to the study central laboratory:

Serum chemistry;

Hematology;

TFPI level;

PT/INR;

aPTT;

Fibrinogen;

TGA;

PF1+2;

D-dimer;

dPT;

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•
PK blood sampling;
•
Immunogenicity (ADA, NAb);
•
After all pre-dose procedures have been completed, administer the investigational 
product (see STUDY TREATMENTS and Administration Sections). 
After dosing, the following procedures will be completed:
•
IV cohorts only: Collect blood samples from the arm not used for IV IP 
administration immediately following completion of the IV line flush after 
completion of the IV infusion.  These blood samples are for shipment to the study 
central laboratory;
•
Monitor infusion/injection site reactions;
•
Assess symptoms by spontaneous reporting of adverse events and by asking the
subjects to respond to a non-leading question such as “How do you feel?”
6.2.7. Day 64 (±2 days), Day 71 (±2 days) and Day 78 (±2 days) Visits
The following procedures will be completed:
•
Cohorts with SC administration: administer the investigational product (see
STUDY TREATMENTS and Administration Sections);
•
Collect information on new bleeding episodes;  
•
Monitor infusion/injection site reactions;  
•
Collect the subject’s diary and review with the subject/caregiver, including 
information about study compliance, bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions.  Dispense new subject diary;
•
Report information regarding the use of concomitant treatment and the occurrence of 
adverse events.
6.2.8. Day 85 (±2 days) Visit
The following procedures will be completed:
•
Obtain information regarding the use of concomitant treatment and the occurrence of 
adverse events;
•
Monitor infusion/injection site reactions;
C
C

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•
Collect information on new bleeding episodes;
•
Conduct a limited physical examination at the discretion of the investigator, if 
clinically indicated, to assess changes from baseline/previous visits of any ongoing 
symptoms;
•
Confirm proper contraception is being used;
•
Collect the subject’s diary and review with the subject/caregiver, including 
information about study compliance, bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions.  Dispense new subject diary;
•
Collect weight;
•
Obtain pulse rate, respiratory rate, oral temperature, and supine blood pressure;
•
Collect urine for urinalysis for shipment to the study central laboratory.
•
Collect blood samples for the following for shipment to the study central laboratory:
•
Serum chemistry;
•
Hematology with differential panel;
•
TFPI level;
•
PT/INR;
•
aPTT;
•
Fibrinogen;
•
TGA;
•
PF1+2;
•
D-dimer;
•
dPT;
•
PK blood sampling;
•
Immunogenicity (ADA, NAb);
C
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6.3. Follow-up Visit/End of Study 
6.3.1. Day 113 (7 days) Visit
The following procedures will be completed:

Obtain information regarding the use of concomitant treatment and the occurrence of 
adverse events;

Collect information on new bleeding episodes;

Monitor infusion/injection site reactions;

Assess symptoms by spontaneous reporting of adverse events and by asking the
subjects to respond to a non-leading question such as “How do you feel?”

Conduct a limited physical examination at the discretion of the investigator, if 
clinically indicated, to assess changes from baseline/previous visits of any ongoing 
symptoms;

Provide instructions regarding study contraception requirements;

Collect the subject’s diary and review with the subject/caregiver, including 
information about study compliance, bleeding assessments (including site and 
traumatic/spontaneous) and injection site reactions;

Collect weight;

Obtain pulse rate, respiratory rate, oral temperature, and supine blood pressure;

Collect urine for urinalysis for shipment to the study central laboratory.

Collect blood samples for the following for shipment to the study central laboratory:

Serum chemistry;

Hematology with differential panel;

TFPI level;

PT/INR;

aPTT;

Fibrinogen;

TGA;

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
PF1+2;

D-dimer;

dPT;

PK blood sampling;

Immunogenicity (ADA, NAb);

Subjects with positive ADA or NAb may be required to attend additional, 
unscheduled follow-up visits after Day 113.  Extended follow-up visits every 
2 weeks for up to 3 months, including vital signs, immunogenicity, AE and 
concomitant treatment assessments, may be performed.

Discharge from study.
6.4. Subject Withdrawal
Withdrawal of consent: Subjects who request to discontinue study treatment 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 subject specifically withdraws consent for any further 
contact with him or persons previously authorized by the subject to provide this information.  
Subjects 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 investigational product or also from study procedures and/or post treatment 
study follow-up, and entered on the appropriate case report form (CRF) page. Publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
Lost to follow-up: All reasonable efforts must be made to locate subjects to determine and 
report their ongoing status. This includes follow-up with persons authorized by the subject 
as noted above. Lost to follow-up is defined by the inability to reach the subject after a 
minimum of 2 documented phone calls, faxes, or e-mails as well as lack of response by the 
subject to 1 registered mail letter. All attempts should be documented in the subject’s 
medical records. If it is determined that the subject has died, the site will use permissible 
local methods to obtain the date and cause of death. If the investigator’s use of a third-party 
representative to assist in the follow-up portion of the study has been included in the 
subject’s informed consent, then the investigator may use a Sponsor-retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by the 
investigator should be reported and documented in the subject’s medical records.

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Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or Sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
product(s), if applicable, request that the subject return for a final visit, if applicable, and 
follow up with the subject regarding any unresolved adverse events.
If a subject withdraws prior to Day 113, the following assessments should be completed:

Obtain information regarding the use of concomitant medication and the occurrence 
of adverse events;

Collect information on new bleeding episodes;

Monitor infusion/injection site reactions;

Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel?”

