A PHASE 1B MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND TOLERABILITY AND DETERMINE THE MAXIMUM TOLERATED DOSE OF PF-05230907 IN SUBJECTS WITH INTRACEREBRAL HEMORRHAGE (ICH)
Phase: PHASE1
Conditions: Intracerebral Hemorrhage
Sponsor: Pfizer

PF-05230907 
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CLINICAL PROTOCOL
A PHASE 1B MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE 
SAFETY AND TOLERABILITY AND DETERMINE THE MAXIMUM 
TOLERATED DOSE OF PF-05230907 IN SUBJECTS WITH INTRACEREBRAL 
HEMORRHAGE (ICH)
Compound:
PF-05230907
Compound Name:
Factor Xa Variant (I16L)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2015-005703-83
Protocol Number:
B2341002
Phase:
1b
CCI

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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 2
17 JAN 2017

Protocol Summary:

Removed the requirement for AEs to be in the 
same system organ class from the criteria for 
sequential dosing and ad hoc eDMC meetings.  
This was required by regulatory authorities in 
Germany.

Schedule of Activities:

Added requirement for Sponsor and investigator 
documentation of TIEs on Day 8 to footnote ‘m’.

Added footnote ‘s’ to indicate the requirement for 
safety labs to be analyzed locally along with 
central lab analysis for sites in Germany. This 
was required by regulatory authorities in 
Germany.

Added foot note ‘t’ to include cardiac troponin T 
samples for local analysis only.

Section 3.1. Sequential Dosing:

Removed the requirement for AEs to be in the 
same system organ class from the criteria for 
sequential dosing.  

Added cardiac troponin T results to the 
requirements for 72-hour safety data review.  
This applies only to sites where cardiac troponin 
T is analyzed locally.

Section 3.3. eDMC Review of Cohort Safety Data:

Removed the requirement for AEs to be in the 
same system organ class from the criteria for ad 
hoc eDMC meetings.  

Section 4.1. Inclusion Criteria:

An additional requirement for informed consent 
(referenced in Appendix 8) was added for 
subjects in Sweden.  This requirement was 
requested by regulatory authorities in Sweden.

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Document
Version Date
Summary of Changes and Rationale

Section 4.6.2.2 Glasgow Coma Scale:

Removed the requirement for certification 
documentation and/or sponsor training.  GCS is a 
standard clinical assessment which does not 
require specific training.

Section 6.2.2. Day 1 Hour 0 Minute 5:

For sites in Germany, the requirement for safety 
labs to be analyzed locally along with central lab 
analysis was added.  

Section 6.2.3. Day 1 Hour 0 Minute 45:

For sites in Germany, the requirement for safety 
labs to be analyzed locally along with central lab 
analysis was added.

Section 6.2.4. Day 1 Hour 3:

Cardiac troponin T, where applicable, was 
included for sample collection.

Section 6.2.5. Day 1 Hour 9:

Cardiac troponin T, where applicable, was 
included for sample collection.

Section 6.2.6. Day 2 (24 Hours):

For sites in Germany, the requirement for safety 
labs to be analyzed locally along with central lab 
analysis was added.

Cardiac troponin T, where applicable, was 
included for sample collection.

Section 6.2.7. Day 3 (48 Hours):

Cardiac troponin T, where applicable, was 
included for sample collection.

Section 6.2.8. Day 4 (72 Hours):

For sites in Germany, the requirement for safety 
labs to be analyzed locally along with central lab 
analysis was added.

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Document
Version Date
Summary of Changes and Rationale

Cardiac troponin T, where applicable, was 
included for sample collection.

Section 7.1.6. Cardiac Troponin I:

A statement on the precedence of centrally-
analyzed troponin I, versus locally analyzed 
troponin T, for safety data review purposes was 
added.

Section 7.1.9 Clinical Laboratory Tests:

For sites in Germany, the requirement for safety 
labs to be analyzed locally along with central lab 
analysis was added.

Section 9.8 Data Monitoring Committee:

Removed the requirement for AEs to be in the 
same system organ class from the criteria for ad 
hoc eDMC meetings.

Section 13. Definition of End of Trial:

Section 13 was revised to define the end of the 
trial as last subject last visit (LSLV) for all 
participating countries.  Previous version had a 
separate definition for EU Member States.  This 
change was required by regulatory authorities in 
Sweden.

Appendix 8  Definition for Subjects Capable of 
Providing Consent in Sweden:

Appendix 8 was added to the protocol to provide 
the definition for subjects capable of providing 
consent in Sweden.  This was a requirement from 
regulatory authorities in Sweden.
Amendment 1
27 JUN 2016

Protocol Summary:

“Changes in Factor V after dosing with 
PF-05230907” was incorrectly listed as an 
exploratory endpoint in this study and was 
removed.  

A paragraph summarizing additional safeguards 
for subject safety requested by regulatory 

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Document
Version Date
Summary of Changes and Rationale
agencies was added, including rules for sequential 
dosing, rules for dose pausing, eDMC dose 
escalation oversight, and additional eDMC safety 
review.

The criteria for a pause in dosing pending eDMC 
review of adverse event data were added.

The requirement for an interim review memo 
from the eDMC chair that authorizes dose 
escalation was added.

eDMC recommendations were added as an input 
for limiting dose escalation increments.

The incorrect visit day (Day 8) was referenced for 
observing treatment emergent modulations of 
laboratory safety biomarkers.  The correct visit 
day - Day 4 – was added.

The maximum sample size was changed from 
50 to 51, to correctly reflect the maximum sample 
size enrolled in this study under mCRM 
restrictions.

Schedule of Activities:

Blood sample for Factor V activity at Screening 
was removed as this parameter will no longer be 
evaluated in this study.

Table and footnote [h] were updated to include 
the collection of baseline height data, which may 
be subject reported.  This requirement was not 
specified in the previous text.

Cardiac troponin I labs were updated to allow 
either local laboratory analysis or central 
laboratory analysis.

Missing text Doppler ultrasonography was added 
to footnote [e].

Section 1.5. Dose Rationale:

Sequential dosing was added as mitigation
against the unanticipated risks of exposure at 
higher doses.

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Document
Version Date
Summary of Changes and Rationale

eDMC recommendations were added as an input 
for limiting dose escalation increments.

Section 3. Study Design:

A paragraph summarizing additional safeguards 
for subject safety requested by regulatory 
agencies was added, including rules for sequential 
dosing, rules for dose pausing, eDMC dose 
escalation oversight, and additional eDMC safety 
review.

Section 3.1. Sequential Dosing:

3.1 added as a new section to describe rules 
governing sequential dosing. 

The requirements and criteria for sequential 
dosing of cohorts (at dose levels not previously 
administered) were added.

Brain imaging for 72 hour safety review was 
revised to correctly reflect the use of both CT and 
MRI.

Cardiac troponin I was added as a parameter for 
72 hour safety review.

The criteria for a pause in dosing pending eDMC 
review of adverse event data were added.

Section 3.2. Progression to Subsequent Cohort:

3.2 added as a new section to describe rules 
governing progression to the next cohort and dose 
escalation. 

eDMC recommendations were added as an input 
for dose level assignments. 

Section 3.3. eDMC Review of Cohort Safety Data:

3.3 added as a new section to describe eDMC 
review of safety data and eDMC chairperson 
authorization for dose escalation. 

The requirement for an interim review memo 
from the eDMC chair that authorizes dose 
escalation was added.

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Document
Version Date
Summary of Changes and Rationale

The criteria for a pause in dosing pending eDMC 
review of adverse event data were added.

Section 3.4. Stopping Rules for mCRM Algorithm:

3.4 added as a new section to describe the 
stopping rules for dose level assignment by the 
mCRM algorithm.

The maximum sample size was changed from 
50 to 51, to correctly reflect the maximum sample 
size enrolled in this study under mCRM 
restrictions.

Table 2 – Dose Escalation Schema was moved to 
this section.

Figure 1 – CRM Process Flow Schematic was 
moved to this section and updated to include 
sequential dosing process steps.

Section 3.5. Duration of Study Participation:

3.5 added as a new section to describe length of 
study participation per subject. No changes were 
made to the text in this section. 

Section 4.1. Inclusion Criteria:

Inclusion criterion #1 was modified to include a 
clause stating that legal representatives may only 
consent subjects in countries where this is 
accepted.

Section 4.6.2.1. Modified Rankin Score mRS:

The requirement for site source documentation 
was added.

Section 5.3.1. Dosage Form(s) and Packaging:

IP descriptions were updated, and reconstitution 
volume with NaCl concentration was added for 
administrative purposes.

Section 5.3.2. Preparation and Dispensing:

IP description was removed, with text added for 
administrative purposes.

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Version Date
Summary of Changes and Rationale

Section 5.5. Investigational Product Storage:

IP description was removed for administrative 
purposes.

Section 5.7.2. Prohibited During the Study:

Low dose subcutaneous low-molecular weight 
heparin and unfractionated heparin were added as 
acceptable treatments in accordance with 
published guidelines for the treatment of stroke.

Section 6.1. Screening:

The collection of baseline height data was added, 
which may be subject reported.  This requirement 
was not specified in the previous text.

Blood sample for Factor V was removed as this 
parameter will no longer be evaluated in this 
study.

Cardiac troponin I labs were updated to allow 
either local laboratory analysis or central 
laboratory analysis.

Section 6.2.3. Day 1 Hour 0:

The PD sample for Factor V was removed as this 
parameter will not be evaluated in this study.

Section 6.2.4. Day 1 Hour 3:

The requirement for obtaining an actual weight as 
soon as possible post-dose was added to conform 
with the requirement listed in the Schedule of 
Activities (footnote h).

Cardiac troponin I labs were updated to allow 
either local laboratory analysis or central 
laboratory analysis.

Section 6.2.5. Day 1 Hour 9:

Cardiac troponin I labs were updated to allow 
either local laboratory analysis or central 
laboratory analysis.

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Version Date
Summary of Changes and Rationale

Section 6.2.6. Day 2:

Blood sample for Factor V was removed as this 
parameter will no longer be evaluated in this 
study.

Cardiac troponin I labs were updated to allow 
either local laboratory analysis or central 
laboratory analysis.

Section 6.2.7. Day 3:

Cardiac troponin I labs were updated to allow 
either local laboratory analysis or central 
laboratory analysis.

Section 6.2.8. Day 4:

A blood sample for ADA, NAb, and Factor X 
activity must be collected if the subject is 
discharged at Day 4. The previous text did not 
include this.

Cardiac troponin I labs were updated to allow 
either local laboratory analysis or central 
laboratory analysis.

Section 6.2.9. Day 8 or Discharge:

A blood sample for Factor X activity must be 
collected at this visit.  The previous text did not 
include this.

Section 8.6.1. Protocol Specified Serious Adverse 
Events:

Peripheral arterial ischemia was added to the list 
comply with Appendix 1.

Section 9.1. Statistical Methods:

The maximum sample size was changed from 
50 to 51, to correctly reflect the maximum sample 
size enrolled in this study under mCRM 
restrictions.

Section 9.3. Sample Size Determination:

The maximum sample size was changed from 
50 to 51, to correctly reflect the maximum sample 
size enrolled in this study under mCRM 
restrictions.

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Version Date
Summary of Changes and Rationale

Section 9.8. Data Monitoring Committee:

The criteria for a pause in dosing pending eDMC 
review of adverse event data were added.

The requirement for an interim review memo 
from the eDMC chair that authorizes dose 
escalation was added.

Section 12.1. Institutional Review Board /Ethics 
Committee: 

It should be noted that for substantial 
amendments to the protocol, national competent 
authority approval is also required prior to 
implementing the amendment.  The previous text 
did not include this.

Section 12.2. Ethical Conduct of the Study:  

The protocol will be conducted in accordance 
with the current version of the Declaration of 
Helsinki.  The protocol incorrectly referenced the 
2008 version; this year was removed from the 
text to comply with regulatory requests.  

References:

A reference for the NIH Stroke Scale contained a 
link to the National Institute of Neurological 
Disorders and Stroke webpage that is no longer 
associated with the NIHSS.  The following 
correct link was added.
http://www.ninds.nih.gov/disorders/stroke/strokescales.htm
Original 
protocol
17 December 
2015
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................15
LIST OF FIGURES .................................................................................................................16
APPENDICES .........................................................................................................................16
PROTOCOL SUMMARY.......................................................................................................17
SCHEDULE OF ACTIVITIES................................................................................................23
1. INTRODUCTION ...............................................................................................................28
1.1. Indication.................................................................................................................28
1.2. Mechanism of Action/Indication.............................................................................28
1.3. Background and Rationale ......................................................................................28
1.3.1. Nonclinical Safety Data..............................................................................28
1.3.1.1. Nonclinical Pharmacology........................................................28
1.3.1.2. Nonclinical Pharmacokinetics and Safety Toxicology .............29
1.3.2. Clinical Experience with PF-05230907......................................................30
1.4. Study Rationale .......................................................................................................32
1.5. Dose Rationale ........................................................................................................32
1.6. Anticipated Risks and Safety Monitoring ...............................................................34
1.6.1. Summary of Risk Benefit ...........................................................................34
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................35
2.1. Objectives................................................................................................................35
2.2. Endpoints.................................................................................................................35
3. STUDY DESIGN.................................................................................................................37
3.1. Sequential Dosing ...................................................................................................37
3.2. Progression to Subsequent Cohort ..........................................................................38
3.3. eDMC Review of Cohort Safety Data.....................................................................39
3.4. Stopping Rules for mCRM Algorithm....................................................................39
3.5. Duration of Study Participation...............................................................................40
4. SUBJECT SELECTION......................................................................................................41
4.1. Inclusion Criteria.....................................................................................................42
4.2. Exclusion Criteria....................................................................................................43
4.3. Randomization Criteria ...........................................................................................44
4.4. Lifestyle Guidelines ................................................................................................44

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4.5. Sponsor’s Qualified Medical Personnel..................................................................45
4.6. Rater Qualifications.................................................................................................45
4.6.1. ABC/2.........................................................................................................45
4.6.2. Neurologic Functional Assessments...........................................................46
4.6.2.1. Modified Rankin Score (mRS)..................................................46
4.6.2.2. Glasgow Coma Scale (GCS).....................................................46
4.6.2.3. National Institutes of Health Stroke Scale (NIHSS) .................46
5. STUDY TREATMENTS.....................................................................................................46
5.1. Allocation to Treatment ..........................................................................................46
5.2. Subject Compliance.................................................................................................47
5.3. Investigational Product Supplies.............................................................................47
5.3.1. Dosage Form(s) and Packaging..................................................................47
5.3.2. Preparation and Dispensing........................................................................48
5.4. Administration.........................................................................................................48
5.5. Investigational Product Storage ..............................................................................48
5.6. Investigational Product Accountability...................................................................49
5.6.1. Destruction of Investigational Product Supplies ........................................49
5.7. Concomitant Treatment(s) and Medication(s) ........................................................50
5.7.1. Prohibited Prior Treatments and Medications............................................50
5.7.2. Prohibited During the Study.......................................................................50
5.7.3. Permitted During the Study ........................................................................50
5.8. Rescue Medication ..................................................................................................51
6. STUDY PROCEDURES .....................................................................................................51
6.1. Screening (Up to 6.0 Hours Pre-dose) ....................................................................51
6.2. Study Period (Hospitalization Period).....................................................................54
6.2.1. Day 1 Hour 0 (Days are Relative to Start of Study Treatment)..................54
6.2.2. Day 1 Hour 0 Minute 5 (2 Minutes).........................................................54
6.2.3. Day 1 Hour 0 Minute 45 (15 Minutes).....................................................55
6.2.4. Day 1 Hour 3 (30 Minutes) ......................................................................56
6.2.5. Day 1 Hour 9 (30 Minutes) ......................................................................56
6.2.6. Day 2 (24 Hours 6 Hours) ........................................................................56
6.2.7. Day 3 (48 Hours 6 Hours) ........................................................................57

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6.2.8. Day 4 (72 Hours 6 Hours) ........................................................................58
6.2.9. Day 8 or Discharge (24 Hours) ................................................................60
6.3. Follow-up Visits......................................................................................................61
6.3.1. Day 43 (7 Days)........................................................................................62
6.3.2. Day 91 (7 Days)........................................................................................62
6.4. Subject Withdrawal.................................................................................................63
7. ASSESSMENTS..................................................................................................................65
7.1. Safety Assessments .................................................................................................65
7.1.1. Physical Examination .................................................................................66
7.1.1.1. Comprehensive Physical Examination......................................66
7.1.1.2. Targeted Physical Examination.................................................66
7.1.1.3. Weight and Height ....................................................................66
7.1.2. Vital Signs ..................................................................................................66
7.1.2.1. Highest Observed Blood Pressure Documentation ...................67
7.1.3. ECG ............................................................................................................67
7.1.4. Thrombosis Clinical Probability Scores .....................................................67
7.1.5. Doppler Lower Extremity Ultrasonography...............................................68
7.1.6. Cardiac Troponin I......................................................................................68
7.1.7. CT or MR Scan at Day 4 (72 Hours Post-dose) .........................................68
7.1.8. TIEs Through Day 8...................................................................................68
7.1.9. Clinical Laboratory Tests ...........................................................................69
7.2. Immunogenicity ......................................................................................................69
7.2.1. Plasma for Analysis of ADA (Anti-PF-05230907) and NAb.....................69
7.2.2. Plasma for Analysis of FX Activity............................................................70
7.2.3. Plasma for Analysis of Anti-Chinese Hamster Ovary (CHO) Protein 
and anti-PACE (furin) Antibodies ...................................................................70
7.3. Pharmacodynamics..................................................................................................70
7.4. Pharmacokinetics ....................................................................................................71
7.5. Exploratory Biomarkers ..........................................................................................71
7.5.1. PD Biomarkers............................................................................................71
7.5.2. Neuro-inflammation Biomarkers................................................................72
7.6. Pharmacogenomics..................................................................................................72