Conduct a limited physical examination at the discretion of the investigator, if 
clinically indicated, to assess changes from baseline/previous visits of any ongoing 
symptoms;

Confirm proper contraception is being used;

Collect the subject’s diary and review with the subject/caregiver, if applicable, 
including information about study compliance, bleeding assessments (including site 
and traumatic/spontaneous) and injection site reactions;

Collect weight;

Obtain pulse rate, respiratory rate, oral temperature, and supine blood pressure;

Collect urine for urinalysis for shipment to the study central laboratory.

Collect blood samples for the following for shipment to the study central laboratory:

Serum chemistry;

Hematology;

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
TFPI level;

PT/INR;

aPTT;

Fibrinogen;

TGA;

PF1+2;

D-dimer;

dPT;

PK blood sampling;

Immunogenicity (ADA, NAb);

Subjects with positive ADA or NAb may be required to attend additional, 
unscheduled follow-up visits.  Extended follow-up visits every 2 weeks for up to 
3 months, including vital signs, immunogenicity, AE and concomitant medication 
assessments, may be performed.

Subjects who are ADA or NAb positive, who have also been administered FVIIa or 
FEIBA, should be followed at all remaining clinic visits up to Day 113 or up to 
3 months following positive ADA/NAb results, whichever is longer.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.

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7.1. Safety
7.1.1. Laboratory Tests
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES 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 labs may be obtained at any time during 
the study to assess any perceived safety concerns.
Table 5.
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
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)
AST, ALT
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Factor V Leiden mutationb
Prothrombin 20210
Mutationb
HBs Agb
Total HbcAbb
HCVAbb
HIVb
Anti-thrombin III
Protein C activityb
Protein S levelb
PT/INR 
aPTT
Fibrinogen
Cardiac Troponin I
Factor VIIIc
Factor IXc
Factor VIII and Factor IX 
inhibitor d
Lipid profileb
CD4 cell countb
Additional Tests (Needed 
for Hy’s law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
At Screening only.
c.
At Screening and Day 1 only.
d.
Only At Screening and only for subjects with hemophilia history of inhibitors, if necessary.  Inhibitor 
test results from up to 6 months prior to Day 1 may be used to meet requirement.

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Any remaining serum/plasma from samples collected for clinical safety labs at baseline and 
at all times post-dosing may be retained and stored for the duration of the study.  Upon 
completion of the study, retained safety samples may be used for the assessment of 
 samples to be used for this purpose will be packaged and 
shipped to Pfizer’s BioBank for storage.  These data will not be included in the clinical study 
report.  Samples will be retained in Pfizer’s Biobank for up to 1 year following completion of 
the study.
7.1.2. Physical Examinations
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
will include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, as well as towards subject reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects 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.
7.1.3. Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at times specified in the Schedule of 
Activities.  Additional collection times, or changes to collection times of blood pressure and 
pulse rate will be permitted, as necessary, to ensure appropriate collection of safety data.
Supine blood pressure will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same 
arm (preferably the dominant arm) should be used throughout the study.  Blood pressure 
should not be taken from the arm with an IV infusion.  Subjects should be instructed not to 
speak during measurements. 
Where possible, the same properly sized and calibrated blood pressure cuff will be used to 
measure blood pressure each time.  The use of an automated device for measuring blood 
pressure (BP) and pulse rate is acceptable, although, when done manually, pulse rate will be 
measured in the brachial/radial artery for at least 30 seconds.  When the timing of these 
measurements coincides with a blood collection, blood pressure and pulse rate should be 
obtained prior to the nominal time of the blood collection.
7.1.4. Respiratory Rate
Respiratory rate should be measured after approximately 5 minutes rest in supine position by 
observing and counting the respirations of the subject for 30 seconds and multiplied by 2.  
When blood pressure is to be taken at the same time, measurement should be done during the 
5 minutes of rest and before blood pressure measurement.
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7.1.5. Temperature
Temperature will be measured orally.  No eating, drinking or smoking is allowed for 
15 minutes prior to the measurement.
7.1.6. Electrocardiogram 
ECGs should be collected at times specified in the Schedule of Activities.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
Triplicate 12-lead ECGs (Day 1 only) will be obtained approximately 2-4 minutes apart; the 
average of the triplicate ECG measurements collected at each nominal time point on 
Day 1 will serve as each subject’s baseline QTcF value.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  If the QTcF interval is increased by 45 msec from 
the baseline, or an absolute QTcF value is 500 msec for any scheduled ECG, then 
2 additional ECGs will be collected, approximately 2-4 minutes apart, to confirm the original 
measurement.  If either of the QTcF values from these repeated ECGs remains above the 
threshold value (45 msec from the baseline; or is 500 msec), then a single ECG must be 
repeated at least hourly until QTcF values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement. 
If the average of QTcF values from the triplicate measurements remains above the threshold 
value (45 msec from the baseline; or is 500 msec), then a single ECG must be repeated at 
least hourly until QTcF values from 2 successive ECGs fall below the threshold value that 
triggered the repeat measurement.
If QTcF values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours 
(or sooner at the discretion of the investigator); or QTcF intervals get progressively longer, 
the subject should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF intervals do not return to less than 500 msec (or to <45 msec above the baseline) 
after 8 hours of monitoring (or sooner at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified physician’s interpretation determines that the QTcF values are in the acceptable 
range.
7.1.7. Injection and Infusion Site Reactions
Injection site reactions will be assessed according to the Schedule of Activities.  Injection site 
reactions may include but are not limited to: erythema, induration, ecchymosis, pain and 
pruritus.  The size and severity of injection site reactions will be assessed and documented.  
If deemed appropriate by the investigator, a consultation with a dermatologist will be 
performed.  Documentation may include a dermatologist report, clinic notes and 
photographs.

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7.2. Efficacy
7.2.1. Hemophilic Bleeding Episodes
During this study, the investigator (or qualified designee) will review the subject diary with 
the subject, and inquire about and record AEs, concomitant treatments, bleeding episodes 
(including location and etiology – traumatic or spontaneous) and any hemostatic treatments 
(including intravenous treatments with factor VII products, factor IX products or bypass 
agents).  Hemostatic therapy that is administered to treat bleeding episodes during the 
Screening period and during the study through the final study visit will be documented as 
concomitant treatment. Subject diary review will include any bleeding episodes treated with 
hemostatic agents.  Bleeding episodes requiring treatment with intravenous coagulation 
factor products or bypass agents will count toward the determination of bleeding episode 
frequency during the period of treatment with PF-06741086. Subject assessment(s) will be 
captured on the subject diary and reviewed by the investigator at study visits.  One 
assessment per infusion will be required.
7.2.2. Bleeding
Occurrences of bleeding episodes treated with hemostatic agent(s) will be obtained from 
subject diaries and medical records.  Where relevant, investigators (or designee) and 
monitors will ensure that there is consistency between the subject’s medical record and/or 
subject diaries and the CRFs.  Bleeding episodes will not be reported as AEs unless 
associated with a serious adverse event, although the concomitant events associated with a 
bleed may be reported as an AE if appropriate (eg, a fracture, pain – see Section 8.6 below 
for guidance on hemophilia related events).  Both spontaneous bleeding episodes and 
traumatic bleeding episodes will be collected.  Only bleeding episodes that are considered 
serious and meet the SAE criteria should be listed on the AE CRF page.  When bleeding 
episodes that meet the SAE criteria are recorded on the AE CRF, the location (site) of the 
bleed and the etiologic classification as spontaneous or traumatic should be included (as 
described in Section 7.2.1 and Section 7.2.3).  The subject diary or medical record will serve 
as the source document for bleeding episodes during the study.  Investigators (or designee) 
and/or monitors will review the subject’s diary/medical records to assist in classification if 
necessary.
7.2.3. Types of Bleeding
For the purposes of this study, a bleed treated with a hemostatic agent will be classified as 
either spontaneous or traumatic. The criteria for spontaneous and traumatic bleeds are 
described below.
Spontaneous Bleeding Episodes: Bleeding episodes should be classified as 
spontaneous if a subject records a bleeding event when there is no known
contributing factor such as definite trauma, antecedent “strenuous” activity, or 
“overuse”. The determination of “strenuous” or “overuse” is at the discretion of the 
subject/caregiver/investigator. For example, if a subject were to wake up in the 
morning and note he was bleeding, a “spontaneous” bleed would be recorded. Target 
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Traumatic Bleeding Episodes: Bleeding episodes should be classified as traumatic 
if a subject records a bleeding event when there is a known or presumed contributing 
factor/reason for the bleed. For example, if a subject were to exercise “strenuously” 
and then have a bleed in the absence of any obvious injury, the bleed would be 
recorded as a traumatic bleed. Target joint bleeding episodes can be traumatic if a 
known action led to bleeding into the joint.
7.2.4. Location of Bleeds
For the purposes of this study, when subjects report a bleed treated with hemostatic therapy, 
the location of the bleed should be recorded in the subject diary or medical record. Bleeds 
will be reported as occurring in 1 of the following locations: joint, muscle/soft tissue, or 
other. Each individual location of multiple-site bleeds will be reported. For joint bleeds, the 
specific joint will be reported. Parameters to identify joint bleeds include: pain on joint 
motion, limitation of motion, and visible swelling of joint.
7.2.5. Treatment of Bleeding Episodes
Bleeding episodes that occur during this study may be treated (on-demand) with hemostatic 
therapy (eg intravenous factor products or rFVIIa bypass agent therapy at approximately 
90 µg/kg) as deemed appropriate by the investigator.  The specific treatment with hemostatic 
therapy is at the discretion of the subject/caregiver/investigator, but all doses of hemostatic 
therapy taken after signing of informed consent will be documented as concomitant 
medications or concomitant treatments.
If a subject experiences a bleeding episode during the washout period preceding screening 
laboratory assessments, the subject is to be stabilized utilizing the subject’s usual hemostatic 
treatment regimen.  Once the bleeding episode has been successfully treated a new washout 
period should be completed prior to obtaining the screening laboratory tests.
If a subject experiences a bleeding episode during the washout period preceding the initial 
administration of PF-06741086 the subject is to be stabilized utilizing the subject’s usual 
hemostatic treatment regimen and a new washout period should be implemented.  Once 
treatment of the bleeding episode with hemostatic agents has been completed a new washout 
period should be initiated in anticipation of the initial treatment with PF-06741086.
If a subject experiences a bleeding episode during the PK assessment period following 
administration of PF-06741086, the subject is to be stabilized utilizing the subject’s usual 
factor VIII or factor IX treatment regimen or rFVIIa bypass agent therapy at approximately 
90 µg/kg, and protocol specified observations and procedures should proceed to completion.
Pausing or withdrawal of treatment with investigational product is not required in the event 
of a breakthrough bleed, but may be considered at the discretion of the investigator.