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7.6.1. Banked Biospecimens.................................................................................72
7.6.1.1. Markers of Drug Response........................................................72
7.6.2. Additional Research....................................................................................73
7.7. Diagnostic Assessments ..........................................................................................73
7.7.1. Brain CT Scan.............................................................................................73
7.7.1.1. ABC/2 Assessment of ICH Volume..........................................74
7.8. Triggered Requirements..........................................................................................74
8. ADVERSE EVENT REPORTING......................................................................................74
8.1. Adverse Events........................................................................................................74
8.2. Reporting Period .....................................................................................................74
8.3. Definition of an Adverse Event...............................................................................75
8.4. Medication Errors....................................................................................................75
8.5. Abnormal Test Findings..........................................................................................76
8.6. Serious Adverse Events...........................................................................................76
8.6.1. Protocol-Specified Serious Adverse Events...............................................78
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................79
8.7. Hospitalization ........................................................................................................80
8.8. Severity Assessment................................................................................................81
8.9. Causality Assessment..............................................................................................81
8.10. Exposure During Pregnancy..................................................................................82
8.11. Occupational Exposure .........................................................................................83
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................83
8.13. Eliciting Adverse Event Information ....................................................................83
8.14. Reporting Requirements........................................................................................83
8.14.1. Serious Adverse Event Reporting Requirements .....................................83
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................84
8.14.3. Medical Device Complaint Reporting Requirements...............................84
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities ................85
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................85
9.1. Statistical Methods ..................................................................................................85
9.2. Simulations for mCRM Design...............................................................................87

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9.3. Sample Size Determination.....................................................................................87
9.4. Efficacy Analysis ....................................................................................................87
9.5. Analysis of Other Endpoints ...................................................................................88
9.5.1. Pharmacokinetic Analysis ..........................................................................88
9.5.2. Pharmacodynamics Analysis......................................................................88
9.6. Safety Analysis........................................................................................................88
9.6.1. Immunogenicity Analysis...........................................................................88
9.7. Interim Analysis ......................................................................................................89
9.8. Data Monitoring Committee ...................................................................................89
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................89
11. DATA HANDLING AND RECORD KEEPING .............................................................90
11.1. Case Report Forms/Electronic Data Record .........................................................90
11.2. Record Retention...................................................................................................91
12. ETHICS..............................................................................................................................91
12.1. Institutional Review Board/Ethics Committee......................................................91
12.2. Ethical Conduct of the Study ................................................................................91
12.3. Subject Information and Consent..........................................................................92
12.4. Subject Recruitment ..............................................................................................93
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................93
13. DEFINITION OF END OF TRIAL...................................................................................93
13.1. End of Trial in All Participating Countries ...........................................................93
14. SPONSOR DISCONTINUATION CRITERIA ................................................................93
15. PUBLICATION OF STUDY RESULTS..........................................................................93
15.1. Communication of Results by Pfizer ....................................................................93
15.2. Publications by Investigators ................................................................................94
16. REFERENCES ..................................................................................................................96
LIST OF TABLES
Table 1.
Predicted Exposure and Margins Relative to Toxicokinetic Limit ......................33
Table 2.
Dose Escalation Schema.......................................................................................40
Table 3.
Estimated Probability of TIE when =1...............................................................86

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LIST OF FIGURES
Figure 1.
mCRM Design Schematic ....................................................................................41
APPENDICES
Appendix 1. Thromboembolic and Ischemic Events (TIEs) and Associated Severity 
Grade (CTCAE V4.03 Scale) for Determination of MTD10.................................98
Appendix 2. Thrombosis Clinical Probability Scores15.........................................................105
Appendix 3. ABC/216.............................................................................................................106
Appendix 4. National Institute of Health Stroke Scale17.......................................................107
Appendix 5. Glasgow Coma Scale18......................................................................................108
Appendix 6. Modified Rankin Scale (mRS)19 .......................................................................109
Appendix 7. Abbreviations....................................................................................................110
Appendix 8. Definition for Subjects Capable of Providing Consent in Sweden...................113

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PROTOCOL SUMMARY
Background and Rationale:
Spontaneous intracerebral hemorrhage (ICH) is a major cause of death and disability 
accounting for approximately 10-15% of stroke cases worldwide.  ICH continues to be 
associated with poor clinical outcomes, approximately 35-52% of patients die within one 
month, mortality at 6 months ranges from 23-58% and a large number of individuals fail to 
regain functional independence by six months.  The current management of ICH is largely 
supportive and the lack of effective treatment for ICH remains a critical and unmet need. 
FXa occupies a central position in the coagulation cascade between thrombin-generation and 
the intrinsic (Factor VIII/Factor IX dependent) and extrinsic (Factor VII/Tissue Factor 
dependent) pathways. Membrane-bound FXa, in the presence of its cofactor Factor Va 
(FVa), converts prothrombin to thrombin, which activates platelets and converts fibrinogen 
to fibrin to form a thrombus. FXa is the only activator of prothrombin. Pfizer and its 
collaborators have identified a novel variant of coagulation FXa (PF-05230907) that may 
establish, without excessive thrombotic risk, localized hemostasis at the site of bleeding in a 
number of clinical situations of uncontrolled bleeding such as ICH.  Given the severe 
morbidity and mortality associated with ICH and given the need to better define the 
maximum tolerated dose (MTD) of PF-05230907 in order to plan future efficacy studies, a 
modified continual reassessment method (mCRM) will be implemented to determine the 
MTD based on frequency of treatment emergent thromboembolic and/or ischemic events 
(TIEs).  A target TIE rate of 15% represents approximately a 5-10% increment above the 
background rate and is considered compatible with acceptable benefit risk in the high 
morbidity, high mortality indication of ICH. 
Objectives and Endpoints:
Primary Objective:

Based on the mCRM algorithm, determine the maximum tolerated dose (MTD) of 
PF-05230907 administered once as an intravenous (IV) bolus in subjects with ICH.

Determine the overall safety and tolerability of PF-05230907.
Secondary Objectives:

Evaluate pharmacodynamic (PD) effects of treatment with PF-05230907.

Determine the frequency of antibody immune response to PF-05230907.
Exploratory Objectives:

Assess hemostatic efficacy of PF-05230907.

Characterize the pharmacokinetic (PK) profile of PF-05230907.

Assess effect of PF-05230907 on exploratory markers of PD in subjects with ICH.

PF-05230907 
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
Assess potential measures of neuro-inflammation and/or neurologic outcomes in 
subjects with ICH.

Assess brain imaging parameters that may be associated with efficacy or safety of 
treatment with PF-05230907 and/or outcomes in ICH.

Determine frequency of antibody immune response against proteins from host cells 
used in manufacture of PF-05230907.

Assess neurological outcome measures.

Assess health resource utilization.
Primary Endpoint:

Frequency of treatment emergent thromboembolic and/or ischemic events (TIEs) in 
subjects treated with PF-05230907 through Day 8. 

Treatment emergent serious adverse events as characterized by type, frequency, 
severity, timing, seriousness and relationship to study treatment through Day 43. 

Treatment emergent adverse events as characterized by type, frequency, severity, 
timing, seriousness and relationship to study treatment through Day 8.

Treatment emergent laboratory abnormalities as characterized by type, frequency, and 
severity through Day 4 (or discharge).

Physical examination changes through Day 8 (or discharge).

Vital sign changes through Day 8 (or discharge).

Electrocardiogram (ECG) results through Day 8 (or discharge).
Secondary Endpoints:

Changes in activated partial thromboplastin time (aPTT) and prothrombin fragment 
1+2 (PF1+2) after dosing with PF-05230907 through Day 2.

Anti-drug antibody/neutralizing antibody (ADA/NAb) and Factor X activity through 
Day 43 and/or Day 91 follow-up visit.
Exploratory Endpoints:

ICH absolute and percent change from baseline volume at 24 hours (see Schedule of 
Activities [SOA]).

PF-05230907 concentration in plasma.

PF-05230907 
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
Changes in other exploratory biomarkers that may reflect pharmacologic effect of 
PF-05230907 or ICH progression may be evaluated.

Potential biomarkers of neuro-inflammation and/or neurological outcomes to better 
understand ICH and/or its outcomes.

Computed tomography (CT) parameters that may inform future investigations of 
PF-05230907 and/or the condition of ICH.

Anti-Chinese hamster ovary (CHO) protein antibodies.

Anti-paired basic amino acid cleaving enzyme (PACE) furin antibodies.

Neurologic function as assessed by the NIHSS.

Surrogate measures for health resource utilization, may include duration of stay in 
stroke/intensive care unit (ICU), duration of hospital stay, duration of inpatient 
rehabilitation, and duration of outpatient rehabilitation.
Study Design:
This study employs a modified continual reassessment method (mCRM) design to estimate 
the MTD, defined as a target toxicity rate of 15% based on the treatment emergent 
thromboembolic and/or ischemic events (TIEs). The mCRM design utilizes Bayesian 
methodology to continuously learn the dose-toxicity relationship, which is characterized by a 
parametric model. The details of this design are described in the statistical method section of 
this protocol.
Subjects will be enrolled in cohorts, starting with an initial dose of 5 g/kg for the first 
cohort (the highest dose safely administered in the first in human clinical study [B2341001]).  
As safeguards for subject safety, (a) dose escalation will be conducted in a limited number of 
subjects per cohort (N=3), (b) sequential dosing of study subjects will be implemented in 
each cohort evaluating a dose level that exceeds previously administered dose levels and 
rules will apply governing additional cohorts at the respective dose level that are subject to 
sequential dosing, (c) dosing will be paused following completion of each cohort until safety 
is assessed for the respective cohort (d) safety laboratory biomarker criteria are implemented 
which trigger smaller maximum increments for dose escalation, (e) enrollment of the next 
cohort will not proceed until a safety review has been completed for the preceding cohort and 
the chair of the external Data Monitoring Committee (eDMC) has provided authorization and 
(f) criteria are implemented which trigger an automatic eDMC review of safety at a 
respective dose level, 
Severity of adverse events (AEs) and serious adverse events (SAEs) will be graded according 
to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. TIEs will be defined as any of the listed events at the respective 
severity grade indicated in Appendix 1. All subjects who receive PF-05230907 are evaluable 
for TIEs. The determination of MTD using mCRM modeling will be based on TIEs which 
occur through 7 days post-dose (Day 8).

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The total length of time planned for study participation is approximately 3 months; 6.0 hours 
for screening, a single dose administration with a 4 day minimum hospital confinement 
period and follow-up visits through Day 91.
The range of doses that may be explored will be from a grid of doses ranging from 1 g/kg to 
47 g/kg. If the modeled rate of TIEs at the 5 g/kg starting dose exceeds the pre-specified 
target toxicity rate of 15% for the MTD, lower doses may be explored. Starting with the 
second cohort, subjects will be assigned to a dose in the predefined dose grid that is closest 
to, but not exceeding, the currently predicted MTD based on a parametric dose-toxicity
model that the mCRM utilizes to learn about the overall dose-TIE relationship subject to 
additional dose escalation constraints and clinical oversights. The dose-toxicity model is 
updated based on the frequency of TIEs in each completed cohort.  Under the adopted 
mCRM design, the dose level for each subsequent cohort can be escalated, deescalated, or 
restudied but always aiming towards the MTD target for frequency of TIEs. However, dose 
level assignments may be modified to more conservative dose levels based upon sponsor 
medical judgment or eDMC recommendations. To prevent overly aggressive 
dose-escalation, the maximum allowed dose increase from the highest dose that has been 
previously studied is limited to 2 increments at a time (ie, not more than one dose level may 
be skipped) which results in 50-67% increase in dose for the 5 g/kg dose and above.  If 
treatment emergent modulation of one or more of the following laboratory safety biomarkers 
is observed during the interval from baseline to Day 4 (or discharge), as indicated below, 
dose increase will be limited to only 1 increment at a time (ie, no more dose skipping):

Fibrinogen:

If baseline value is within normal reference range: a post-dose value 50% of the
lower limit of normal.

If baseline value < lower limit of normal reference range: a post-dose value 
50% of the baseline value.

Platelet Count:

If baseline value is within normal reference range: a post-dose value of <100,000.

If baseline value < lower limit of normal reference range: a post-dose value 
50% of the baseline value.

PT: a post-dose value that is prolonged by >4 seconds above the baseline value.
If a Suspected Unexpected Serious Adverse Reaction (SUSAR) or 2 or more grade 3 or 
higher adverse events that are considered at least possibly related to treatment with 
PF-05230907 are observed in the initial cohort evaluating a dose level that exceeds 
previously investigated dose levels, then the subsequent (second) cohort evaluating the 
respective dose level will also be subject to sequential dosing restrictions.  If either of these 
criteria are met, then dosing at the respective dose level (and at higher dose levels) will be 
paused until a meeting of the eDMC has been convened.

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In addition to TIEs and available safety biomarker data, other available safety data (including 
clinically significant AEs or SAEs) will also be assessed. These events will not have any 
impact on mCRM-determined dose recommendations but may be used to inform dose 
assignments more conservative than those derived by the mCRM dose-toxicity model. An 
enrollment pause will occur after each respective cohort completes dosing until the following 
are completed: sponsor review of the available safety data through Day 8 (or discharge) 
post-dose administration, discussion with the investigator(s)/sub-investigator(s) for each 
subject in the respective cohort, submission of an interim review memo including all 7-day 
safety data to the eDMC chair (or designee), authorization to proceed with enrollment from 
the eDMC chair (or designee), mCRM-determined dose recommendation, and adjustment of 
mCRM-determined dose to more conservative dose levels when deemed appropriate by the 
sponsor or eDMC.
Study Treatment:
The investigational product should be prepared and dispensed by appropriately qualified and 
trained site personnel (eg, pharmacist, pharmacy technician, study nurse) designated to 
participate in the study as permitted by local, state, and institutional guidance.  PF-05230907 
will be reconstituted as outlined in the Investigational Product Manual.  Depending on the 
total dose required for a subject, one Placebo for PF-05230907 (diluent) vial may be required 
for dilution of the investigational product to prepare an appropriate concentration of the final 
dosing solution. The appropriate dose will be drawn up into an individual dosing syringe for 
administration. Investigator site personnel will administer investigational product as a single 
IV bolus on Day 1.
Statistical Methods:
This study employs a modified (mCRM) design similar to Goodman et al. to estimate the 
MTD. The mCRM design utilizes Bayesian methodology to learn the dose-toxicity 
relationship continuously after each cohort’s thromboembolic and/or ischemic event (TIE) 
data becomes available.  The underlying dose-TIE relationship is assumed to follow a 
one-parameter hyperbolic-tangent model. 
where is an unknown parameter with a prior distribution pre-specified at the beginning of 
the trial, x an adjusted dose which is computed from an initial (=1) dose-toxicity curve
projected based on clinical input, and tanh is the hyperbolic-tangent function.
Once all the TIE data become available from the current cohort, the posterior distribution of 
will be generated through the Markov Chain Monte Carlo (MCMC) simulations in adaptive 
design explorer (ADE).  The model-based MTD will be estimated as 
, where 
0.15 is the pre-specified target TIE rate at MTD and 
is the posterior mean of .  The next 
cohort of 3 subjects will be dosed at the dose level closest to this estimated MTD but not 
exceeding it, subject to additional pre-specified dose escalation constraints and clinical 

PF-05230907 
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oversight.  The posterior distribution of β will become the prior distribution in the next 
round of updates.  This process is continued until at least one of the following stopping rules 
is met:
1. Maximum sample size of 51 subjects has been reached. 
2. MTD has been identified with sufficient accuracy, ie, 12 subjects have been 
accumulated on a dose that is currently estimated to be the MTD.
3. All doses appear to be overly toxic and MTD cannot be determined in the current trial 
setting.
Starting from the second cohort and until the end of the trial, the above described mCRM 
algorithm constantly incorporates additional information about dose-TIE relationship learned 
from the data via modeling and that is reflected on the projected MTD. By design, such dose 
allocation procedure will eventually cluster dose assignments around the dose yielding an 
approximate 15% TIE rate.
Pharmacokinetics Analysis
PF-05230907 concentration in plasma is an exploratory endpoint.  Available plasma 
concentration of PF-05230907 will be descriptively summarized and plotted by nominal PK 
sampling time and dose group.
Pharmacodynamics Analysis
The pharmacodynamic endpoints include aPTT or PTT and PF1+2, within 2 days of dosing. 
These will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate.
Safety Analysis
All subjects who received the treatment of PF-05230907 will be included for safety analysis. 
Safety endpoints, including the primary endpoints of treatment emergent TIEs, AEs, SAEs, 
and laboratory abnormalities; physical examination and vital signs changes; ECG results and 
other safety data will be summarized descriptively by dose group. As discussed in 
Section 9.1, the TIE data from the current cohort will be utilized for the mCRM design along 
with clinical and eDMC oversight to determine the dose for the next cohort.
Immunogenicity Analysis
ADA, NAb and Factor X activity level will be summarized by dose and time points for 
samples tested.  Subjects with ADA and NAb immune responses will be summarized by 
dose.