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7.3. Pharmacokinetics (PK)
7.3.1. Plasma for Analysis of PF-06741086
During all study periods, blood samples (4.5 mL) to provide approximately 1.5 mL plasma 
for PK analysis will be collected into appropriately labeled tubes containing sodium citrate at 
times specified in the Schedule of Activities.  During periods with IV dosing, the PK sample 
should be taken from the opposite arm from the IV dosing.
The actual times may change but the number of PK samples will remain the same.  All 
efforts will be made to obtain the PK samples at the exact nominal time relative to dosing.  
Samples should be obtained within the time window specified in the Schedule of Activities; 
at the end of the IV infusion, samples obtained from 0 to 5 minutes after the end of the 
infusion will not be captured as a protocol deviation (6 or more minutes after the end of the 
infusion will be a deviation).
•
Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the central lab manual.
•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
The PK samples must be processed and shipped as indicated to maintain sample 
integrity. Any deviations from the PK processing steps, including any actions taken, 
must be documented and reported to the Sponsor. On a case-by-case basis, the 
Sponsor may make a determination as to whether sample integrity has been 
compromised.  Any sample deemed outside of established stability, or of questionable 
integrity, will be considered a protocol deviation.
•
 
 
 
 
7.3.2. Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.4. Immunogenicity
7.4.1. Immunogenicity Analyses
The immunogenicity samples must be processed and shipped as indicated to maintain sample 
integrity.  Any deviations from the immunogenicity processing steps, including any actions 
taken, must be documented and reported to the Sponsor.  On a case-by-case basis, the
Sponsor may make a determination as to whether sample integrity has been compromised.  
Any sample deemed outside of established stability, or of questionable integrity, will be 
considered a protocol deviation.
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7.4.2. Plasma for Analysis of ADA (Anti-PF-06741086) and NAb
During all study periods, blood samples (9.0 mL) to provide approximately 3.0 mL plasma 
for ADA and NAb analysis will be collected into appropriately labeled tubes containing 
sodium citrate at times specified in the Schedule of Activities. 
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the central lab manual.
7.4.3. Shipment of Immunogenicity Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.5. Pharmacodynamics 
7.5.1. Pharmacodynamic Markers
The PD samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the PD processing steps, including any actions taken, must be 
documented and reported to the Sponsor. On a case-by-case basis, the Sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed 
outside of established stability, or of questionable integrity, will be considered a protocol 
deviation.
 
7.5.1.1. Samples for TFPI Level
During all study periods, blood samples (2.7 mL) to provide approximately 1.0 mL plasma
for TFPI level analysis will be collected into appropriately labeled tubes containing sodium 
citrate at times specified in the Schedule of Activities. 
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the central lab manual.
7.5.1.2. Samples for Thrombin Generation
During all study periods, blood samples (3.5 mL) to provide approximately 600 μL plasma 
for TGA analysis will be collected into appropriately labeled tubes containing sodium citrate 
at times specified in the Schedule of Activities. 
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the central lab manual.
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7.5.1.3. Samples for Prothrombin Fragment 1 and 2 and D-dimer
During all study periods, blood samples (4.5 mL) to provide approximately 250 μL plasma 
for PF1+2 analysis, approximately 1.0 mL for coagulation tests analyses (D-dimer along with 
the following safety laboratories: Fibrinogen, PT/INR, aPTT, Protein C, Protein S and 
ATIII), and remaining up to approximately 1.0 mL for back-up will be collected into 
appropriately labeled tubes containing sodium citrate at times specified in the Schedule of 
Activities.
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the central lab manual.
7.5.1.4. Samples for Dilute Prothrombin Time 
During all study periods, blood samples (2.7 mL) to provide approximately 200 μL plasma 
for dPT analysis will be collected into appropriately labeled tubes containing sodium citrate 
at times specified in the Schedule of Activities. 
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the central lab manual.
7.5.2. Shipment of Pharmacodynamic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.7. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
389.3 mL for SC cohorts and 428.7 mL for IV cohorts (based on Screening through 
Day 113).  The table below reflects approximate sample volumes needed for each measured 
endpoint.  The actual collection times of blood sampling may change, but the total blood 
volume collected should not increase.  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 30 consecutive days.
Table 6.
Blood Volume for SC Cohorts
Sample Type
Sample 
Volume 
(mL)
Number of Sampling Times
Total 
Volume 
(mL)
Screening
Study 
Period
Follow-Up
Safety Labs 
157
Serum chemistry (with Lipid profilea)
5
1
7
1
45
Hematology
3
1
7
1
27
Prothrombin 20210 mutation
3
1
0
0
3
Factor V Leiden mutation testing
3.5
1
0
0
3.5
aPTT, PT/INR, Anti-thrombin IIIb, 
Factor VIII and Factor IX activityc, 
Fibrinogen,  Protein Ca, Protein Sa, 
D-dimer, PF1+2 (PD samples) [Single 
combined sample]
4.5
1
11
1
58.5
Serology (HBs Ag, HBc Ab, HCV Ab, 
and HIV)
5
1
0
0
5
Cardiac Troponin Id
3
0
5
0
15
PK
4.5
0
11
1
54
Immunogenicity (ADA, NAb)
9
0
5
1
54
PD (note some PD assayed from safety 
samples)
106.8
TFPI level
2.7
0
11
1
32.4
TGA
3.5
0
11
1
42
dPT
2.7
0
11
1
32.4
Factor VIII and Factor IX inhibitora
4.5
1
0
0
4.5
Banked biospecimens
4
0
1
0
4
TOTAL
393.8
a at Screening only.
b at Screening and Days 1, 8, 15, 22 and 29 only.
c at Screening and Day 1 only.
d at Days 1, 8, 15, 22 and 29 only.
C
C
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Table 7.
Blood Volume for IV Cohorts
Sample Type
Sample 
Volume 
(mL)
Number of Sampling Times
Total 
Volume 
(mL)
Screening
Study 
Period
Follow-Up
Safety Labs 
161.5
Serum chemistry (with Lipid profilea)
5
1
7
1
45
Hematology
3
1
7
1
27
Prothrombin 20210 mutation
3
1
0
0
3
Factor V Leiden mutation testing
3.5
1
0
0
3.5
aPTT, PT/INR, Anti-thrombin IIIb, 
Factor VIII and Factor IX activityc,
Fibrinogen,  Protein Ca, Protein Sa, 
D-dimer, PF1+2 (PD samples) [Single 
combined sample]
4.5
1
12
1
63
Serology (HBs Ag, HBc Ab, HCV Ab, 
and HIV)
5
1
0
0
5
Cardiac Troponin Id
3
0
5
0
15
PK
4.5
0
15
1
72
Immunogenicity (ADA, NAb)
9
0
5
1
54
PD (note some PD assayed from safety 
samples)
115.7
TFPI level
2.7
0
12
1
35.1
TGA
3.5
0
12
1
45.5
dPT
2.7
0
12
1
35.1
Factor VIII and Factor IX inhibitora
4.5
1
0
0
4.5
Exploratory biomarkers
2.7
0
5
0
13.5
Banked biospecimens
4
0
1
0
4
Discard tube
2
0
4
0
8
TOTAL
433.2
a at Screening only.
b at Screening and Days 1, 8, 15, 22 and 29 only.
c at Screening and Day 1 only.
d at Days 1, 8, 15, 22 and 29 only.
7.8. Triggered Requirements
Condition
Action

Platelet count <75,000/L.

Fibrinogen level < LLN.

Hemoglobin level <10 gm/dL.

PT/INR 1.25 times the ULN
Subjects who are found to have one of the 
coagulation pathway abnormalities defined by 
these corresponding lab value criteria should be 
brought into the clinic immediately for an
unscheduled visit and the respective laboratory test 
should be repeated.
Positive ADA
Subjects may be requested to return for additional 
follow-up visits after Day 113.  Extended 
follow-up visits every 2 weeks for up to 3 months, 
including vital signs, immunogenicity, AE and 
concomitant medication assessments, may be 
performed.

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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any nonserious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the Sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
Sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last 
visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

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
Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.3.1. Adverse Events of Special Interest  
PF-06741086 may increase the risk of formation of thrombi or emboli, and thus may increase 
the risk of AEs associated with thrombi or emboli.  AEs that are associated with or 
reasonably suspected to be related to thrombi or emboli will require expedited reporting to 
the Sponsor as defined in Section 8.15.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the Sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.

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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Hemophilia Events
Hemophilia events are certain AEs that are likely to occur due to the subject’s hemophilia.
For example, pain, swelling, or decreased range of motion due to a bleed may be an expected 
consequence of hemophilia (the bleeding episode itself is not reported as an AE, unless the 
bleeding episode meets the criteria for a Serious Adverse Event, see Section 8.7).
Investigators should determine if an AE is expected because of the subject’s hemophilia.
Bleeding or bruising, not due to the subject’s hemophilia, will be recorded as an AE, and not 
a hemophilia event.  Hemophilia events that require hospitalization or meet other SAE 
criteria should be reported as SAEs.
8.7. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.

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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.7.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.7.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with 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).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches 3 × ULN (whichever is smaller).

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The subject should return to the investigational 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, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected. 
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.8. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

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
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.9. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:
MILD
Does not interfere with subject’s usual function.
MODERATE
Interferes to some extent with subject’s usual function.
SEVERE
Interferes significantly with subject’s usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
Severity grading for dose limiting toxicities (≥ Grade 3), per Appendix 2, will follow the 
NIAID DMID scale.7

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8.10. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see the section on Reporting Requirements).  If the 
investigator’s causality assessment is “unknown but not related to investigational product,”
this should be clearly documented on study records. 
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, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.11. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products);
3. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure. The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).

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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer 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 pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  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 study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.12. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.

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8.13. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.14. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent(s)/legal guardian/legally acceptable representative.  In addition, each 
study subject/parent(s)/legal guardian/legally acceptable representative will be questioned 
about AEs.
8.15. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.15.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 

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8.15.2. Adverse Events of Special Interest
Thromboembolic or ischemic events are considered important medical events (see 
Section 8.7).  As medically important events, Pfizer is to be notified within 24 hours of 
awareness of the thromboembolic or ischemic event.  Data entry and additional reporting 
requirements will follow the same instructions for all other SAEs as listed in Section 8.15.1.
8.15.3. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.15.4. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
are outlined here and further detailed in a Statistical Analysis Plan (SAP), which will be 
maintained by the Sponsor.  The Statistical Analysis Plan may modify what is outlined in the 
protocol where appropriate; however, any major modifications of the endpoint definitions or 
their analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The total sample size of approximately 24 subjects for 4 dose cohorts is based on clinical 
considerations to provide adequate safety, tolerability, PK, PD and efficacy information at 
each dose level and/or route of administration.  Each single dose cohort includes 6 subjects to 
ensure sufficient sample size for assessment of safety, PK, PD and efficacy.  Additional 
subjects and/or cohorts may be added to fully explore the dose range and efficacy.
This sample size is also considered sufficient to support initial analyses for efficacy based on 
the endpoint of annualized bleeding rate (ABR).  With 6 subjects per cohort, there is greater 
than 80% power to detect an 85% reduction in ABR compared to a historical 
factor-replacement treatment (control group) at one-sided alpha of 0.1.  The power 
calculation is based on a Poisson regression model with assumptions that the historical 
control group has a bleeding rate of 2.36/patient-month and the study duration is 3 months.
9.2. Efficacy Analysis
9.2.1. Analysis of the Efficacy Endpoint
ABR will be calculated and summarized descriptively by dose level.  ABR will also be 
summarized by inhibitor status, overall and by dose level and may be evaluated by factor 
deficiency (Factor VIII vs Factor IX). 