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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.
Protocol Activity
Screening
Hospital Confinement
Outpatient 
Follow-Up
Visit Identifier
Day 1
Day 1 
Hr 0
Day 1 
Hr 0 
Min 5
Day 1 
Hr 0 
Min 45
Day 1
Hr 3 and
Hr 9
Day 2
(24 hr)
Day 3 
(48 hr)
Day 4 
(72 hr)a
Day 
8/dischargeb
Day 43
Day 91
Visit Windowc
Up to 6.0 Hr
pre-dose
2 min
15 min
30 min
6 hours
6 hours
6 hours
24 hours
7 days
7 days
Informed consentd
X
Demography
Xe
Medical history and smoking 
history
Xe
Medical Procedures
Comprehensive physical 
examination
X
X
Targeted physical exam
X
X
X
Vital signsf
X
X
X
X
X
X
X
Highest observed BP 
documentationg
X
ECG (12-lead)
X
X
X
X
Weight and heighth
X
Brain CT Scan
X
X
Xi
ICH Volume by ABC/2
X
Doppler lower extremity 
ultrasonography
Xe
X
Safety Laboratory
D-dimer-local lab
X
X
X
Prothrombin G20210A 
Mutation
Xe

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Protocol Activity
Screening
Hospital Confinement
Outpatient 
Follow-Up
Visit Identifier
Day 1
Day 1 
Hr 0
Day 1 
Hr 0 
Min 5
Day 1 
Hr 0 
Min 45
Day 1
Hr 3 and
Hr 9
Day 2
(24 hr)
Day 3 
(48 hr)
Day 4 
(72 hr)a
Day 
8/dischargeb
Day 43
Day 91
Visit Windowc
Up to 6.0 Hr
pre-dose
2 min
15 min
30 min
6 hours
6 hours
6 hours
24 hours
7 days
7 days
Factor V Leiden Mutation
Xe
TFPI
X
Blood chemistry
X
X
PT/INRs
X
X
X
X
X
Fibrinogens
X
X
X
X
ATIII
X
X
X
X
Protein S level
X
X
X
X
Protein C activity
X
X
X
X
Hematologys
X
X
X
X
Cardiac troponin I (local or 
central lab)t
X
X
X
X
X
Urinalysis
Xe
X
Pharmacodynamics
aPTT/PTT
X
X
X
X
X
PF1+2
X
X
X
X
Exploratory biomarker
X
X
X
X
X
Pharmacokinetics
PK
X
X
X
Immunogenicity
ADA
X
X
X
Xj
NAb
X
X
X
Xj
FX activity
X
X
X
Xj
Anti-CHO
X
X
Anti-PACE
X
X
Banked biospecimens
Prep D1
Xe
Other biomarkers
Exploratory biomarker(s) of 
neuro-inflammation
X
X
X
X

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Protocol Activity
Screening
Hospital Confinement
Outpatient 
Follow-Up
Visit Identifier
Day 1
Day 1 
Hr 0
Day 1 
Hr 0 
Min 5
Day 1 
Hr 0 
Min 45
Day 1
Hr 3 and
Hr 9
Day 2
(24 hr)
Day 3 
(48 hr)
Day 4 
(72 hr)a
Day 
8/dischargeb
Day 43
Day 91
Visit Windowc
Up to 6.0 Hr
pre-dose
2 min
15 min
30 min
6 hours
6 hours
6 hours
24 hours
7 days
7 days
Trial Treatment Procedures
Review Inclusion/Exclusion 
Criteria
X
Treatment Allocation
X
Investigational product
administration
X
Discussion and documentation of 
contraceptionk
X
X
Approval for release of health 
care informationl
X
Concomitant Medications
Xe









Concomitant Treatments
Xe









Adverse Events (AEs)
X





m
Serious Adverse Events (SAEs)
X









Health resource utilization 
(HRU)n
X


Assessments
Glasgow Coma Scaleo
Xo
Xo
X
Modified Rankin Scale (mRS)p
X
X
X
X
X
National Institute of Health 
Stroke Scale (NIHSS)q
Xe
X
X
X
X
X
Thrombosis clinical 
probability scoresr
X
X
Abbreviations: = ongoing/continuous event; ADA = anti-drug antibody; AEs = adverse events; Anti-CHO = anti-Chinese hamster ovary; 
anti-PACE = anti-paired basic amino acid cleaving enzyme; aPTT = activated partial thromboplastin time; ATIII = antithrombin III; BP = blood pressure; 
CT = computed tomography; ECG = electrocardiogram; FX = factor X; Hr = hour(s); HRU = health resource utilization; ICU = intensive care unit; 
IVH = intraventricular hemorrhage; Min = minute(s); MR = magnetic resonance;  mRS = modified rankin scale; NAb = neutralizing antibody; 
PD = pharmacodynamic; PF1+2 = prothrombin fragment 1+2; PK = pharmacokinetic; PT/INR = prothrombin time/international normalized ratio; PTT = partial 
thromboplastin time; SAEs = serious adverse events; TFPI = tissue factor pathway inhibitor.
a.
Subjects in the study must stay in the hospital/stroke unit/ICU at a minimum through Day 4.  If a subject is discharged on Day 4 see Section 6.2.8.

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b.
See Section 6.2.9 if subject was discharged prior to Day 8.
c.
Day relative to start of study treatment (Day 1).
d.
ICH related information from medical records (such as Glasgow Coma Scale [GCS] assessment by emergency medical services, CT scan and ICH 
characteristics, vital signs, ECG, physical examination, laboratory test results, demography, weight, medical history, concomitant medications, concomitant 
treatments) which is collected prior to the time of consent but within 6.0 hours of ICH symptom onset may be used to assist with inclusion/exclusion 
determination. 
e.
If the following cannot be collected during the Screening Day 1 period, the site may collect as soon as possible post-dose but prior to Day 4-see Section 6.1:

Demography that does not affect eligibility (race and ethnicity).

Prothrombin G20210A Mutation.

Factor V Leiden Mutation.

Urinalysis (if not collected pre-dose collect as soon as possible post-dose).

Prep D1 banked biospecimen (unless prohibited by local regulations or ethics committee decision) and additional consent to allow banked biospecimen
Prep D1 to be used for additional purposes (unless prohibited by local regulations or ethics committee decision).

Medical history that does not affect eligibility. 

The following medical history elements affect study eligibility and must be collected during the screening period: non-ICH related severe 
uncontrolled medical conditions, other severe acute and chronic medical and psychiatric conditions and laboratory abnormalities that may increase 
the risk associated with study participation; ischemic, vaso-occlusive and thrombotic events or conditions; prothrombotic disorders; 
thrombocytopenia; coagulopathy, acute sepsis, crush injury, and disseminated intravascular coagulation events or conditions; and hamster protein 
allergies.

Concomitant medications taken within 7 days of study enrollment that do not affect eligibility. The following concomitant medication information 
affects study eligibility and must be collected during the screening period: oral anti-coagulant(s) [eg, warfarin or novel oral anticoagulant], low 
molecular weight heparin and heparin (except when used as catheter flush).

Concomitant treatments within 7 days of study enrollment that do not affect eligibility.

Doppler lower extremity ultrasonography.

NIHSS.
f.
If during hospital confinement period, the magnitude of a vital sign abnormality is sufficient to be reported as an AE then vital signs should be collected as a 
daily unscheduled observation during the hospital confinement period (eg, Day 5 through Day 8/discharge) and should be followed until the AE resolves or 
stabilizes-see Section 8.1. 
g.
The highest observed blood pressure result for each of the following Day 1 post-dose time intervals to be collected: hour 0-3, hour 3-6, hour 6-12, and 
hour 12-24 for a total of 4 collected highest observed BP results.
h.
Subject reported weight measured within the last 3 months is acceptable if actual weight cannot be obtained. If subject reported weight is utilized, actual 
weight should be collected as soon as possible post-dose.  Subject reported height is acceptable.

PF-05230907 
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i.
CT scan is the preferred imaging modality however for the Day 4 assessment a site may substitute an MR scan based on local standard of care (SoC), local 
regulatory, or clinical considerations at the investigator’s discretion. 
j.
ADA, NAb and FX activity to be collected at Day 91 only if subject tested positive for antibody immune response at Day 43.
k.
At the Day 8/discharge visit, a discussion of the birth control protocol specifications is to occur and is to be documented in male subjects’ charts that are able 
to father children and are sexually active and at risk of pregnancy.  The Day 43 visit will require documenting the birth control method utilized for male 
subjects who are able to father children and are sexually active and at risk of pregnancy-see Section 4.4. 
l.
Secure approval for release of health care information from study subject/legal guardian/legally acceptable representative as permitted by local, state, and 
institutional guidance to assist with collection of adverse events through Day 8 and collection of serious adverse events through Day 43. 
m. Sponsor and investigator documentation of TIEs must occur at Day 8.  Telephone follow-up call on Day 8 for collection of adverse events if subject was 
discharged prior to Day 8.
n.
Health resource utilization information to be collected during the study include admission date of subject to the stroke unit/ICU, discharge date of the subject 
from the stroke/ICU unit, admission/discharge date of the subject from the hospital (if moved from stroke unit/ICU), date subject began in-patient 
rehabilitation, discharge date subject completed in-patient rehabilitation, date subject began out-patient rehabilitation, and discharge date subject completed 
out-patient rehabilitation.
o.
See Appendix 5 for Glasgow Coma Scale.  Screening GCS assessments to be collected include both an assessment by emergency medical services prior to 
hospital admission (if possible) and a bedside assessment by a study team member as soon as possible after arrival at the study site.  The Day 1 / Hour 0 
GCS should be performed immediately prior to dosing.
p.
See Appendix 6 for mRS.  Retrospective (prior to ICH) mRS completed at screening. 
q.
See Appendix 4 for NIHSS.  Screening period NIHSS assessment should be performed within 2 hours prior to planned dosing and as close to time of dosing 
as is feasible.
r.
See Appendix 2 for Thrombosis Clinical Probability Scores Assessment.
s.
For sites in Germany, samples collected after Day 1, Hour 0 (post-dose) should also be analyzed locally.
t.
For sites where only cardiac troponin T analysis is available at the local laboratory, cardiac troponin T results are allowed for the 72-hour safety data review
for sequential dosing. Cardiac troponin I samples are still required and must be shipped to the central lab for processing.

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1. INTRODUCTION
1.1. Indication
Spontaneous intracerebral hemorrhage (ICH) is a major cause of death and disability 
accounting for approximately 10-15% of stroke cases worldwide.1,2  ICH continues to be 
associated with poor clinical outcomes, approximately 35-52% of patients die within one 
month, mortality at 6 months ranges from 23-58% and a large number of individuals fail to 
regain functional independence by six months.1,3  The current management of ICH is largely 
supportive and the lack of effective treatment for ICH remains a critical and unmet need. 
The investigational product PF-05230907, a variant of recombinant activated coagulation 
factor X (FXa) formerly known as rFXaI16L, is being developed as a single dose treatment for
patients with ICH. 
This investigation product will be referenced only as PF-05230907 in all subsequent sections 
of this protocol document. 
1.2. Mechanism of Action/Indication
FXa occupies a central position in the coagulation cascade between thrombin-generation and 
the intrinsic (Factor VIII/Factor IX dependent) and extrinsic (Factor VII/Tissue Factor 
dependent) pathways. Membrane-bound FXa, in the presence of its cofactor Factor Va 
(FVa), converts prothrombin to thrombin, which activates platelets and converts fibrinogen 
to fibrin to form a thrombus. FXa is the only activator of prothrombin. In principle, 
replacement therapy with direct FXa infusion could correct bleeding, however the therapeutic 
potential of FXa is limited due to a very short plasma half-life and a potential for excessive 
coagulation due to activation of other coagulation factors.  Pfizer and its collaborators have 
identified a novel variant of coagulation FXa (PF-05230907) that may establish, without 
excessive thrombotic risk, localized hemostasis at the site of bleeding in a number of clinical 
situations of uncontrolled bleeding such as ICH.4
1.3. Background and Rationale
1.3.1. Nonclinical Safety Data
1.3.1.1. Nonclinical Pharmacology
In response to an injury, FVa is generated at the site of injury and the interaction of FXa with 
FVa leads to localized thrombin generation.  PF-05230907 is a variant of FXa that has an 
isoleucine to leucine substitution at its 16 position (Chymotrypsin numbering) and is more 
protected from inactivation by serum protease inhibitors. It regains susceptibility to 
inactivation by serum protease inhibitors when activated by cofactor FVa, similar to native 
FXa.
PF-05230907 caused a dose-dependent shortening of clotting times in vitro in citrated pooled 
plasma from humans (
), cynomolgus 
monkeys (EC50=49 ng/mL; 1.1 nM), mice (EC50=89 ng/mL; 1.93 nM), and rats 
(EC50=91 ng/mL; 1.98 nM), as evaluated by measuring activated partial thromboplastin time 
(aPTT).  Furthermore, in the thrombin generation assay, PF-05230907 caused a 
CCI

PF-05230907 
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dose-dependent increase in thrombin generation and a shortening of the lag time in plasma 
from humans 
), monkeys (EC50=17 ng/mL; 0.37 nM), mice 
(EC50=5 ng/mL; 0.11 nM), and rats (EC50=12 ng/mL; 0.27 nM).  In the thrombin generation 
assay, the inactivation of Factor V/Va by the activated protein C (APC) pathway effectively 
regulated PF-05230907.  In vitro treatment of platelets with PF-05230907 up to 4,600 ng/mL 
(100 nM) did not lead to platelet activation in vitro, as evaluated by aggregation and flow 
cytometry using antibodies as markers of platelet surface activation. PF-05230907 was 
efficacious in a number of in vivo models.  Specifically, PF-05230907 shortened aPTT in 
FVIII-deficient dogs (at 0.1 g/kg/day); decreased hemoglobin content in homogenized 
brain tissue (a marker of hematoma blood volume) from mice (50% effective dose 
[ED50]=3.05 g/kg) and rats (minimum effective dose [MED]=10 g/kg) with 
collagenase-induced intracerebral hemorrhage; and decreased blood loss associated with tail 
transaction in mice (ED50=46 g/kg) and Sprague Dawley rats (ED50=38 g/kg).  Additional 
information may be found in the Investigator’s Brochure. 
1.3.1.2. Nonclinical Pharmacokinetics and Safety Toxicology
PF-05230907 was not evaluated in stand-alone safety pharmacology studies.  However, 
endpoints that evaluated for effects on the cardiovascular, central nervous system, and 
respiratory systems were included in the 3-day and 1-month good laboratory practices (GLP)
toxicity studies in cynomolgus monkeys given PF-05230907 at twice daily (BID) doses 
approximately 8 hours apart.  In these studies, there were no test article-related effects on 
electrocardiogram (ECG) parameters, blood pressure, heart rate, body temperature (only 
evaluated in the 1-month study), or effects on neurobehavioral or respiratory assessments at 
any dose tested.
It is known that endogenous FXa is rapidly inactivated by complex formation with plasma 
protease inhibitors such as, antithrombin III (ATIII), 2-Macroglobulin and 1-antitrypsin.5
In a [125I]-FXa study, two minutes after intravenous injection (IV), the majority of FXa was 
found to be bound with protease inhibitors and eliminated from the plasma by low-density 
lipoprotein receptor-related protein (LRP)-mediated clearance. Pharmacokinetics 
(PK)/toxicokinetics (TK) of PF-05230907 after a single and multiple IV doses were 
characterized in mice, rats and monkeys.  PF-05230907, with high plasma protein binding, 
exhibits low volume of distribution, high clearance and a very short half-life.  The terminal 
elimination half-life ranged from 4-9 minutes in mice, rats and monkeys.  At non 
thrombogenic doses, the volume of distribution for PF-05230907 was small indicating that 
PF-05230907 is mainly confined in the intravascular fluid.  Systemic exposure of 
PF-05230907 was generally dose-related; no accumulation of PF-05230907 was observed in 
cynomolgus monkey after repeat twice daily dosing (BID) for three days.
PF-05230907 was evaluated in single- and repeat-dose toxicity studies up to 1 month in 
duration in mice, rats, and monkeys; in a single-dose thrombogenicity study in rabbits; and in 
single- and/or repeat-dose biomarker studies in mice, rats, and monkeys and an in vitro 
biomarker study with human plasma.  Pivotal studies were the 3-day studies in rats and 
monkeys.  Administration of increasing doses of PF-05230907 resulted in a spectrum of 
events that ranged between findings consistent with pharmacologic effects at relatively low 
doses, findings consistent with exaggerated pharmacology and excessive thrombi/emboli
CCI

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formation at higher doses, and findings consistent with consumptive coagulopathy at the 
highest doses.  The primary effects of PF-05230907 observed in these studies were adverse 
thrombi/emboli in the lungs, heart, injection site/tail, kidney, and/or liver at 0.1 mg/kg/day 
in monkeys, 0.04 mg/kg/day in mice, 0.6 mg/kg/day in rats, and 0.06 mg/kg in rabbits.  
The incidence and severity of thrombi/emboli formation was dependent upon the dose and 
duration of dosing.  In monkeys given 0.1 to 0.5 mg/kg/day, thrombi/emboli were not 
associated with clinical signs, but were associated with shortened followed by prolonged 
aPTT, increased thrombin-antithrombin (TAT), and marked decreases in protein C and 
fibrinogen.  However results from an in vitro study indicate that the pharmacological activity 
of PF-05230907 can interfere with Protein C measurements in human plasma when evaluated 
with the Staclot assay.6  In monkeys given 3 mg/kg/day, some animals were electively 
euthanized due to findings consistent with consumptive coagulopathy which included an 
inability to stop bleeding at blood collection sites despite applying pressure for a prolonged 
period of time (up to 1 hour), marked decreases in platelets and fibrinogen, prolongation of 
prothrombin time (PT), and microscopic findings of hemorrhage at the injection site that 
penetrated into the adjacent subcutaneous tissue and muscle.  In mice and rats, transient tail 
discolorations occurred at 0.04 mg/kg/day (mice) and at 2 mg/kg/day (rats).  The No 
Observed Effects Level (NOEL) for thrombi/emboli and the No Observed Adverse Effect 
Level (NOAEL) for PF-05230907 when administered for 3 days were 0.3 mg/kg/day in rats 
and 0.05 mg/kg/day in monkeys.
1.3.2. Clinical Experience with PF-05230907
To date, a single clinical study has been conducted with PF-05230907.  The clinical program 
for PF-05230907 was initiated in September 2013 with a Phase 1 first in human, randomized, 
double-blind, sponsor-open, placebo-controlled study (B2341001) evaluating the safety, 
tolerability, PK and pharmacodynamic (PD) of escalating single doses of PF-05230907 in 
healthy adult subjects age 18 to 35 with no demographic, acquired or hereditary 
prothrombotic risk factors.  This completed study enrolled 49 male subjects at a single site.  
PF-05230907 was sequentially evaluated at dose levels of 0.1, 0.3, 1.0, 2.0, 3.0 and 5.0 g/kg 
and subjects in the respective cohorts were randomized to receive either PF-05230907 or 
placebo at a ratio of 6:2.  All dose levels evaluated in this study were safe and well tolerated 
and evidence of pharmacologic activity was observed.  The following data represent the 
completed study results.
There were no deaths, no serious adverse events (SAEs), or discontinuations reported in the 
study.  Treatment emergent adverse events (TEAEs) in PF-05230907 treated subjects were 
mild in severity (23/28) or moderate in severity (5/28) and there were no severe TEAEs or 
withdrawals due to TEAEs.  There did not appear to be any dose-related trends in frequency 
of TEAEs across the dose levels of PF-05230907 or placebo.  Of the 37 subjects in the 
6 treatment groups who received PF-05230907, 1 subject experienced a treatment-related
TEAE.  This single treatment-related TEAE was headache, classified as mild in severity, and 
reported in the 5 g/kg treatment group.  Thrombosis and pulmonary embolus clinical 
probability assessments were performed for all subjects and were scored as low probability 
for all subjects at all assessments.

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There were no clinically significant changes from baseline in vital sign (blood pressure, pulse 
rate, oral temperature and respiration rate) measurements, 12-lead electrocardiogram (ECG) 
parameters or physical examinations noted in individual subjects or within treatment groups. 
Treatment emergent changes in clinical safety laboratory values were generally small and 
sporadic, with no clinically significant changes in hematology including platelet count, 
PT/INR, fibrinogen, ATIII, cardiac troponin I, or D-dimer (Day 7 and on).  Dose dependent 
modulation of Protein C and Protein S activity, when analyzed with a clot based assay, were 
observed.  Non-clinical studies indicate these changes reflect pharmacologic activity of the 
drug.6  Protein C activity and free Protein S level measured using non-clot-based assays for 
the 3 and 5 g/kg dose groups showed no treatment-related reduction.  No subject had an 
adverse event (AE) related to abnormal laboratory test results and no subject met the 
pre-specified stopping rule criteria. 
One weak and transient anti-drug antibody (ADA) response was detected in one subject from 
the 3 g/kg cohort at a single time point of Day 29. ADA results for the same subject on 
Day 1 (baseline), Day 15, Day 43, and the 6 month follow-up were negative.  The positive 
anti-drug antibody did not cross react with native factor X or factor Xa and had no 
neutralizing activity.  Based on all the available data, the sponsor, investigator, and the study 
eDMC determined that this finding did not alter the benefit risk profile of PF-05230907 for 
the intended indication of intracerebral hemorrhage.
Based on the PK data for all the subjects enrolled in the study, peak plasma concentration of 
PF-05230907 (Cmax) was reached between 2 to 5 minutes post-dose and PF-05230907 
concentration declined very rapidly thereafter.  In all subjects except one (from the 5 g/kg
dose group), plasma PF-05230907 concentration was non-detectable by 40 minutes after 
dosing.  The terminal half-life was calculated for 3 and 5 g/kg, which are 4.6 (coefficient of 
variation [CV] =8%) and 3.7 (CV=2%) minutes respectively.  Exposure appeared to increase 
dose-proportionally, especially at the higher doses where PK can be characterized more 
accurately.  The very fast clearance of PF-05230907 is consistent with the observations in 
non-clinical studies. 
Dose-dependent PD changes including plasma aPTT, plasma prothrombin fragment 1+2 
(PF1+2), plasma thrombin-anti-thrombin complex (TAT) and plasma D-dimer were observed 
in study B2341001.  Maximum aPTT shortening occurred between 2 to 5 minutes coincident 
with maximal exposure and returned to baseline by 2 hours at all dose levels.  At the highest 
tested dose (5 g/kg), median maximum aPTT shortening was 8.92 seconds.  PF1+2, TAT 
and D-dimer are in vivo biomarkers and their increases were delayed compared with aPTT 
and the durations of change were prolonged compared with PK exposure. 
Please refer to the Investigator’s Brochure for more detailed information.

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1.4. Study Rationale
This study will determine the maximum tolerated dose (MTD) of PF-05230907 and evaluate 
safety and tolerability of a single administration of PF-05230907 in subjects with 
spontaneous intracerebral hemorrhage (ICH).  Given the severe morbidity and mortality 
associated with the condition and given the need to better define the maximum tolerated dose 
of PF-05230907 in order to plan future efficacy studies, a modified continual reassessment 
method (mCRM) will be implemented to determine the MTD (see Section 9) based on 
frequency of treatment emergent thromboembolic and/or ischemic events (to be referred to as 
TIEs throughout this document).  A target TIE rate of 15% represents approximately a 5-10% 
increment above the background rate and is considered compatible with acceptable benefit 
risk in the high morbidity, high mortality indication of ICH.  A background rate of 
approximately 5-10% in the ICH population is based upon published literature for 
spontaneous ICH from studies of activated coagulation factor VII in ICH and the 
placebo-treated subject-level datasets from 4 studies performed contemporaneously with the 
clinical studies of NovoSeven in ICH contained within the Virtual International Stroke Trial 
Archive (VISTA).7,8,9  The TIE rate in the internal analysis of the VISTA placebo datasets 
filtered to reflect the intended population for treatment with PF-05230907, was 
approximately 5.5% within the first 8 days from the baseline computed tomography (CT)
scan.
Selection of the PD biomarkers included in the study (aPTT and PF1+2) is informed by the 
results from the study B2341001.  The PD results will provide information on target 
engagement and coagulation pathway activation at the various dose levels studied.
1.5. Dose Rationale
The starting dose planned for this study is 5 g/kg, which is the highest dose level tested that 
was safe and tolerated in the Phase 1 first-in-human (FIH) study of PF-05230907 in healthy 
volunteers (B2341001).  Based on the data from Study B2341001, Cmax of 46.13 ng/mL and 
AUClast of 5.452 ng•h/mL at this dose have a 
-fold and 
-fold safety margin respectively 
in comparison to the exposure at the NOAEL in monkeys 
, AUClast was 
; and a 
-fold and 
-fold safety margins respectively in comparison to 
the exposure at the NOAEL in rats 
 
For this study, a pre-specified dose grid (Table 1) will be used for dose assignments based on 
the mCRM algorithm.  Beginning from the starting dose of 5 g/kg, the mCRM dose grid 
will be in increments of approximately 25-30%.  The dose increment step is based on the 
variability of PK observed in Study B2341001. 
The highest dose for this study will be established based on safety observed during the study 
and therefore cannot be pre-specified.  For purposes of implementing the mCRM assessment 
of MTD, the proposed maximum dose is 47 g/kg (see Section 3), which is predicted to have 
approximately twice the exposure for both Cmax and AUC at NOAEL in monkeys which is 
the more sensitive species compared with rats (Table 1). The NOAEL is established in 
monkeys based on 3 days of BID dosing in the pivotal toxicity studies while in this study 
(B2341002), only a single dose is planned for administration. The condition of ICH is 
CC
I
CC
ICCI
CCI
CCI
CCI
CCI

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associated with substantial morbidity and mortality and, as is the case for other high 
mortality conditions, cautious dose escalation beyond the NOAEL can be justified.  In ICH a 
modest increase above the background rate of treatment emergent thromboembolic or 
ischemic events is compatible with favorable benefit risk for a potentially efficacious 
hemostatic agent.  
To mitigate potential risk from dose escalation beyond exposure at the NOAEL in monkeys, 
dose escalation will be conducted in a limited number of subjects per cohort (N=3), 
sequential dosing of subjects will be implemented in each cohort evaluating a dose level that 
exceeds previously administered dose levels, and dosing will be paused following completion 
of each cohort until safety is assessed for the respective cohort.  As described below (see 
Section 3), dose escalation will take place in limited increments.  The increments may be 
further reduced based on results from laboratory safety parameters, clinical safety 
observations, eDMC recommendations and continuous integration of safety data into the 
mCRM model.  In summary, the severity of the condition of ICH in combination with the 
measures for monitoring subject safety, the limited increments in dose escalation and the 
limited number of subjects exposed in each dosing cohort provide justification for cautious 
dose escalation that may exceed exposure at the NOAEL in monkeys.
If the 47 g/kg dose is well tolerated and the MTD has not been established, the protocol 
may be amended and submitted to ethics committees and to regulatory authorities as required 
to permit evaluation of a higher dose(s).  Predicted exposure and safety margin compared 
with exposure at the NOAEL for monkeys, the more sensitive species, at the potential dose 
levels to be tested in the study are presented in Table 1.
Table 1.
Predicted Exposure and Margins Relative to Toxicokinetic Limit
Proposed 
Human Dose 
(g/kg)
Predicted Human PKa
Safety Multiple
Cmax
(ng/mL)
AUC
(ng∙h/mL)
Based on Monkey NOAEL Dose of 
0.025 mg/kg/doseb
Cmax = 229 ng/mL
AUC = 22.9 ng∙h/mL
1
9.23
1.09
24.8
21.0
2
18.45
2.18
12.4
10.5
3
27.68
3.27
8.3
7.0
4
36.90
4.36
6.2
5.3
5
46.13
5.45
5.0
4.2
6
55.36
6.54
4.1
3.5
8
73.81
8.72
3.1
2.6
10
92.26
10.90
2.5
2.1
12
110.71
13.08
2.1
1.8
15
138.39
16.36
1.7
1.4
19
175.29
20.72
1.3
1.1
24
221.42
26.17
1.0
0.9
30
276.78
32.71
0.8
0.7
37
341.36
40.34
0.7
0.6
47
433.62
51.25
0.5
0.4
a
Prediction based on dose linear extrapolation from the values observed at 5 g/kg from 
Study B2341001.
b
NOAEL established from 3 day BID dosing study in monkey.

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1.6. Anticipated Risks and Safety Monitoring
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure. 
Human experience with PF-05230907 is limited to Phase 1 Study B2341001.  There are no 
identified adverse drug reactions to PF-05230907.  Potential risks are based on clinical and 
toxicology data.
Possible risks for PF-05230907 include the potential for thromboembolic and ischemic 
complications and the potential for immunogenicity including, but not limited to, infusion 
reactions, anaphylaxis, and formation of ADA which may affect functions of endogenous 
FXa and FX.  Although the possibility of ADA development is considered to be low to 
moderate, the perceived immunogenicity risk of PF-05230907 is considered to be high based 
on the severe consequence that the ADA may affect function of endogenous FXa and FX. 
1.6.1. Summary of Risk Benefit
Based on the potential risks, subjects will be monitored for the following treatment emergent 
parameters: laboratory, vital sign, physical examination and ECG abnormalities and adverse 
events including TIEs.  Monitoring will also include the Wells Thrombosis Probability 
Assessments (Appendix 1), a CT or magnetic resonance (MR) scan of the brain at 72 hours, 
and Doppler ultrasonography of the lower extremities at 72 hours.  Monitoring for antibody 
immune response will use a tiered testing strategy including measurement of ADA to 
PF-05230907 and further characterization of any positive anti-body immune responses such 
as testing for neutralizing antibody (see Section 9.6.1).
PF-05230907 is being developed as a single administration treatment of the life threatening 
condition ICH, wherein affected patients incur substantial mortality and long term morbidity. 
Safety was demonstrated at all tested dose levels up to 5 g/kg in Phase 1 Study B2341001
and there did not appear to be any dose-related trends in frequency of reported treatment 
emergent adverse events.  Possible risks from treatment with PF-05230907 include the 
potential for thromboembolic and ischemic events, hypersensitivity reaction, antibody 
immune response with formation of anti-drug antibodies. These risks are believed to be
manageable because: 1) thrombi/emboli formation was reversible in animals, 2) changes in
coagulation parameters/biomarkers in monkeys that were associated with the presence or
absence of thrombi/emboli can be monitored in the clinical setting, and 3) the potential 
toxicity of thrombi/emboli, hypersensitivity response and antibody immune response is 
considered compatible with acceptable benefit/risk in the life-threatening and severely 
disabling condition of ICH.

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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective:

Based on the mCRM algorithm, determine the maximum tolerated dose (MTD) of 
PF-05230907 administered once as an IV bolus in subjects with ICH.

Determine the overall safety and tolerability of PF-05230907.
Secondary Objectives:

Evaluate PD effects of treatment with PF-05230907.

Determine the frequency of antibody immune response to PF-05230907.
Exploratory Objectives:

Assess hemostatic efficacy of PF-05230907.

Characterize the PK profile of PF-05230907.

Assess effect of PF-05230907 on exploratory biomarkers of PD in subjects with ICH.

Assess potential measures of neuro-inflammation and/or neurologic outcomes in 
subjects with ICH.

Assess brain imaging parameters that may be associated with efficacy or safety of 
treatment with PF-05230907 and/or outcomes in ICH.

Determine frequency of antibody immune response against proteins from host cells 
used in manufacture of PF-05230907.

Assess neurological outcome measures.

Assess health resource utilization.
2.2. Endpoints
Primary Endpoint:

Frequency of treatment emergent thromboembolic and/or ischemic events (TIEs) in 
subjects treated with PF-05230907 through Day 8.

Treatment emergent serious adverse events as characterized by type, frequency, 
severity, timing, seriousness and relationship to study treatment through Day 43.

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
Treatment emergent adverse events as characterized by type, frequency, severity, 
timing, seriousness and relationship to study treatment through Day 8.

Treatment emergent laboratory abnormalities as characterized by type, frequency, and 
severity through Day 4 (Day 8/discharge for D-dimer).

Physical examination changes through Day 8 (or discharge).

Vital sign changes through Day 8 (or discharge).

ECG results through Day 8 (or discharge).
Secondary Endpoints:

Changes in aPTT and PF1+2 after dosing with PF-05230907 through Day 2.

ADA/neutralizing antibody (NAb) and Factor X activity through Day 43 and/or 
Day 91 follow-up visit.
Exploratory Endpoints:

ICH absolute and percent change from baseline volume at 24 hours (see SOA).

PF-05230907 concentration in plasma.

Change in other exploratory biomarkers that may reflect pharmacologic effect of 
PF-05230907 or ICH progression may be evaluated.

Potential biomarkers of neuro-inflammation and/or neurological outcomes to better 
understand ICH and/or its outcomes.

CT parameters that may inform future investigations of PF-05230907 and/or the 
condition of ICH.

Anti-Chinese hamster ovary (CHO) protein antibodies.

Anti-paired basic amino acid cleaving enzyme (PACE) furin antibodies.

Neurologic function as assessed by the NIHSS.

Surrogate measures for health resource utilization, may include duration of stay in 
stroke/ICU unit, duration of hospital stay, duration of inpatient rehabilitation, and 
duration of outpatient rehabilitation.
Some of the planned biomarker(s) may not be performed if not supported by data from the 
ongoing pre-clinical work.

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3. STUDY DESIGN
This is a Phase 1b, multi-center, open-label study to determine the maximum tolerated dose 
(MTD) and assess the safety and tolerability, and PD of PF-05230907 administered once as 
an IV bolus in subjects with ICH. A modified continual reassessment method (mCRM)
design based on the endpoints of treatment emergent thromboembolic and/or ischemic events 
(TIEs) will be adopted. The mCRM design utilizes Bayesian methodology to continuously 
learn the dose-toxicity relationship, which is characterized by a parametric model. The 
starting dose will be 5 g/kg based on the highest dose safely administered in the first in 
human (FIH) clinical study (B2341001). 
As safeguards for subject safety, (a) dose escalation will be conducted in a limited number of 
subjects per cohort (N=3), (b) sequential dosing of study subjects will be implemented in 
each cohort evaluating a dose level that exceeds previously administered dose levels and 
rules will apply governing additional cohorts at the respective dose level that are subject to 
sequential dosing (section 3.1), (c) dosing will be paused following completion of each 
cohort until safety is assessed for the respective cohort, (d) safety laboratory biomarker 
criteria are implemented which trigger smaller maximum increments for dose escalation 
(Section 3.2) (e) enrollment of the next cohort will not proceed until a safety review has 
completed for the preceding cohort and the chair of the eDMC has provided authorization
(Section 3.3) and (f) criteria are implemented which trigger an automatic eDMC review of 
safety at a respective dose level (Section 3.3).
3.1. Sequential Dosing
Sequential dosing of subjects will be implemented in each cohort evaluating a dose level that 
exceeds previously administered dose levels.  An enrollment pause will be implemented 
following dosing of each subject in the cohort to allow for medical monitor safety data 
review prior to dosing the next subject.  For the safety review that will take place during the 
enrollment pause, clinical observation results collected on the respective subject during the 
initial 72-hour period following dosing (treatment emergent adverse events [TEAEs], SAEs, 
vital sign changes, electrocardiogram [ECG] changes, Brain imaging study [CT MRI] scan, 
Doppler ultrasound of the lower extremity and cardiac troponin I [and cardiac troponin T, 
where applicable]) will be reviewed by the medical monitor.  Other available laboratory test 
results at the time of this safety review will also be assessed.
If a Suspected Unexpected Serious Adverse Reaction (SUSAR) or 2 or more grade 3 or 
higher adverse events that are considered at least possibly related to treatment with PF-
05230907 are observed in the initial cohort evaluating a dose level that exceeds previously 
investigated dose levels, then the subsequent (second) cohort evaluating the respective dose 
level will also be subject to sequential dosing restrictions.
Severity of adverse events (AEs) and serious adverse events (SAEs) will be graded according 
to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.10 TIEs will be defined as any of the listed events at the respective 
severity grade indicated in Appendix 1. All subjects who receive PF-05230907 are evaluable 
for TIEs. The determination of MTD using mCRM dose-toxicity modeling will be based on 
TIEs which occur through 7 days post-dose (Day 8).

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3.2. Progression to Subsequent Cohort
A target 15% TIE rate at the MTD will be employed for the MTD determination. The range 
of doses that may be explored will be from a grid of doses ranging from 1 g/kg to 47 g/kg
(Table 2).  Subjects will be enrolled in cohorts, starting with an initial dose of 5 g/kg for the 
first cohort (the highest dose safely administered in the first in human clinical study 
[B2341001]). If the modeled rate of TIEs at the 5 g/kg starting dose exceeds the 
pre-specified target toxicity rate of 15% for the MTD, lower doses may be explored. Starting 
with the second cohort, subjects will be assigned to a dose in the pre-defined dose grid that is 
closest to, but not exceeding, the currently predicted MTD based on a parametric 
dose-toxicity model that the mCRM utilizes to learn about the overall dose-TIE relationship
subject to additional dose escalation constraints and clinical oversight. The dose-toxicity
model is updated based on the frequency of TIEs in each completed cohort.  Under the 
adopted mCRM design, the dose level for each subsequent cohort can be escalated, 
deescalated, or restudied but always aiming towards the MTD target based on the frequency 
of TIEs. However, dose level assignments may be modified to more conservative dose levels 
based upon sponsor medical judgment or eDMC recommendations. To prevent overly 
aggressive dose-escalation, the maximum allowed dose increase from the highest dose that 
has been previously studied is limited to 2 increments at a time (ie, not more than one dose 
level may be skipped-see (Table 2), which results in 50-67% increase in dose from the
5 g/kg dose and above.  If treatment emergent modulation of one or more of the following 
laboratory safety biomarkers is observed during the interval from baseline to Day 4 (where 
available), as indicated below, dose increase will be limited to only 1 increment at a time (ie, 
no more dose skipping):

Fibrinogen:

If baseline value is within normal reference range: a post-dose value 50% of the
lower limit of normal.

If baseline value < lower limit of normal reference range: a post-dose value 
50% of the baseline value.

Platelet Count:

If baseline value is within normal reference range: a post-dose value of <100,000.

If baseline value < lower limit of normal reference range: a post-dose value 
50% of the baseline value.