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The ABR will be analyzed using a Poisson regression model with over dispersion, if 
appropriate.  The model based ABR and upper and lower 80% CI will be presented.  The 
details will be included in the SAP.
9.3. Analysis of Pharmacokinetic Endpoints
For non-compartmental analysis (NCA) calculations with QW dosing frequency, the 
Day 36 plasma concentration will be imputed as the same as the Day 29 concentration.
The concentration of PF-06741086 will be descriptively summarized by PK dose and study 
day.  Individual subject and median profiles of the PF-06741086 concentration versus time 
data will be plotted by dose using actual and nominal times respectively.  Median profiles 
will be presented on both linear and logarithmic scales.
Noncompartmental PK parameters for PF-06741086 will be descriptively summarized by 
dose level and study day in accordance with Pfizer data standards. 
Dose normalized AUCτ and Cmax of PF-06741086 will be plotted against dose (using a 
logarithmic scale), and will include individual subject values and the geometric means for 
each dose.  These plots will be used to help understand the relationship between the PK 
parameters and dose.
9.4. Analysis of Pharmacodynamic Endpoints
The PD endpoints include total TFPI, thrombin generation (parameters include lag time, peak 
thrombin generation, and endogenous thrombin generation potential), prothrombin fragments 
1+2, D-dimers, and dilute PT. 
Absolute and change from baseline values will be listed and summarized descriptively by 
dose level and study day.  Change from baseline of each PD endpoint will be analyzed using 
a mixed model for repeated measures (MMRM) with a restricted maximum likelihood 
method for the estimation of the covariance parameters.  Details will be provided in the SAP.
dPT-concentration relationship will be explored.  Dose-response relationship for other PD 
endpoints may also be explored.
 
 
CCI

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9.6. Safety Analysis
Adverse events, ECGs, vital signs (blood pressure, pulse rate, temperature and respiratory 
rate), physical examinations and safety laboratory data (including hematology, PT/INR, 
aPTT, chemistry, urinalysis, fibrinogen, anti-thrombin III activity and cardiac troponin I) will 
be reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
subjects.  Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  Incidence and severity of TEAEs, withdrawals due to 
TEAEs, and infusion and injection site reactions will be summarized by dose level.  
Abnormal and clinically relevant changes in vital signs and ECG parameters will be 
summarized by dose level and study day.  Incidence and magnitude of abnormal laboratory 
findings will be summarized by dose level. Abnormal safety findings will also be presented 
separately for inhibitor subjects by dose level.
Only positive ADA samples and the corresponding baseline sample will be tested in the NAb 
assay.  Frequencies of ADA and NAb will be summarized by dose level and study day for 
samples collected. 
Medical history, medication history and physical examination information, as applicable,
collected during the course of the study will be captured for inclusion into the study database, 
unless otherwise noted.  Any untoward findings identified on physical examination 
conducted after the administration of the first dose of investigational product will be captured
as an adverse event, if those findings meet the definition of an adverse event. Data collected 
at Screening that are used for inclusion/exclusion criteria, such as laboratory data, ECGs and 
vital signs will be included in the study database.  Demographic data collected at Screening 
will be reported.
9.6.1. Derivation of Vital Signs Parameters
Supine blood pressures and pulse rate will be recorded at each assessment time indicated in 
the Schedule of Activities.  Baseline for vital signs will be defined as the last measurement 
before the Day 1 investigational product administration.
Vital signs (BP; PR) will be assessed for clinically relevant trends.  The standard algorithms 
and reporting formats will be applied for analyzing all safety data. 
Absolute values and changes from baseline in for systolic and diastolic blood pressure and 
pulse rate will be summarized by dose level and study day.
Maximum absolute values and maximum changes from baseline for vital signs will also be 
summarized descriptively by dose level using categories as defined in the SAP.  Numbers 
and percentages of subjects meeting the categorical criteria will be provided and individual 
values listed in the study report.

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9.6.2. Electrocardiogram (ECG) Analysis
Baseline for ECG will be defined as the mean of triplicate measurement before the 
Day 1 study drug administration.  Changes from baseline for the ECG parameters QT 
interval, pulse rate, QTcF interval, PR interval and QRS interval will be summarized by dose 
level and study day.
The number (%) of subjects with maximum post dose QTc values and maximum increases 
from baseline in the following categories will be tabulated by dose level: 
Safety QTcF
Borderline (msec)
Prolonged (msec)
Absolute Value
450 - < 480
480
Absolute Change
30 - < 60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized.
If more than one ECG is collected at a nominal time post dose (for example, triplicate 
ECGs), the mean of the replicate measurements will be used to represent a single observation 
at that time point.  If any of the three individual ECG tracings has a QTcF value 500 msec, 
but the mean of the triplicates is not 500 msec, the data from the subject’s individual tracing 
will be described in a safety section of the study report in order to place the 500 msec value 
in appropriate clinical context.  However, values from individual tracings within triplicate 
measurements that are 500 msec will not be included in the categorical analysis unless the 
average from the triplicate measurements is also 500 msec.  Changes from baseline will be 
defined as the change between QTcF post dose from the average of the last pre-dose 
triplicate values on the dosing day in each period.
9.7. Interim Analysis
Cumulative data will be reviewed for dose escalation as defined in Section 3.3.  The safety, 
PK, PD and efficacy data will be routinely reviewed by the study team for internal decisions 
regarding future study planning. Additional cohort(s) may be added, and a cohort may be 
expanded to fully explore the dose range and/or efficacy endpoint following the review of the 
cumulative data. 
No formal interim analysis will be conducted for this study. However, as this is a 
Sponsor-open study, the Sponsor may conduct unblinded reviews of the data during the 
course of the study for the purpose of safety assessment, facilitating dose escalation 
decisions, facilitating PK/PD modeling, and/or to support clinical development.  Unblinded 
results will be reviewed by a designated limited number of Sponsor colleagues within the 
study team. Refer to the study’s Data Blinding Plan and/or SAP for specific details including 
delineation of study team members who will be involved in these unblinded reviews as well 
as steps to be instituted ahead of initiation of any unblinded review to ensure study integrity 
is maintained.