PT: a post-dose value that is prolonged by >4 seconds above the baseline value.

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In addition to TIEs and available safety biomarkers data, other available safety data 
(including clinically significant AEs or SAEs) will also be assessed. These events will not 
have any impact on mCRM-determined dose recommendations but may be used to inform 
dose assignments more conservative than those derived by the dose-toxicity model.  An 
enrollment pause will occur after each respective cohort completes dosing until the following 
are completed; sponsor review of the available safety data through Day 8 (or discharge) 
post-dose administration, discussion with the investigator(s)/sub-investigator(s) for each 
subject in the respective cohort, submission of an interim review memo including all 7-day 
safety data to the eDMC chair (or designee), authorization to proceed with enrollment from 
the eDMC chair (or designee), mCRM-determined dose recommendation, and adjustment of 
mCRM-determined dose to more conservative dose levels when deemed appropriate by the 
sponsor or eDMC.  Additional detail of the safety assessment process is discussed in 
Section 7.1.
3.3. eDMC Review of Cohort Safety Data
The eDMC will be responsible for ongoing cumulative reviews of the study safety data 
(Section 9.8).  In addition, progression to each subsequent cohort of study subjects will not 
occur until an interim review memo including all specified 7-day safety data has been 
provided to the eDMC chair (or designee), the mCRM-determined dose recommendation or
adjustment of mCRM-determined dose to more conservative dose levels (when deemed 
appropriate by the sponsor) and authorization has been received from the eDMC chair (or 
designee) to proceed with enrollment of the subsequent cohort.  At the discretion of the 
eDMC chair (or designee), the eDMC may direct that dosing at the respective dose level (or 
higher dose levels) be paused until a full meeting of the eDMC has been convened.  If a 
Suspected Unexpected Serious Adverse Reaction (SUSAR) or 2 or more grade 3 or higher 
adverse events that are considered at least possibly related to treatment with PF-05230907 
are observed in the initial cohort evaluating a dose level that exceeds previously investigated 
dose levels, then dosing at the respective dose level (and at higher dose levels) will be paused 
until a meeting of the eDMC has been convened.
3.4. Stopping Rules for mCRM Algorithm
Study enrollment will stop if (1) the maximum sample size has been achieved (51 subjects), 
(2) 12 subjects have been accumulated on a dose that is predicted to be the MTD by the fitted 
dose-toxicity curve or (3) all doses appear to be overly toxic and the MTD cannot be 
determined in the current trial. Available doses and percentage increments between doses 
corresponding to possible dose-escalation steps (1, or 2 at a time) are summarized in the table 
below (Table 2). Note that a particular dose-assignment sequence and number of subjects 
treated at each dose cannot be pre-specified in advance due to the dynamic nature of the 
Bayesian allocation procedure, and not every dose listed will be actually studied. Doses will 
be limited to the maximum that has been specified in Section 1.5.
Subjects who withdraw prior to Day 8/discharge may be replaced at the discretion of the 
Sponsor.  Additional subjects may be added to one or more cohorts to further define the 
MTD or safety of PF-05230907.

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3.5. Duration of Study Participation
The total length of time planned for study participation is approximately 3 months; 6.0 hours 
for screening, a single dose administration with a 4 day minimum hospital confinement 
period and follow-up visits through Day 91.
Table 2.
Dose Escalation Schema
Dose (g/kg)
Increment from prior dose
Escalation = increment of 1 
dose level
Escalation = increment of 2 dose 
level (skipped dose)
1
2
100%
3
50%
200%
4
33%
100%
5*
25%
67%
6
20%
50%
8
33%
60%
10
25%
67%
12
20%
50%
15
25%
50%
19
27%
58%
24
26%
60%
30
25%
58%
37
23%
54%
47
27%
57%
* The starting dose is 5 g/kg. If the TIE rate at the starting dose exceeds the 
pre-specified limit for the MTD, lower doses in the dose grid may be explored.  

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The following (Figure 1) is a schematic of the general Bayesian mCRM design incorporating 
the sequential dosing decision process.
Figure 1.
mCRM Design Schematic
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.
ICH related information from medical records (such as Glasgow Coma Scale [GCS]
assessment by emergency medical services, CT scan, vital signs, ECG, physical examination, 
laboratory test results, demography, weight and height, medical history, concomitant 
medications, concomitant treatments) which is collected prior to the time of consent but 
within 6.0 hours of ICH symptom onset may be used to assist with the inclusion/exclusion 
determination. 
CT scan completed and assessed by the investigator/designee within 6.0 hours from subject’s 
symptom onset and prior to informed consent may be utilized for this study for purposes of 
determining study eligibility and to provide a baseline assessment of ICH volume (by 
ABC/2 method).

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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 into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative/legal guardian, in countries where it 
is accepted) has been informed of all pertinent aspects of the study.
For sites in Sweden, only subjects that comply with the criteria specified in 
Appendix 8 may consent for the study.
2. Reasonable likelihood subject will comply with scheduled visits, laboratory tests, and
other study procedures.
3. Male and/or female subjects (female subjects must be of non-child bearing potential) 
between the ages of 18 and 79 years of age.
Female subjects who are of non-childbearing potential are defined as meeting at least 
1 of the following criteria:

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.
All other female subjects (including females with tubal ligations) are considered to be 
of childbearing potential. 
4. ICH as documented by CT scan within 6.0 hours of symptom onset.
5. Baseline ICH volume >5 mL and <60 mL based on the ABC/2 method (see 
Appendix 3).
6. At the time of treatment allocation, capability to treat with investigational product 
within 6.0 hours of symptom onset.
7. Body Mass Index (BMI) must be 40 kg/m2.

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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects who are 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.
2. Known participation in other studies involving investigational drug(s) within 30 days 
prior to study entry and/or during study participation.
3. Non-ICH related known presence of severe uncontrolled medical condition(s), or 
other known severe acute or chronic medical or psychiatric condition(s) 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.
4. Pregnant female subjects; breastfeeding female subjects; male subjects 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 active treatment 
period (Day 1) and for 28 days after the single dose of investigational product.
5. Deep coma defined as Glasgow Coma Scale (GCS) score of 3-5 (see Appendix 5).
6. Prior disability defined as a modified Rankin Score (mRS) of >3 prior to ICH onset 
(see Appendix 6).
7. Known history of ischemic, vaso-occlusive or thrombotic events or conditions within 
6 months prior to screening.
8. Known prothrombotic disorders.
9. Known secondary ICH related to aneurysm, arteriovenous malformation, 
subarachnoid hemorrhage, trauma, or other causes.  CT angiography, MR, or other 
diagnostic studies obtained as part of the standard of care may be used to assess 
eligibility.
10. Known thrombocytopenia.
11. Known history of coagulopathy, acute sepsis, crush injury, or disseminated 
intravascular coagulation within 2 weeks prior to screening.
12. Subjects in whom surgical intervention is considered likely.

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13. Known tumors of any etiology, except for basal or squamous cell carcinoma which 
has been treated and fully resolved for a minimum of 5 years.
14. Known use of oral anticoagulant(s) (eg, warfarin or novel oral anticoagulant).
15. Known use of low molecular-weight heparin (LMWH) or heparin (except when used 
to flush intravenous catheters).
16. Planned use of thrombolytic agents.
17. Known or suspected allergy to hamster protein.
4.3. Randomization Criteria 
Subjects who meet the inclusion and exclusion criteria cannot be allocated to treatment
unless there is an open study cohort at the intended time of allocation.
4.4. Lifestyle Guidelines 
All male subjects who are able to father children and are sexually active and at risk for 
pregnancy must agree to use with their partner(s) a highly effective method of contraception 
consistently and correctly for the duration of the active treatment period (Day 1) and for at 
least 28 days after the single dose of investigational product.  The investigator or his or her 
designee, will discuss with the subject the need to use highly effective contraception from the 
permitted list of contraception methods (see below) 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 or 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 oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the subject 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 copper-containing intrauterine device (IUD). 
3. Male condom or female condom used 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.

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5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. 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.
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 only be 
used 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.
4.6. Rater Qualifications 
4.6.1. ABC/2
The ABC/2 assessment of ICH volume will be completed by a trained physician.  Training to 
conduct the ABC/2 will be provided by the sponsor or sponsor designee.  Upon completion, 
documentation of training will be retained at the study site.  If a physician holds ABC/2
certification from a previous study and the certification was received within 2 years, the 
study team will review for potential certification acceptance.

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4.6.2. Neurologic Functional Assessments
4.6.2.1. Modified Rankin Score (mRS)
The mRS will be completed by a trained physician, trained physician assistant, trained nurse 
practitioner or equivalent as acceptable according to local regulation. Training to conduct the 
mRS will be provided by the sponsor or sponsor designee. Upon training completion, 
certification will be provided to the trained individual and should be retained at the study site.
If a physician, physician assistant, nurse practitioner or equivalent holds mRS certification 
from a previous study and the certification was received within 2 years, the study team will 
review for potential certification acceptance. 
4.6.2.2. Glasgow Coma Scale (GCS)
The GCS will be completed by a trained physician, trained physician assistant, trained nurse 
practitioner or equivalent as acceptable according to local regulations. 
4.6.2.3. National Institutes of Health Stroke Scale (NIHSS)
The NIHSS will be conducted by a physician, trained physician assistant, nurse practitioner 
or equivalent as acceptable according to local regulation. The training will be provided by 
the sponsor or sponsor designee. Upon training completion, documentation of training in the 
respective endpoints will be retained at the study site.
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).
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 (interactive web-based response [IWR]/interactive voice 
response [IVR] system). Allocation of subjects to treatment groups may be paused between 
cohorts to permit safety assessments that inform future dose assignments.  The dispensing 
personnel will be required to enter or select information including but not limited to the 
user’s ID and password, the protocol number, the subject number and the date of birth of the 
subject. The dispenser will then be provided with a treatment assignment. The IRT system 
will provide a confirmation report containing the subject number. The confirmation report 
must be retained by the dispenser in the site files.

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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. 
Note: The IRT system will provide the subject number at the end of the first IRT subject 
transaction.
5.2. Subject Compliance
Study treatment will be administered under the supervision of investigator site personnel.
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
PF-05230907
 for Solution for Injection and diluent for PF-05230907 
Powder for Solution for Injection will be provided by Pfizer Worldwide Research and 
Development (PWRD) as a lyophilized powder in single-use, sterile vials.  The lyophilized 
placebo vial has been developed specifically for PF-05230907 and will be used after 
reconstitution with 
as a diluent for lower 
dose preparation as may be required per the dosage and administration instructions described 
in the Investigational Product Manual. In the remainder of the protocol diluent for 
PF-05230907 Powder for Solution for Injection will be referred to as diluent.  Both 
PF-05230907 and diluent vials contain a white uniform cake.
PF-05230907 is supplied in a 6 mL clear glass tubing vial sealed with a coated rubber stopper 
and an aluminum seal with flip off cap.  Each vial of PF-05230907 is designed to be 
reconstituted 
.  The reconstituted 
solution of PF-05230907 has an extractable dose of 
 as indicated on the label and is 
clear in appearance.
Diluent is supplied in a 6 mL clear glass tubing vial sealed with a coated rubber stopper and 
an aluminum seal with flip off cap. It is designed to be reconstituted with 
 
. The reconstituted solution of diluent has a nominal 
volume 
 and is clear in appearance. 
Sterile vials will be supplied as individual vials for reconstitution and subsequent unit dosing 
preparation. 
PF-05230907 and diluent will be packaged as open-label supplies.  Each carton will contain a 
single vial of study medication and ancillary items which include one 13 mm vial adapter and 
one infusion set with suitable hypodermic needle, as described in the Investigational Product 
Manual.  Each carton will be packaged with a tamper-resistant seal.  The sponsor must be 
notified of any study medication in which the tamper-resistant seal has been broken and this 
medication should not be used.
Further details will be detailed in the Investigational Product Manual.
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Ancillary supplies used to prepare and administer doses are expected to be provided by the 
clinical site conducting the study unless otherwise agreed by the sponsor.  Further guidance 
will be detailed in the Investigational Product Manual.
5.3.2. Preparation and Dispensing
PF-05230907 and vials labeled as diluent (if necessary based on dose) will be reconstituted
 using a 13 mm vial adapter as outlined in the 
Investigational Product Manual.  Depending on the total dose required for a subject, one 
diluent vial may be required for dilution of the investigational product to prepare an 
appropriate concentration of the final dosing solution. The appropriate dose will be drawn up 
into an individual dosing syringe for administration.
The investigational product should be prepared and dispensed by appropriately qualified and 
experienced members of the study staff (eg, physician, nurse, physician’s assistant, 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance.  All dosage 
and administration calculations and dose preparation must be performed and checked by one 
clinical site personnel and verified by a second clinical site personnel.  One of these two 
individuals must be a licensed health care professional. Dose preparation must be performed 
with locally accepted sterile handling technique.  See the dosage and administration 
instructions in the Investigational Product Manual for instructions on how to prepare the 
investigational product for administration. 
Appropriately qualified and experienced members of the study team who will prepare and 
dispense the investigational product, will receive study specific training on the obligations of 
the role and will sign an agreement that will be maintained in the Site Master File.
5.4. Administration
Subject should not be treated with study drug if more than 6.0 hours have elapsed since onset 
of ICH symptoms.  Investigator site personnel will administer investigational product as a 
single IV bolus on Day 1. Consult the dosage and administration instructions in the 
Investigational Product Manual for detailed instructions regarding administration, permitted 
flush solutions and timing.  The start and stop time of administration will be recorded.  
Time 0 is the time when investigational product administration begins.
Following preparation of the investigational product (PF-05230907) by the appropriately 
qualified and experienced member of the study team, the investigational product treatment 
will be administered to the subject. 
5.5. Investigational Product Storage
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. Upon receipt 
at the study site, the investigational product (PF-05230907 and diluent) must be stored in a 
2 to 8C temperature-monitored refrigerator and in the original carton, according to labeled 
storage conditions. The investigational product and diluent cannot be used after the 
expiration date on the label. 
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Investigational product should be stored in its original container and in accordance with the 
label.  See the Investigational Product Manual for storage conditions of the product once 
reconstituted and/or diluted. 
Storage conditions stated in the single reference safety document (SRSD) (ie, 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 locations in which study 
products will be stored (as applicable, including frozen, refrigerated and/or room temperature 
products). This should be captured from the time of investigational product and diluent
receipt throughout the study. Even for continuous monitoring systems, a log or site 
procedure that ensures active daily evaluation for excursions should be available. 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.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions.
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 
Pfizer, and all destruction must be adequately documented.

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5.7. Concomitant Treatment(s) and Medication(s)

Subjects will abstain from all prohibited concomitant treatments and medications, 
except if required for the treatment of AEs.

All concomitant treatments and medications taken during the study will be recorded 
with the indication and start and stop dates of administration. All subjects will be 
questioned about concomitant treatments and medications at each visit.

Concomitant treatments and medications taken within 7 days prior to study 
enrollment will be documented as prior treatments and medications. Treatments and 
medications taken after Day 1 Hour 0 (post-dose administration) will be documented 
as concomitant treatments and medications. 
5.7.1. Prohibited Prior Treatments and Medications

Known use of oral anticoagulant(s) [eg, warfarin or novel oral anticoagulant];

Known use of low molecular-weight heparin (LMWH) or heparin (except when used 
to flush intravenous catheters);

Known use of investigational drug(s) within 30 days prior to screening;

Experimental treatment(s) and/or medication(s) within 30 days prior to screening. 
5.7.2. Prohibited During the Study 

Oral anticoagulant(s) [eg, warfarin or novel oral anticoagulant];

LMWH or heparin at therapeutic doses;

After documentation of cessation of bleeding, low dose subcutaneous low-
molecular weight heparin or unfractionated heparin may be considered for 
prevention of venous thromboembolism in accord with published guidelines from 
the American Heart Association/American Stroke Association (AHA/ASA) 
and/or the European Stroke Organisation (ESO).11,12

Investigational treatment(s) and/or medication(s).
5.7.3. Permitted During the Study

Supportive care (medications and treatments) should be in alignment with the most 
current recommendations from the AHA/ASA Guidelines for the Management of 
Spontaneous Intracerebral Hemorrhage in Adults in the United States and/or the ESO 
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage.11,12
Recommended mechanical measures for thrombo-prophylaxis should be considered.
Local standard of care not in alignment with the above recommendations should be 
reviewed with the medical monitor on a case-by-case basis. 

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
Pre-study use of antiplatelet medication for an approved indication may be continued 
during the study at the discretion of the investigator.
5.8. Rescue Medication
There is no known specific antidote for overdose with PF-05230907. Treatment of overdose 
should consist of general supportive measures. 
6. STUDY PROCEDURES 
6.1. Screening (Up to 6.0 Hours Pre-dose)
Subjects will have completed all screening procedures as indicated to confirm they meet the 
eligibility criteria for the study, treatment allocation and PF-05230907 drug administration 
within 6.0 hours of symptom onset.  The study investigator or a sub investigator will discuss, 
with each subject or their legally acceptable representative/legal guardian, the nature of the 
study, its requirements, and its restrictions.
The following procedures will be completed.  Information that is in the medical record or 
procedures performed prior to informed consent as elements of the standard of care may be 
utilized to meet the respective study procedures:

Obtain written informed consent.

Collect subject demography: the following information should be collected; date of 
birth, sex, race and ethnicity.  Date of birth and sex affect study eligibility and must 
be collected during the screening period.  If the remaining demography (race and 
ethnicity) cannot be collected during the Screening Day 1 period, the site may collect 
this data as soon as possible post-dose but prior to Day 4.

Collect medical history: the following information should be collected; GCS 
assessment by emergency medical services (if available), presence of chronic 
conditions and/or medical history of significance including history of coronary artery 
disease, thromboembolic disorders and ischemic disease, smoking history, and drug 
and non-drug allergies.  The following medical history elements affect study 
eligibility and must be collected during the screening period: 

Non-ICH related severe uncontrolled medical conditions, other severe acute and 
chronic medical and psychiatric conditions and laboratory abnormalities that may 
increase the risk associated with study participation.

Ischemic, vaso-occlusive and thrombotic events or conditions.

Prothrombotic disorders.

Thrombocytopenia.

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
Coagulopathy, acute sepsis, crush injury, and disseminated intravascular 
coagulation events or conditions.

Hamster protein allergies.

If the remaining medical history elements cannot be collected during the 
Screening Day 1 period the site may collect this data as soon as possible post-dose 
but prior to Day 4.

Collect concomitant medications: the following information should be collected; 
history of all known prescriptions and nonprescription drugs, and dietary and herbal 
supplements taken within 7 days of study enrollment.  The following concomitant 
medication information affects study eligibility and must be collected during the 
screening period: 

Oral anti-coagulant(s) (eg, warfarin or novel oral anticoagulant).

Low molecular-weight heparin or heparin. 

If the remaining concomitant medication information cannot be collected during 
the Screening Day 1 period the site may collect this data as possible post-dose but 
prior to Day 4.

Collect concomitant treatments: the following information should be collected; 
history of all known concomitant treatments which occurred within 7 days prior to 
study enrollment.  If all concomitant treatments cannot be collected during the 
Screening Day 1 period, the site may collect this data as soon as possible post-dose 
but prior to Day 4.

Collect vital signs: including temperature, blood pressure, pulse rate, and respiratory 
rate (supine).

Complete comprehensive physical examination: physical examination should consist 
of assessments of general appearance, head, eyes, ears, nose and throat (HEENT), 
skin, heart (auscultation), lungs (auscultation), abdomen (palpitation and 
auscultation), and extremities with attention to swelling, general or localized 
tenderness, entire leg or calf swelling, edema, and collateral superficial veins.

Obtain weight: subject reported weight measured within the last 3 months is 
acceptable if actual weight cannot be obtained.  If subject reported weight is utilized, 
actual weight should be collected as soon as possible post-dose.

Obtain height:  subject reported height is acceptable.

Collect ECG: a single standard supine 12-lead ECG.

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
Obtain CT scan: a CT scan is to be completed within 6.0 hours of spontaneous 
intracerebral hemorrhage symptom onset.  Intracerebral hemorrhage diagnosis will be 
based on investigator interpretation of the CT scan.  The CT scan will be submitted to 
a central vendor for final interpretation. 

Conduct ABC/2 assessment of ICH volume: investigator (or appropriately trained 
delegate as permitted by local, state, and institutional guidance) to complete 
assessment of ICH volume based on ABC/2 calculation. See Appendix 3.

Collect ICH characteristics (cause of ICH, location of ICH, presence of 
intraventricular hemorrhage [IVH], presence of edema, presence of 
hydrocephalus, presence of midline shift).

Collect results of CT angiogram (if performed as part of standard of care).

Conduct Glasgow Coma Scale (GCS): GCS score result must be 6.

Conduct retrospective mRS: mRS score result (prior to ICH onset) must be 3.

Conduct the NIH Stroke Scale (NIHSS).  Screening NIHSS assessment should be 
collected within 2 hours prior to planned treatment with PF-05230907 and as close to 
the time of treatment as is feasible.

Collect the following blood samples:

Safety: 

D-dimer sample collection to be processed at local laboratory. 

Cardiac troponin I sample collection to be processed at local laboratory (with
cardiac troponin T, where applicable) or shipped to a central laboratory.

Prothrombin G20210A Mutation, Factor V Leiden Mutation, tissue factor 
pathway inhibitor (TFPI), blood chemistry, prothrombin time/international 
normalized ratio (PT/INR), fibrinogen, ATIII, Protein S level, Protein C 
activity, and hematology (white blood cell [WBC] count, differential, 
hematocrit, hemoglobin, platelet) sample collections for shipment to a central 
laboratory. If Prothrombin G20210A and Factor V Leiden Mutation cannot 
be collected during the Screening Day 1 period, the site may collect as soon as 
possible post-dose but prior to Day 4.

PD sample collections (aPTT/PTT, PF1+2, and exploratory biomarker) for 
shipment to a central laboratory.

PK sample collection for shipment to a central laboratory.

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
Immunogenicity sample collections (ADA, NAb, FX activity, Anti-CHO and 
Anti-PACE) for shipment to a central laboratory. 

Neuro-inflammation biomarker sample collection for shipment to a central 
laboratory.

Banked biospecimen: Prep D1 sample collections for shipment to a central 
laboratory.  If Prep D1 cannot be collected during the Screening Day 1 period, the 
site may collect the Prep D1 as soon as possible post-dose but prior to Day 4.

Collect urine sample for urinalysis (if possible) for shipment to a central laboratory.  
If not feasible during the Screening Day 1 period, then sample should be collected as 
soon as possible post-dose. 

Obtain lower extremity Doppler Ultrasonography.  If lower extremity Doppler 
Ultrasonography cannot be collected during the Screening Day 1 period, the site may 
collect this data as soon as possible post-dose; no nicotine intake should occur for 
approximately 1 hour prior to testing.

Monitoring of serious adverse events.

Review inclusion/exclusion criteria.  Ensure subject meets screening entry criteria. 

Treatment allocation after eligibility is confirmed.
6.2. Study Period (Hospitalization Period)
6.2.1. Day 1 Hour 0 (Days are Relative to Start of Study Treatment)

Conduct Glasgow Coma Scale (GCS) immediately prior to dosing.

Drug administration: 

The qualified administrator will administer the investigational product to subject 
as described in the Investigation Product Manual sent under separate cover.
6.2.2. Day 1 Hour 0 Minute 5 (2 Minutes)
The following procedures will be completed:

Collect vital signs: including temperature, blood pressure, pulse rate, and respiratory 
rate (supine).

Collect the following blood samples:

Safety: PT/INR sample collection for shipment to a central laboratory.

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
For sites in Germany, PT/INR, fibrinogen, and hematology safety labs should 
also be analyzed locally.

PD sample collections (aPTT/PTT, PF1+2, and exploratory biomarker) for 
shipment to a central laboratory. 

PK sample collection for shipment to a central laboratory.  Sample should be 
drawn from the opposite arm of IV infusion, and never should be drawn through 
the infusion catheter.

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments.
6.2.3. Day 1 Hour 0 Minute 45 (15 Minutes)
The following procedures will be completed:

Collect vital signs: including temperature, blood pressure, pulse rate, and respiratory 
rate (supine). 

Conduct the GCS.

Conduct the NIHSS.

Collect the following blood samples.

Safety: PT/INR, fibrinogen, ATIII, Protein S level, Protein C activity and 
hematology (WBC count, hematocrit, hemoglobin, platelet) sample collections for 
shipment to a central laboratory.

For sites in Germany, PT/INR, fibrinogen, and hematology safety labs should 
also be analyzed locally.

PD sample collections (aPTT/PTT, PF1+2, and exploratory biomarker) for 
shipment to a central laboratory. 

PK sample collection for shipment to a central laboratory.

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments.

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6.2.4. Day 1 Hour 3 (30 Minutes)

Collect the following blood samples:

Safety:  

Cardiac troponin I sample collection to be processed at local laboratory or 
shipped to a central laboratory (with cardiac troponin T, where applicable).

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments.

If not already done, collect actual weight of study subject (as soon as possible post 
dose).
6.2.5. Day 1 Hour 9 (30 Minutes)

Collect the following blood samples:

Safety:  

Cardiac troponin I sample collection to be processed at local laboratory or 
shipped to a central laboratory (with cardiac troponin T, where applicable).

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments.
6.2.6. Day 2 (24 Hours 6 Hours)
The following procedures will be completed:

Complete targeted physical examination: physical examination should consist of 
assessments of general appearance, skin, heart (auscultation), lungs (auscultation), 
abdomen (palpitation and auscultation), and extremities with attention to swelling, 
general or localized tenderness, entire leg or calf swelling, edema, and collateral 
superficial veins.

Collect vital signs: including temperature, blood pressure, pulse rate, and respiratory 
rate (supine). 

Collect ECG: single standard supine 12-lead ECG will be collected.

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
Obtain CT scan 24 hours (6 hours) after the baseline scan was performed: the CT 
scan will be submitted to a central vendor for analysis.

Collect the following blood samples:

Safety: 

Cardiac troponin I sample collection to be processed at local laboratory or 
shipped to a central laboratory (with cardiac troponin T, where applicable).

PT/INR, fibrinogen, ATIII, Protein S level, Protein C activity, and 
hematology (WBC count, hematocrit, hemoglobin, platelet) sample 
collections for shipment to a central laboratory.

For sites in Germany, PT/INR, fibrinogen, and hematology safety labs 
should also be analyzed locally.

PD sample collections (aPTT/PTT, PF1+2, and exploratory biomarker) for 
shipment to a central laboratory.

Neuro-inflammation biomarker sample collection for shipment to a central 
laboratory.

Conduct the mRS.

Conduct the NIHSS.

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments.
6.2.7. Day 3 (48 Hours 6 Hours)
The following procedures will be completed:

Complete targeted physical examination: physical examination should consist of 
assessments of general appearance, skin, heart (auscultation), lungs (auscultation), 
abdomen (palpitation and auscultation), and extremities with attention to swelling, 
general or localized tenderness, entire leg or calf swelling, edema, and collateral 
superficial veins.

Collect vital signs: including temperature, blood pressure, pulse rate, and respiratory 
rate (supine). 

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
Collect the following blood samples:

Safety: 

Cardiac troponin I sample collection to be processed at local laboratory or 
shipped to a central laboratory (with cardiac troponin T, where applicable).

Neuro-inflammation biomarker sample collection for shipment to a central 
laboratory.

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments. 
6.2.8. Day 4 (72 Hours 6 Hours)
Subjects in the study must stay in the hospital/stroke unit/ICU at a minimum through Day 4. 
The following procedures will be completed:

Complete targeted physical examination: physical examination should consist of 
assessments of general appearance, skin, heart (auscultation), lungs (auscultation), 
abdomen (palpitation and auscultation), and extremities with attention to swelling, 
general or localized tenderness, entire leg or calf swelling, edema, and collateral 
superficial veins.

Collect vital signs: including temperature, blood pressure, pulse rate, and respiratory 
rate (supine).

Collect ECG: single standard supine 12-lead ECG will be collected.

Obtain CT or MR scan: CT or MR scan will be completed and reviewed locally for 
evidence of a treatment emergent ischemic event and sent to central vendor for final 
analysis.  CT scan is the preferred imaging modality however for the Day 4 
assessment a site may substitute an MR scan based on local standard of care (SoC), 
local regulatory, or clinical considerations at the investigator’s discretion. 

Collect the following blood samples:

Safety:

D-dimer sample collection to be processed at local laboratory.

Cardiac troponin I sample collection to be processed at local laboratory (or 
cardiac troponin T, where applicable) or shipped to a central laboratory.

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
Blood chemistry, PT/INR, fibrinogen, ATIII, Protein S level, Protein C 
activity, and hematology (WBC count, differential, hematocrit, hemoglobin, 
platelet) sample collections for shipment to a central laboratory.

For sites in Germany, PT/INR, fibrinogen, and hematology safety labs 
should also be analyzed locally.

PD sample collection (aPTT/PTT and exploratory biomarkers) for shipment to a 
central laboratory.

Neuro-inflammation biomarker sample collection for shipment to a central 
laboratory.

Obtain lower extremity Doppler Ultrasonography; no nicotine intake should occur for 
approximately 1 hour prior to testing.

Complete Thrombosis Clinical Probability Scores.

Review Wells’ algorithm (Appendix 2).15  If indicated, obtain pulmonary imaging 
study.

Conduct the mRS.

Conduct the NIHSS.

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments.
If Day 4 is the date of discharge then the following additional procedures should be 
completed:

Complete the comprehensive physical examination in place of targeted physical 
examination: physical examination should consist of assessments of general 
appearance, HEENT, skin, heart (auscultation), lungs (auscultation), abdomen 
(palpitation and auscultation), and extremities with attention to swelling, general or 
localized tenderness, entire leg or calf swelling, edema, and collateral superficial 
veins.

The highest observed blood pressure result (based on systolic blood pressure) for each 
of the following Day 1 post-dose time intervals is to be collected: Hour 0-3, Hour 3-6, 
Hour 6-12, and Hour 12-24 for a total of 4 documented highest observed blood 
pressure (BP) results.

Collect urine sample for urinalysis for shipment to a central laboratory.

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
Collect the following blood samples:

Immunogenicity sample collections (ADA, NAb, FX activity).

Discuss birth control protocol specifications.  This is to be documented in the 
subject’s chart.

Collect appropriate health resource utilization information which includes: admission 
date of subject to the stroke unit/ICU, discharge date of the subject from the stroke 
unit/ICU, admission/discharge date from the hospital (if moved from stroke unit/ICU) 
and as applicable, date subject began in-patient rehabilitation, and discharge date 
subject completed in-patient rehabilitation.

Secure approval for release of health care information from study subject/legal 
guardian/legally acceptable representative as permitted by local, state, and 
institutional guidance to assist with collection of adverse events through Day 8 and 
collection of serious adverse events through Day 43.

Telephone follow-up on Day 8 for collection of serious adverse events and adverse 
events since discharge.
6.2.9. Day 8 or Discharge (24 Hours)
If the subject was discharged on Day 4 then follow directives in Section 6.2.8 and do not 
have subject return for a Day 8 visit.  Sponsor and investigator documentation of TIEs must
occur at Day 8.  A telephone follow-up on Day 8 for collection of serious adverse events and 
adverse events since discharge will be completed if the subject is discharged prior to Day 8.  
If the subject was not discharged on Day 4, the following procedures will be completed on 
the day the subject is discharged (Day 5, Day 6, Day 7, or Day 8) or Day 8 if the subject 
remains in the hospital longer than Day 8:

Complete comprehensive physical examination: physical examination should consist 
of assessments of general appearance, HEENT, skin, heart (auscultation), lungs 
(auscultation), abdomen (palpitation and auscultation), and extremities with attention 
to swelling, general or localized tenderness, entire leg or calf swelling, edema, and 
collateral superficial veins.

Collect vital signs: including temperature, blood pressure, pulse rate, and respiratory 
rate (supine).

The highest observed blood pressure result for each of the following Day 1 post-dose 
time intervals is to be collected: Hour 0-3, Hour 3-6, Hour 6-12, and Hour 12-24 for a 
total of 4 documented highest observed BP results (based on systolic blood pressure).

Collect ECG: single standard supine 12-lead ECG will be collected.

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
Collect the following blood samples:

Safety: 

D-dimer sample collection to be processed at local laboratory. 

Immunogenicity sample collections (ADA, NAb, FX activity).

Collect urine sample for urinalysis for shipment to a central laboratory. 

Complete Thrombosis Clinical Probability Scores.

Review Wells’ algorithm (Appendix 2).15  If indicated, obtain lower extremity 
Doppler Ultrasonography and/or pulmonary imaging study; no nicotine intake 
should occur for approximately 1 hour prior to testing.

Discuss birth control protocol specifications to male subjects who are able to father 
children and are sexually active and at risk of pregnancy-see Section 4.4.  This is to 
be documented in the subject’s chart.

Secure approval for release of health care information from study subject/legal 
guardian/legally acceptable representative as permitted by local, state, and 
institutional guidance to assist with collection of adverse events through Day 8 (if 
discharged prior to Day 8) and collection of serious adverse events through Day 43.

Monitoring of serious adverse events and adverse events. Telephone follow-up call 
on Day 8 for collection of serious adverse events and adverse events if subject was 
discharged prior to Day 8.

Monitoring of concomitant medications and treatments.

Collect appropriate health resource utilization information which includes: admission 
date of subject to the stroke unit/ICU, discharge date of the subject from the stroke 
unit/ICU, admission/discharge date from the hospital (if moved from stroke unit/ICU) 
and as applicable, date subject began in-patient rehabilitation, and discharge date 
subject completed in-patient rehabilitation.
6.3. Follow-up Visits
A study site should make every effort to have the subject attend the follow-up office/clinic
visits, including arranging transportation if feasible (Day 43 and Day 91). If a subject is 
unable to attend the Day 43 and/or Day 91 study visit, or attend a scheduled remote visit on 
these days, a telephone follow-up for collection of serious adverse events since the last visit 
should occur if permitted per local, state, and institutional guidance.

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6.3.1. Day 43 (7 Days)
The following procedures will be completed:

Collect the following blood samples:

Immunogenicity sample collections (ADA, NAb, FX activity, Anti-CHO and 
Anti-PACE) for shipment to a central laboratory.

Conduct the mRS.

Conduct the NIHSS. 

Document birth control utilized through the protocol required 28 days after the single 
dose of investigational product for male subjects who are able to father children and 
are sexually active and at risk of pregnancy, see Section 4.4. 

Monitoring of serious adverse events.

Monitoring of concomitant medications and treatments.

Collect appropriate health resource utilization information which includes: as 
applicable, date subject began in-patient rehabilitation, discharge date subject 
completed in-patient rehabilitation, date subject began out-patient rehabilitation, and 
discharge date subject completed out-patient rehabilitation. 
6.3.2. Day 91 (7 Days)
The following procedures will be completed:

Collect the following blood samples only if subject tested positive for antibody 
immune response to PF-05230907 at Day 43 (sites will be notified if a subject has 
evidence of a previous antibody immune response to PF-05230907):

Immunogenicity sample collections (ADA, NAb, and FX activity) for shipment to 
a central laboratory. 

Conduct the mRS.

Conduct the NIHSS. 

Collect appropriate health resource utilization information which includes: as 
applicable, date subject began out-patient rehabilitation, and discharge date subject 
completed out-patient rehabilitation.

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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 her 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 and entered on the appropriate 
case report form (CRF) page.  In the event that vital status (whether the subject is alive or 
dead) is being measured, publicly available information should be used to determine vital 
status only as appropriately directed in accordance with local law.
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 to contact the subject and information 
received during contact 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.
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 for a final early withdrawal 
visit, if applicable, and follow up with the subject regarding any unresolved adverse events 
(AEs).
If a subject is homebound or in a rehabilitation facility and unable to attend the Day 43 
and/or Day 91 visit, a study site should make every effort to assist the subject with attending 
an office/clinic visit (eg, arrange transportation) within the protocol window time period if at 
all possible as indicated in Section 6.3.1.  If the subject is unable to attend a study withdrawal 

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visit, or is unable to attend a scheduled remote study withdrawal visit, a telephone follow-up 
for collection of all adverse events since the last visit should occur if permitted per local, 
state, and institutional guidance.
If a subject withdraws prior to Day 8/discharge, the following assessments should be 
completed:

The highest observed blood pressure result (based on systolic blood pressure) for each 
of the following Day 1 post-dose time intervals is to be collected: Hour 0-3, Hour 3-6, 
Hour 6-12, and Hour 12-24 for a total of 4 documented highest observed BP results.