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9.8. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 

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In most cases, the source documents are the hospital’s or the physician’s subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent/assent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer’s written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/EC and national competent authority.  
All correspondence with the IRB/EC should be retained in the investigator file.  Copies of 
IRB/EC approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.

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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed and approved by the Sponsor, approved by the IRB/EC before use, and available 
for inspection.
The investigator must ensure that each study subject or his legally acceptable representative,
or parent(s) or legal guardian if a minor, is fully informed about the nature and objectives of 
the study and possible risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent, spouse), and that the subject’s assent 
was obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.

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If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject’s legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC. The 
investigator will retain the original of each subject’s signed consent/assent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/Ecs and investigator databases may be used as recruitment 
procedures. 
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
12.5. 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 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last subject last visit (LSLV).

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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06741086 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-Sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-Sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.

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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-Sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II -– “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.

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16. REFERENCES
1.
Berntorp E, Shapiro AD. Modern haemophilia care. Lancet. 2012;379(9824):1447-56
2.
Astermark J.  Overview of inhibitors. Semin Hematol. 2006; 43(suppl 4): S3-S7.
3.
Maroney SA, Ellery PE, Wood JP, Ferrel JP, et al. Comparison of the inhibitory activity 
of human TFPIα and TFPIβ. Thromb Haemost 2013; 11:911-918.
4.
Knappe S, Gorczyca ME, Jilma B, et al. Plasmatic tissue factor pathway inhibitor is a 
major determinant of clotting in factor VIII inhibited plasma or blood. Thromb 
Haemost. 2013; 109:450-7.
5.
Dahm A, Vlieg AVH, Bendz B et al.  Low levels of tissue factor pathway inhibitor 
(TFPI) increase the risk of venous thrombosis.  Blood. 2003;101:4387-4392.
6.
Chowdary P, Lethagen S, Friedrich U, et al.  Safety and pharmacokinetics of anti-TFPI 
antibody (concizumab) in healthy volunteers and patients with hemophilia:  and 
randomized first human dose trial.  J Thromb Haemost.  2015;13:743-54.
7.
NIAID Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity 
Tables (available at https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf)

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Abbreviations 
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ABR
annualized bleeding rate
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
ALB
albumin
ALT
alanine aminotransferase
APCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATIII
antithrombin III
AUC
area under the curve
BMI
body mass index
BP
blood pressure
BU
Bethesda Units
CDC
complement dependent cytotoxicity
CDS
core data sheet
Cmax
peak or maximum observed concentration
Cmin
minimum observed concentration
CNS
central nervous system
CRF
case report form
CSA
clinical study agreement
CSF
cerebrospinal fluid
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
DMC
data monitoring committee
DNA
deoxyribonucleic acid
dPT
dilute prothrombin time
DU
dispensable unit
EC
ethics committee
EC50
half maximal effective concentration
ECG
electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United 
States)

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Abbreviation
Term
FEIBA
Factor Eight Inhibitor Bypass Agent
FIB
fibrinogen
FIH
first-in-human
FIX
coagulation factor IX
FIXa
activated factor X
FSH
follicle-stimulating hormone
FV
coagulation factor V
rFVIIa
activated coagulation factor VII
FVIII
coagulation factor VIII
GCP
Good Clinical Practice
GLOB
globulin
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
HBc Ab
hepatitis B core antibody
HBs Ag
hepatitis B surface antigen
HCV Ab
hepatitis C antibody
HIV
human immunodeficiency virus
Hr
hour
HRQL
health-related quality of life
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IgG1
immunoglobulin of the G isotype, subclass 1
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IPM
investigational product manual
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous 
IVIG
intravenous immunoglobulin
IVR
interactive voice response
IWR
interactive web response
JET
jacketed external telemetry
KD
binding affinity
LFT
liver function test
LLN
lower limit of normal
LPD
local product document
LSLV
last subject last visit 
MAD
multiple ascending dose
Min
minute

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Abbreviation
Term
MMRM
mixed model for repeated measures
MTD
maximum tolerated dose
N/A
not applicable
NAb
neutralizing antibodies
NCA
non-compartmental analysis
NIAID DMID
National Institute of Allergy and Infectious Diseases
Division of Microbiology and Infectious Diseases
NOAEL
no observed adverse effect level
PCD
primary completion date
PD
pharmacodynamic
PE
physical examination
PF1+2
prothrombin fragment 1+2
PFS
pre-filled syringe
PI
principal investigator
PK
pharmacokinetic
PT
prothrombin time
PT/INR
prothrombin time/international normalized ratio
QM
once monthly, eg once every 28 days
QW
once weekly, eg once every 7 days
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCL
Supply Chain Lead
SIB
suicidal ideation and behavior
SOP
standard operating procedure
SPC
summary of product characteristics
SPR
surface plasmon resonance
SRSD
single reference safety document
TBD
to be determined
TEAE
treatment emergent adverse event
TEG
thromboelastography
TFPI
tissue factor pathway inhibitor
TGA
thrombin generation assay
TK
toxicokinetic
Tmax
time to reach maximum concentration
TMDD
target mediated drug disposition
ULN
upper limit of normal
US
United States
USPI
United States package insert
Vss
volume of distribution at steady state
WHO
World Health Organization