Monitoring of serious adverse events.

Monitoring of adverse events.

Monitoring of concomitant medications and treatments.

Collect appropriate health resource utilization information which includes: admission 
date of subject to the stroke unit/ICU, discharge date of the subject from the stroke 
unit/ICU, admission/discharge date from the hospital (if moved from stroke unit/ICU) 
and as applicable, date subject began in-patient rehabilitation, and discharge date 
subject completed in-patient rehabilitation. 
If a subject withdraws after Day 8/discharge and prior to Day 43 or if antibody results at 
Day 43 are not yet available, the following assessments should be completed:

Collect the following blood samples:

Immunogenicity sample collection (ADA, NAb, and FX activity) for shipment to 
a central vendor.

Conduct the mRS.

Conduct the NIHSS.

Document birth control utilized through the protocol required 28 days after the single 
dose of investigational product for male subjects who are able to father children and 
are sexually active and at risk of pregnancy, see Section 4.4.

Monitoring of concomitant medications and treatments.

Monitoring of serious adverse events. 

Collect appropriate health resource utilization information which includes: as 
applicable, date subject began out-patient rehabilitation and discharge date subject 
completed out-patient rehabilitation. 

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If a subject withdraws after Day 43 and prior to Day 91, the following assessments should be 
completed:

Collect the following blood samples only if subject tested positive for antibody 
immune response to PF-05230907 at Day 43 (sites will be notified if a subject has 
evidence of a previous antibody immune response to PF-05230907):

Immunogenicity sample collections (ADA, NAb, and FX activity) for shipment to 
a central vendor. 

Conduct the mRS.

Conduct the NIHSS.

Collect appropriate health resource utilization information which includes: as 
applicable, date subject began out-patient rehabilitation and discharge date subject 
completed out-patient rehabilitation. 
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
Investigational sites are encouraged to explore the option for remote visits at the subject’s 
point-of-care as an alternative mechanism to conduct the study specified visits. 
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.
7.1. Safety Assessments
Safety will be assessed by physical examinations, vital signs, ECGs, clinical safety 
laboratory results, Thrombosis Clinical Probability Scores, CT or MR scan of the brain at 
72 hours, Doppler ultrasonography of the lower extremities at 72 hours (and discharge/Day 8 
if applicable), and spontaneous reporting of SAEs and AEs including TIEs in all subjects 
who receive at least one dose of study drug. 

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Unscheduled safety assessments may be performed at any time during the study to assess any 
perceived safety concerns.  Investigators and Pfizer Clinicians (or designees) will review 
individual subject data throughout the conduct of the study and the eDMC will be responsible 
for ongoing monitoring of study safety data (see Section 9.8).
7.1.1. Physical Examination
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation.  Comprehensive physical 
examinations and targeted physical examinations are performed at the visits specified in the 
Schedule of Activities.  Clinically significant abnormalities that represent a change from the
most recent prior observation should be considered for recording as AEs.
7.1.1.1. Comprehensive Physical Examination
A comprehensive physical examination will include the following parameters and body 
systems: general appearance, HEENT, skin, heart (auscultation), lungs (auscultation), 
abdomen (palpitation and auscultation) and extremities with attention to swelling, general or 
localized tenderness, entire leg or calf swelling, edema, and collateral superficial veins.
7.1.1.2. Targeted Physical Examination
A targeted physical examination will include the following parameters and body systems: 
general appearance, skin, heart (auscultation), lungs (auscultation), abdomen (palpitation and 
auscultation), and extremities with attention to swelling, general or localized tenderness, 
entire leg or calf swelling, edema, and collateral superficial veins.
7.1.1.3. Weight and Height
Actual weight should be measured in kilograms (kg). If actual weight cannot be obtained at 
screening, then subject reported weight from within the last 3 months may be utilized and 
actual weight should be collected as soon as possible post-dose. Subject reported height is 
acceptable.
7.1.2. Vital Signs 
Vitals signs including temperature, blood pressure, pulse rate, and respiratory rate (supine)
will be measured at the visits specified in the Schedule of Activities. Clinically significant 
abnormalities that represent a change from the most recent prior observation should be 
considered for recording as AEs. If during hospital confinement period, the magnitude of a 
vital sign abnormality is sufficient to be reported as an AE, then vital signs should be 
collected as a daily unscheduled observation during the hospital confinement period 
(eg, Day 5 through Day 8/discharge) and should be followed until the AE resolves or 
stabilizes (see Section 8.1).

Body temperature should be measured by oral, tympanic, axillary or temporal 
method.  The method chosen should be used consistently throughout the study.

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
Supine blood pressure (BP) measurement should be measured with the subject’s arm 
supported at the level of the heart and recorded to the nearest mm Hg after 5 minutes 
of rest whenever possible and as permitted by the subject’s medical condition. Blood 
pressure should not be taken from the arm with an intravenous infusion.  The same 
arm (preferably the dominant arm) should be used throughout the study.  A properly 
sized and calibrated blood pressure cuff will be used to measure blood pressure each 
time.  The use of an automated device for measuring 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.

Respiratory rate (RR) should be measured after 5 minutes rest in supine position by 
observing and counting the respirations of the subject for 30 seconds and multiplied 
by 2. The use of an automated device for measuring RR is acceptable.  When blood 
pressure is to be taken at the same time, respiration measurement should start after 
5 minutes of rest and before blood pressure measurement.
7.1.2.1. Highest Observed Blood Pressure Documentation
The highest observed blood pressure (systolic pressure) result reflected in the hospital 
record/source documents will be recorded for the time-intervals specified in the Schedule of 
Activities. 
7.1.3. ECG
A single standard supine 12-lead ECG should be performed after the subject has rested 
quietly for at least 10 minutes in a supine position at times specified in the Schedule of 
Activities.  Clinically significant abnormalities that represent a change from the Day 1 
screening/baseline visit should be considered for recording as AEs and evaluated further as 
clinically warranted.
The Day 1 screening ECG values will serve as each subject’s baseline values. When the 
timing of the measurements coincides with a blood collection, the ECG should be obtained 
prior to the nominal time of the blood collection. To ensure safety of the subjects, a qualified 
individual (eg, investigator, sub-investigator) at the study site will make comparisons to 
baseline measurements. A paper or digital copy of the ECG should be filed in the subjects 
chart and must be available to the sponsor upon request. 
If a scheduled single ECG assessment reveals a clinically significant abnormality (other than 
the Day 1 screening value) then 2 additional ECGs should be collected to confirm the 
original observation.
7.1.4. Thrombosis Clinical Probability Scores 
Thrombosis clinical probability scores consist of two assessments, the Simplified Clinical 
Model for Assessment of deep vein thrombosis (DVT) and Variables Used to Determine 
Patient Pretest Probability for Pulmonary Embolism (PE).  These assessments are used to 

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categorize subjects as having low, moderate or high probability of having a DVT or PE 
respectfully.  A physician, trained physician’s assistant, or nurse practitioner as acceptable 
according to local regulation will complete each assessment by reviewing the clinical 
variables and indicating the corresponding score.  These scores are totaled and compared 
with the coordinating probability score located in the footnote of each assessment scale. 
The Probability Scores will be completed and calculated at times specified in the Schedule of 
Activities. Sites should refer to Well’s publication “Integrated strategies for the diagnosis of 
venous thromboembolism” for additional guidance regarding recommended post treatment 
evaluation for possible deep vein thrombosis and/or pulmonary embolism, which may require 
additional Doppler lower extremity ultrasonography.15
7.1.5. Doppler Lower Extremity Ultrasonography
A Doppler lower extremity ultrasonography will be completed at the time specified in the 
Schedule of Activities. In the event of abnormal Doppler lower extremity ultrasonography
result, the investigator should initiate treatment and/or additional diagnostic studies as 
clinically warranted. No nicotine intake should occur for approximately 1 hour prior to 
testing.
7.1.6. Cardiac Troponin I
Serial results of cardiac troponin I should be followed in conjunction with other correlated 
parameters including ECG in order to assess for the possibility of acute evolving or recent 
MI based on criteria from Myocardial infarction redefined – A consensus document of The 
Joint European Society of Cardiology/American College of Cardiology Committee for the 
redefinition of myocardial infarction.20  For safety analyses the central laboratory results for 
cardiac troponin I will take precedence over local determinations for cardiac troponin T.
7.1.7. CT or MR Scan at Day 4 (72 Hours Post-dose)
A CT or MR scan will be completed as indicated in the Schedule of Activities and reviewed
locally by a qualified physician for evidence of a treatment emergent ischemic event at Day 4 
(72 hours post-dose). CT scan is the preferred imaging modality however for the Day 4 
assessment a site may substitute an MR scan based on local standard of care (SoC), local 
regulatory, or clinical considerations at the investigator’s discretion. Clinically significant 
results that represent changes from the Day 2 (24 hour post-dose) imaging should be 
considered for recording as AEs or SAEs per protocol Section 8. The scan will be sent to 
central vendor for final analysis.
7.1.8. TIEs Through Day 8
TIEs (Appendix 1) are to be reported by the study site following protocol Section 8.6.1 and 
Section 8.14. The dose toxicity relationship for each cohort is based upon the TIE data and is 
reviewed as part of the mCRM design, therefore it is essential these events be reported as 
AEs or SAEs in a timely manner by the study site.

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7.1.9. Clinical Laboratory Tests 
Blood and urine samples will be collected at the time specified in the Schedule of Activities. 
Protocol required testing includes Prothrombin G20210A Mutation, Factor V Leiden
Mutation, TFPI, D-dimer (local laboratory), blood chemistry, PT/INR, Fibrinogen, ATIII, 
Protein S level, Protein C activity, hematology, cardiac troponin I, and urinalysis.  All tests 
will be shipped to the central laboratory unless otherwise noted. For sites in Germany, 
PT/INR, fibrinogen, and hematology labs collected after Day 1, Hour 0 (post-dose) should 
also be analyzed locally.
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the central laboratory manual prior to initiation of the trial. Unscheduled 
clinical laboratory testing may be obtained at any time during the study to assess any 
perceived safety concerns.  Clinically significant abnormal findings that represent changes 
from the most recent prior assessment should be recorded as AEs per Section 8.5 and 
Section 8.6.1.
7.2. Immunogenicity
7.2.1. Plasma for Analysis of ADA (Anti-PF-05230907) and NAb
During all study periods, blood samples will be collected at times specified in the Schedule 
of Activities.  Samples will be tested for ADA using a tiered strategy of screen, confirm 
specificity, and characterize titer.  ADA positive samples will further be characterized for
cross reactivity to native FX, cross reactivity to native FXa, and NAb. 

Anti-PF-05230907 antibody samples will be analyzed using a validated bridging 
electrochemiluminescent assay in compliance with Pfizer standard operating 
procedures.  Cross reactivity to native FX and FXa will be assessed using additional 
confirmatory tiers in the anti-PF-05230907 antibody assay.

Neutralizing anti-PF-05230907 antibody samples will be analyzed using a partially 
validated chromogenic bioassay in compliance with Pfizer standard operating 
procedures as applicable.

Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site in the study laboratory manual prior 
to initiation of the trial. 

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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
As part of understanding the immunogenicity of the study drug, samples may be used 
for evaluation of the bioanalytical method.  These data will be used for internal 
exploratory purposes and will not be included in the clinical report.
7.2.2. Plasma for Analysis of FX Activity
During all study periods, blood samples will be collected at times specified in the Schedule 
of Activities.
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided to the investigator site in the study laboratory manual prior to initiation of the 
trial. 
7.2.3. Plasma for Analysis of Anti-Chinese Hamster Ovary (CHO) Protein and 
anti-PACE (furin) Antibodies 
During all study periods, blood will be collected at times specified in the Schedule of 
Activities.  Samples will be tested in each assay using a tiered strategy of screen, confirm 
specificity, and titer characterization. 

Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site in the study laboratory manual prior 
to initiation of the trial.

Anti-CHO protein antibodies and anti-PACE antibodies will be assessed using direct 
enzyme-linked immunosorbent assays (ELISAs) validated in compliance with Pfizer 
standard operating procedures.
7.3. Pharmacodynamics
Blood samples will be collected at the time specified in the Schedule of Activities.  Protocol
required testing includes aPTT/PTT and PF1+2.  Details regarding the collection, processing, 
storage and shipping of the blood samples will be provided to the investigator site in the 
study laboratory manual prior to initiation of the trial.
The pharmacodynamic (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.
As part of understanding the pharmacodynamics of the study drug, samples may be used for 
evaluation of the bioanalytical method.  These data will be used for internal exploratory 
purposes and will not be included in the clinical report.

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7.4. Pharmacokinetics
Blood samples will be collected at times specified in the Schedule of Activities. 
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the pharmacokinetic samples at the exact nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) from dosing or 2 minute for samples less than 10 minutes from dosing 
will not be captured as a protocol deviation, as long as the exact time of the sample collection 
is noted on the source document and data collection tool (eg, CRF).
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided to the investigator site in the study laboratory manual prior to initiation of the 
trial. 

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.

As part of understanding the pharmacokinetics of the study drug, samples may be 
used for metabolite identification and/or evaluation of the bioanalytical method.  This 
data will be used for internal exploratory purposes and will not be included in the 
clinical study report.  Samples collected for this purpose will be retained in 
accordance to local regulations and if not used within this timeframe, will be 
destroyed.
7.5. Exploratory Biomarkers
Some of the planned biomarker(s) may not be performed if not supported by data from the 
ongoing pre-clinical work.
7.5.1. PD Biomarkers
Blood samples for exploratory biomarkers that may reflect pharmacologic effect of 
PF-05230907 or ICH progression will be collected at the time specified in the Schedule of 
Activities.  Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site in the study laboratory manual prior to 
initiation of the trial.

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7.5.2. Neuro-inflammation Biomarkers
Blood samples for neuro-inflammation and/or neurological outcomes to better understand 
ICH will be collected at the time specified in the Schedule of Activities.  Details regarding 
the collection, processing, storage and shipping of the blood samples will be provided to the 
investigator site in the study laboratory manual prior to initiation of the trial.
7.6. Pharmacogenomics
7.6.1. Banked Biospecimens
7.6.1.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomics/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment. Collecting biospecimens 
for exploratory pharmacogenomics/biomarker analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study. Providing these biospecimens is a required 
study activity for study sites and subjects, unless prohibited as such by local regulations or 
ethics committee decision. 
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study identification (ID) number. Samples will be kept in a 
facility accessible only by swiping a badge. Data will be stored on password-protected 
computer systems. The key between the code and the subject’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information. Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/subject information sheet; any other uses require additional ethical approval. 
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
post-marketing research. Subjects can withdraw their consent for the use of their 
biospecimens at any time by making a request to the investigator, in which event any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
continue to be stored to protect the integrity of existing analyses. It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants. Subjects are notified in the informed 
consent document/subject information sheet that their results will not be given to them, 
unless required by local laws or regulations, in which case results will be returned via the 
investigator. Results will not be provided to family members or other physicians, nor will 
they be recorded in the subject’s medical record. There is no intention to contact subjects 
after completion of the clinical study.

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A 4-mL blood biospecimen Prep D1 (K2 edetic acid [ethylenediaminetetraacetic acid]
[EDTA] whole blood collection optimized for DNA analysis) will be collected per the 
Schedule of Activities to be retained for potential pharmacogenomics/biomarker analyses 
related to drug response, unless prohibited by local regulations or ethics committee decision.  
For example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
examined.
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage, and 
shipment instructions are provided in the central laboratory manual. 
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/subject information sheet that 
they will not be compensated in this event.
7.6.2. Additional Research
Unless prohibited by local regulations or ethics committee decision, subjects will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:

Investigations of the disease under study in the clinical study, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation among people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in the Markers of Drug Response section will be used.  Subjects may 
still participate in the clinical study if they elect not to allow their banked biospecimens to be 
used for the additional purposes described in this section.
7.7. Diagnostic Assessments
7.7.1. Brain CT Scan
A diagnostic brain CT scan is to be completed within 6.0 hours from subject’s symptom 
onset. The CT scan completed within 6.0 hours from subject’s symptom onset is to be 
assessed by a qualified physician at the investigator site for purposes of determining study 
eligibility and to provide a baseline assessment of ICH volume (by ABC/2 method, see 
Section 4.6.1). The CT scan will be sent to the central vendor for final analysis. 
An imaging procedure manual will be provided to the Investigator site prior to initiation of 
the trial. CT angiography data will be collected if performed as part of the standard of care.

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7.7.1.1. ABC/2 Assessment of ICH Volume
The ABC/2 is to be completed within 6.0 hours from subject’s symptom onset and prior to 
enrollment in the study by a qualified physician at the investigator site (see Section 4.6.1). 
7.8. Triggered Requirements
Condition
Action
Subjects with previous evidence of an antibody immune 
response to PF-05230907 at Day 43 (sites will be 
notified if a subject has evidence of a previous antibody 
immune response to PF-05230907 as defined in 
Section 9.6.1).
Collect immunogencity blood samples (ADA, 
Nab, and FX activity) at Day 91 for shipment to a 
central vendor. 
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 42 calendar days post-dose (Day 43)
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.
SAEs should be recorded on the case report form (CRF) from the time the subject has signed 
the informed consent document through 42 days post-dose (Day 43).

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AEs should be recorded on the case report form (CRF) from the time the subject has taken at 
least 1 dose of investigational product through 7 days post-dose (Day 8).
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;

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.
8.4. 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, at the wrong dosage strength, or the 
administration of investigational product that has undergone temperature excursion from the 

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specified storage range as indicated in the Investigational Product Manual, unless it is 
determined by the sponsor that the investigational product under question is acceptable for 
use. 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.
The Investigational Product Manual provides criteria for departures from the actual protocol 
specified dose that will be considered medication errors. 
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. 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);

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
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.
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.
Medical device complaints may meet the SAE reporting requirement criteria (see the section 
on Medical Device Complaint Reporting Requirements).  An incident is any malfunction (ie,
the failure of a device to meet its performance specifications or to perform as intended; 
performance specifications include all claims made in the labeling for the device) that, 
directly or indirectly, might lead to or might have led to the death of a subject, or user, or of 
other persons, or to a serious deterioration in their state of health. 
A serious injury that can cause a serious deterioration in state of health can include:

a life-threatening illness, even if temporary in nature;

a permanent impairment of a body function or permanent damage to a body structure;

a condition necessitating medical or surgical intervention to prevent the above 
2 bulleted items;
Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization;

any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

fetal distress, fetal death, or any congenital abnormality or birth defects.