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Appendix 1. Thrombotic Adverse Events for Stopping Criteria
Acute coronary syndrome
Hepatic artery thrombosis 
Retinal artery embolism 
Acute myocardial infarction
Hepatic vascular thrombosis
Retinal artery occlusion 
Aortic embolus 
Hepatic vein thrombosis 
Retinal artery thrombosis 
Aortic thrombosis 
Iliac artery embolism
Retinal vascular thrombosis 
Arterial thrombosis 
Intracardiac mass
Retinal vein occlusion 
Atrial thrombosis
Intracardiac thrombus
Retinal vein thrombosis 
Axillary vein thrombosis 
Intracranial venous sinus 
thrombosis 
Silent myocardial infarction
Basilar artery thrombosis 
Intrapericardial thrombosis
Spinal artery embolism 
Blue toe syndrome 
Jugular vein thrombosis 
Spinal artery thrombosis 
Budd-Chiari syndrome 
Mesenteric artery embolism 
Splenic vein thrombosis 
Carotid arterial embolus 
Mesenteric artery thrombosis Subclavian artery embolism 
Carotid artery thrombosis 
Mesenteric vein thrombosis 
Subclavian artery thrombosis 
Cavernous sinus thrombosis 
Microembolism
Subclavian vein thrombosis 
Cerebellar artery thrombosis 
Myocardial infarction
Subendocardial ischaemia
Cerebellar embolism 
Pelvic venous thrombosis 
Superior sagital sinus 
thrombosis
Cerebral artery embolism 
Penile vein thrombosis 
Myocardial ischaemia
Cerebral artery thrombosis 
Peripheral artery thrombosis 
Thrombosis corpora cavernosa 
Cerebral thrombosis 
Peripheral embolism 
Thrombosis mesenteric vessel 
Cerebral venous thrombosis 
Precerebral artery thrombosis Thrombotic cerebral infarction 
Cerebrospinal thrombotic 
tamponade 
Portosplenomesenteric 
thrombosis
Thrombotic microangiopathy 
Coronary artery embolism
Portal vein thrombosis 
Thrombotic stroke 
Coronary artery thrombosis
Pulmonary artery thrombosis Transverse sinus thrombosis 
Deep vein thrombosis 
Pulmonary embolism 
Truncus coeliacus thrombosis 
Disseminated intravascular 
coagulation 
Pulmonary microemboli 
Vena cava embolism 
Embolia cutis medicamentosa 
Pulmonary thrombosis 
Vena cava thrombosis 
Embolic cerebral infarction 
Pulmonary venous thrombosis Vena caval embolism and 
thrombosis
Embolic stroke 
Purpura fulminans
Venous thrombosis 
Embolism 
Renal artery thrombosis 
Venous thrombosis limb 
Embolism arterial 
Renal embolism 
Vertebral artery thrombosis
Embolism venous 
Renal vascular thrombosis 
Femoral artery embolism 
Renal vein embolism 
Hepatic artery embolism 
Renal vein thrombosis 

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Appendix 2. Criteria for Dose Limiting Toxicity
Adverse Events
Unless incontrovertibly due to extraneous causes, treatment emergent events conforming to 
the following criteria will constitute dose limiting toxicity: 
1. Laboratory, vital sign or electrocardiogram findings conforming to the criteria 
provided below; 
2. When not covered by the criteria listed below, treatment emergent adverse event 
graded as severe or ≥ Grade 3 under the NIAID Division of Microbiology and 
Infectious Diseases Adult Toxicity Tables (2007 Draft Version).
Hematology
Hemoglobin
<0.8 times the LLN or <80% times the baseline value if the 
baseline result is less than the lower limit of the reference 
range
Hematocrit
<0.8 times the LLN or <80% times the baseline value if the 
baseline result is less than the lower limit of the reference 
range
Platelets
<100,000 or 0.77 times the baseline value if the baseline 
result is less than the lower limit of the reference range.
Chemistry
Total bilirubin
>1.5 times the ULN
Direct bilirubin
>1.5 times the ULN
Indirect bilirubin
>1.5 times the ULN
Creatinine kinase
>2.0 times the ULN
Creatinine
>1.3 times the ULN
Coagulation Pathway 
PT
4 seconds above the baseline value
Cardiac Troponin I
If values are normal at baseline, any results above the 
myocardial ischemia range
Any result in the myocardial infarction range, regardless of 
baseline values

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Fibrinogen
0.5 times LLN or 0.5 times the baseline value
Vital Signs
Temperature
>38.5C
Pulse Rate
<40 or >120 BPM
Blood Pressure
Systolic 30 mm Hg change from baseline in same posture
Systolic <90 mm Hg
Diastolic 20 mm Hg change from baseline in same posture
Diastolic <50 mm Hg
Electrocardiogram
PR interval
300 msec 
1.25 times baseline when baseline >200 msec
1.50 times baseline when baseline 200 msec
QRS interval
140 msec
1.50 times baseline
QTcF interval
500 msec