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8.6.1. Protocol-Specified Serious Adverse Events 
Unless the investigator believes that there is a causal relationship between the investigational 
product and an event specified below, these events should not be reported by the investigator 
as SAEs as described in the Serious Adverse Event Reporting Requirements section of this 
protocol. These events are anticipated to occur commonly in a population with intracerebral 
hemorrhage.  However, these events should still be captured as AEs in the CRF.
Protocol-specified events that will not normally be reported in an expedited manner: 
1. Disseminated intravascular coagulation.
2. Acute coronary syndrome.
3. Cardiac arrest.
4. Myocardial infarction.
5. Cardiac troponin I increased.
6. Ischemic stroke.
7. Transient ischemic attacks.
8. Purpura.
9. Superior vena cava syndrome.
10. Thromboembolic event.
11. Visceral arterial ischemia.
12. Peripheral arterial ischemia.
13. Hospitalization due to ICH.
14. DVT.
15. Hemorrhagic stroke.
16. Arterial ischemic events.
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected based on the expectation of frequency of the event(s) in question in the 
population for comparison, eg, based on epidemiological data, literature, or other data, then 
this will be submitted and reported in accordance with Pfizer’s safety reporting requirements.  
Aggregate analysis of safety data will be performed on a regular basis per internal standard 
operating procedures. 

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8.6.2. 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).
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.

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8.7. 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: 

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;

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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.
8.8. Severity Assessment
Severity of adverse events will be graded based on Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.  The CTCAE displays Grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on the following general guidance: 
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
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.
8.9. 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.

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8.10. 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;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (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).
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;

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
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the 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.
8.11. 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.
8.12. 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.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/legal guardian/legally acceptable representative.  In addition, each study 
subject/legal guardian/legally acceptable representative will be questioned about AEs.
8.14. 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.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.

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As noted in the Protocol-Specified Serious Adverse Events section, should an investigator 
judge one of the identified protocol-specified SAEs to have a causal relationship with the 
investigational product, the investigator must report the event to the sponsor within 24 hours 
of investigator awareness, even if that event is a component of the endpoint.
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. 
8.14.2. 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.
8.14.3. Medical Device Complaint Reporting Requirements
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be collected on the applicable pages within the CRF.  This 
includes potential incidents or malfunctions associated with the use of a medical device 
product.  An incident or malfunction is an event that might have led to death or serious 
deterioration in health, or if it occurred again might have led to death or serious deterioration 
in health.
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.  Sites should contact their study monitor (or equivalent).

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8.14.4. 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 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
sponsor. This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 
Summary statistics and listings will be used to analyze the study data.  Summary of 
demographic and baseline characteristics, safety (including immunogenicity), efficacy and 
PK/PD data will be conducted by dose group (and overall if appropriate).
9.1. Statistical Methods
A general description of the original continual reassessment method (CRM) design and its 
various modified CRM (mCRM) designs can be found in a tutorial paper by Garrett-Mayer.13
This study employs a mCRM design similar to Goodman et al. to estimate the MTD.14 In
this study, the mCRM design utilizes Bayesian methodology to learn the dose-toxicity 
relationship continuously after each cohort’s thromboembolic and/or ischemic event (TIE) 
data becomes available.  The underlying dose-TIE relationship is assumed to follow a 
one-parameter hyperbolic-tangent model. 
where x is an adjusted dose which could be computed from an initiate dose-toxicity curve, 
is an unknown parameter with a prior distribution pre-specified at the beginning of the trial, 
and tanh is the hyperbolic-tangent function. 
The dose grid for the mCRM design is specified in Table 2.  The starting dose is 5 g/kg, but 
lower doses are included in the dose grid to allow step-down option if a high TIE rate occurs 
in the first cohort assigned to 5 g/kg by chance.  A prior uniform distribution, Unif [0,3], 
placed on the model parameter and the vector of estimated probability of TIE when =1,
shown in Table 3, define the “starting point” of the mCRM algorithm.  Based on clinical 
input, this initial dose-TIE profile assumes that a TIE rate of 15% can occur as early as 
8-10 g/kg and further increases to 27% and 49% at 15 g/kg and 37 g/kg, respectively.  
The estimated TIE rates for other doses were imputed based on the projected initial dose-TIE 
curve.  The adjusted doses (ie, x in the hyperbolic-tangent model) were computed from the 
hyperbolic tangent model by setting =1.

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Table 3.
Estimated Probability of TIE when =1
Dose (g/kg)
Estimated TIE Rate
Adjusted Dose (x)
1
2.5%
-1.83
2
3.3%
-1.69
3
4.5%
-1.53
4
6%
-1.38
5*
8%
-1.22
6
10.5%
-1.07
8
13.5%
-0.93
10
17.5%
-0.78
12
22%
-0.63
15
27%
-0.50
19
32.5%
-0.37
24
38%
-0.24
30
43%
-0.14
37
49%
-0.02
47
55%
0.10
* starting dose
After the TIE data from the first cohort (5 g/kg) becomes available, the prior distribution of 
will be updated into a posterior distribution through Bayesian Markov Chain Monte Carlo 
(MCMC) simulations in adaptive design explorer (ADE).  The model-based MTD will be 
estimated as 
, where 0.15 is the pre-specified target TIE rate at MTD and 
is 
the posterior mean of .  The next cohort of 3 subjects will be dosed at the dose level closest 
to this estimated MTD but not exceeding it, subject to additional pre-specified dose 
escalation constraints and clinical oversight.  The posterior distribution of β will become the 
prior distribution in the next round of updates.  The details of Bayesian analyses will be 
documented in the statistical analysis plan.  This process is continued until at least one of the 
following stopping rules is met:
1. Maximum sample size of 51 subjects has been reached. 
2. MTD has been identified with sufficient accuracy, ie, 12 subjects have been 
accumulated on a dose that is currently estimated to be the MTD.
3. All doses appear to be overly toxic and MTD cannot be determined in the current trial 
setting.
Starting from the second cohort and until the end of the trial, the above described mCRM 
algorithm constantly incorporates additional information about dose-TIE relationship learned 
from the data via modeling and that is reflected on the projected MTD. By design, such dose 
allocation procedure will eventually cluster dose assignments around the dose yielding an 
approximately 15% TIE rate. 
Like all Bayesian methods, the adopted mCRM design may be sensitive to prior information 
placed on the model parameter at the beginning of the trial. However, as the trial 
progresses and the DLT data accumulates, it eventually overrules the prior information and 
latter becomes less important. 

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9.2. Simulations for mCRM Design
Extensive simulations were performed to compare the operating characteristics of various 
competing mCRM designs in order to fine-tune mCRM performance and choose the ‘best’ 
mCRM design. Below is a brief description of the simulation setup and key findings. All the 
simulations were performed in ADE (v3.0.2.1).
Different combinations of cohort sizes (2 or 3), maximum dose escalation allowed between 
cohorts (1, 2 or 3 doses), stopping rules (maximum number of 6, 9, 12, 15, 18 and 24 subjects
on MTD), mCRM dose-toxicity model (power or hyperbolic-tangent), and starting dose 
(5 g/kg or 8 g/kg) were examined. Competing designs were evaluated under 6 different 
plausible scenarios of dose-TIE curves varying in steepness, location of the true MTD and 
overall toxicity level in the range of the dosing grid. 
For each of the above competing designs, the operating characteristics were compared by 
scenario to evaluate the trade-off between precision of MTD estimation and study efficiency.
The final chosen design is a mCRM design with cohort size of 3, a starting dose of 5 g/kg, 
and the stopping rule with maximum 12 subjects on MTD using the hyperbolic-tangent 
dose-toxicity working model. Based on simulations, this design provides, on average, a more 
accurate estimate of MTD and comparable or less proportion of subjects receiving doses 
higher than the MTD than the conventional 3+3 design, with an acceptable increase in the 
average sample size. Details of the simulations were documented in a simulation report for 
this study. 
9.3. Sample Size Determination
No formal sample size calculation is performed. The minimum sample size of the study is 
approximately 20.  The maximum study sample size is set as 51 in order to have a reasonable 
chance to identify the correct MTD based on statistical simulations.  The actual sample size 
of the study will depend on the underlying dose-TIE relationship and variability in the actual 
data realization.  The cohort size is 3.  If the study stops with a MTD declared and the 
maximum sample size has not been reached, 12 subjects must have been studied at the MTD 
dose.  The actual number of subjects at each dose will vary. 
9.4. Efficacy Analysis
All study efficacy endpoints, including hemostatic endpoints (ICH absolute and percent 
change from baseline volume) and neurological outcomes (mRS and NIHSS) are exploratory 
endpoints. 
 
 If appropriate, a mixed-effects model for repeated measure will also be utilized to 
summary the hemostatic endpoints with fixed effects of dose group, CT scan time and dose 
group by CT scan time interaction and an appropriate covariance matrix for repeated 
measurements.  Point estimates and confidence intervals of the hemostatic endpoints for each 
dose group will be produced by CT scan time.
CCI

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9.5. Analysis of Other Endpoints
9.5.1. Pharmacokinetic Analysis
PF-05230907 concentration in plasma is an exploratory endpoint.  Available plasma 
concentration of PF-05230907 will be descriptively summarized and plotted by nominal PK 
sampling time and dose group.  Due to the short half-life (t½) and limited sampling, 
noncompartmental parameters will not be calculated for the study report.
9.5.2. Pharmacodynamics Analysis
The pharmacodynamic endpoints include aPTT or PTT and PF1+2, within 2 days of dosing. 
These will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate.
9.6. Safety Analysis
All subjects who received the treatment of PF-05230907 will be included for safety analysis. 
Safety endpoints, including treatment emergent TIEs, treatment emergent serious adverse 
events, treatment emergent adverse events, treatment emergent laboratory abnormality, 
physician examination changes, vital signs changes, ECG results and other safety data will be 
summarized descriptive by dose group. Listings and/or graphic displays will also be 
generated, where appropriate. As discussed in Section 9.1, the TIE data from the current 
cohort will be utilized for the mCRM design along with clinical and eDMC oversight to 
determine the dose for the next cohort.
9.6.1. Immunogenicity Analysis
ADA, NAb and Factor X activity level will be summarized by dose and time points for 
samples tested.  Subjects with ADA and NAb immune responses will be summarized by 
dose.  An ADA immune response following study drug administration is defined as:

A confirmed post-treatment positive assay result in combination with a negative 
baseline sample assay result; or

A confirmed post-treatment positive assay result in combination with at least one 
dilution factor increase in titer relative to a positive baseline sample assay result.
Positive ADA responses to PF-05230907 will be further confirmed for cross reactivity 
against native FX and native FXa.  Positive ADA responses will also be evaluated for 
neutralizing antibody immune response against PF-05230907.  Neutralizing antibody 
immune responses will be assessed by results from a neutralizing assay and/or from the 
factor X activity assay.  A subject with neutralizing antibody immune response is defined as 
either:

A positive result from at least one sample tested in the neutralizing assay; or

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
Depletion of study subject factor X activity (>50% reduction relative to baseline) in 
the basal state, at assessments subsequent to study drug administration in combination 
with a demonstrated positive ADA immune response and in the absence of any other 
plausible explanation for decline in factor X activity. 
In the presence of ADA to PF-05230907 that is cross reactive with native FX or native FXa, 
a positive neutralizing antibody response against PF-05230907 will be imputed to be cross 
reactive against native FX or native FXa respectively.
9.7. Interim Analysis 
There are no formal statistical interim analyses.  For the determination of the dose for the 
next cohort, analyses of all available TIE data will be performed after TIE data becomes 
available for the current cohort.  Observed TIE data will be used to update the dose-toxicity
model, which will recommend a dose for the next cohort of subjects.  Other safety biomarker 
data from the trial will also be taken into consideration to provide clinical oversight in 
determining the dose for the next cohort.  Study will be stopped if at least one of the stopping 
criteria described in Section 9.1 has been met.
9.8. Data Monitoring Committee 
This study will use an external data monitoring committee (eDMC).  The eDMC will be 
responsible for ongoing cumulative reviews of the study safety data.    The eDMC chair (or 
designee) will also be required to review an interim review memo including all 7-day safety 
data for each completed cohort, in order to provide authorization to proceed with enrollment.  
At his/her discretion, the eDMC chair may direct that dosing at the respective dose level (or 
higher dose levels) be paused until a full meeting of the eDMC has been convened.  In 
addition, if a SUSAR or 2 or more grade 3 or higher adverse events that are considered at 
least possibly related to treatment with PF-05230907 are observed in the initial cohort 
evaluating a dose level that exceeds previously investigated dose levels, dosing at the 
respective dose level (or higher dose level) will be paused and the eDMC will be convened.  
These eDMC requirements will also be specified in the eDMC charter.  Review of efficacy 
data will not be a responsibility of this committee.  The recommendations made by the 
eDMC to alter the conduct of the study will be forwarded to Pfizer for final decision.  Pfizer 
will forward such decisions to regulatory authorities as appropriate. 
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.

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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. 
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.

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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 (CA).  All correspondence with the IRB/EC/CA should be retained in the 
investigator file.  Copies of IRB/EC/CA approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC/CA
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/CA and Pfizer in writing 
immediately after the implementation.
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.

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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.
Adult subjects with ICH will present in acute care settings (eg, emergency room, ICU), may 
be decisionally impaired and may be unable to provide written informed consent. Due to the 
life-threatening and severely disabling nature of ICH and the lack of effective treatment for 
ICH, treatment with PF-05230907 may have the potential for benefit in this vulnerable 
population.  Based on local regulations and institutional policies, the respective study 
investigators will determine if consent may be obtained from a subject’s legally acceptable 
representative or legal guardian. Whenever consent is obtained from a subject’s legally 
acceptable representative or legal guardian and the investigator determines the subject has 
regained the capacity to provide consent, the subject’s consent is to be obtained. 
The investigator must ensure that each study subject or his or her legally acceptable 
representative or legal guardian, 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 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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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject’s legally acceptable representative or legal guardian 
and the subject’s assent (if 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
Subject recruitment efforts are not required for this study because this study will be 
conducted in an acute condition (ICH) with rapid onset which generally is not by definition 
diagnosed until subjects are at the study site.
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 All Participating Countries 
End of trial in all participating countries is defined as last subject last visit (LSLV).
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-05230907 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 2-4 weeks.  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. 

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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 prespecified protocol or was 
terminated.
EudraCT
Pfizer posts 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.
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.

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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.
Broderick J, Feldmann E, Hanley D, et al. Guidelines for the management of 
spontaneous intracerebral hemorrhage in adults 2007 update. Stroke 2007;38:2001-23.
2.
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015
update: a report from the American Heart Association. Circulation 2015; 131:e29-322. 
3.
Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N 
Engl J Med 2001;344:1450-60.
4.
Ivanciu L, Toso R, Margaritis P, et al. A zymogen-like factor Xa variant corrects the 
coagulation defect in hemophilia. Nat Biotechnol 2011;29:1028-33.
5.
Fuchs HE, Pizzo SV. Regulation of factor Xa in vitro in human and mouse plasma and 
in vivo in mouse. Role of the endothelium and plasma proteinase inhibitors. J Clin 
Invest 1983;72(6):2041-9.
6.
Bolt M, Hua F, Brenneman K, et al. 4237 Evaluation of potential safety biomarkers for 
monitoring thrombogenic potential of FXaI16L. Oral poster and abstract from 56th ASH 
Annual Meeting & Exposition; available at 
https://ash.confex.com/ash/2014/webprogram/Paper72741.html
7.
Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated 
FVII for acute intracerebral hemorrhage. N Engl J Med 2008;358:2127-37.
8.
Mayer SA, Davis SM, Skolnick BE, et al. Can a subset of intracerebral hemorrhage
patients benefit from hemostatic therapy with recombinant activated FVII? Stroke 
2009;40:833-40.
9.
Diringer MN, Skolnick BE, Mayer SA, et al.  Thromboembolic events with 
recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from 
the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial.  Stroke 2010;41:48-53.
10.
CTCAE V4.03 Scale available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
11.
Broderick J, Connolly S, Feldmann E, et al. AHA/ASA guideline: guidelines for the 
management of spontaneous intracerebral hemorrhage in adults 2007 update a guideline 
from the American heart association, American stroke association stroke council, high 
blood pressure research council and the quality of care and outcomes in research 
interdisciplinary working group. Stroke 2007;38:2001-2023.
12.
Steiner T, Al-Shahi Salman RA, Beer R, et al. European stroke organization (ESO) 
guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 
2014;9(7):840-55.

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13.
Garrett-Mayer E. The continual reassessment method for dose-finding studies: a 
tutorial. Clinical Trials. 2006; 3(1): 57-71.
14.
Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the 
continual reassessment method for phase I studies. Stat in Medicine 1995; 14: 149-61.
15.
Wells P.S. Integrated strategies for the diagnosis of venous thromboembolism. J 
Thromb Haemost 2007;5(Suppl. 1):41-50
16.
Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral 
hemorrhage volumes. Stroke 1996;27:1304-5.
17.
National Institute of Health, National Institute of Neurological Disorders and Stroke. 
http://www.ninds.nih.gov/disorders/stroke/strokescales.htm
18.
Glasgow Coma Scale available at: http://glasgowcomascale.org/
19.
mRS available at: http://rankinscale.org/
20.
Thygesen K, Alpert JS, Jaffe AS et al.  Third universal definition of myocardial 
infarction.  Journal of the American College of Cardiology 2012; 60:1581-98.

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Appendix 1. Thromboembolic and Ischemic Events (TIEs) and Associated Severity Grade (CTCAE V4.03 Scale) for 
Determination of MTD10
Adverse Event
Grade Defining a TIE
Grade and Description
Disseminated intravascular coagulation
3 or higher
1: Not defined
2: Laboratory findings with no bleeding
3: Laboratory findings and bleeding
4: Life-threatening consequences; urgent intervention 
indicated
5: Death
Acute coronary syndrome 
3 or higher
1: Not defined
2: Symptomatic, progressive angina; cardiac enzymes 
normal, hemodynamically stable
3: Symptomatic, unstable angina and/or acute 
myocardial infarction, cardiac enzymes abnormal, 
hemodynamically stable
4: Symptomatic, unstable angina and/or acute 
myocardial infarction, cardiac enzymes abnormal, 
hemodynamically unstable
5: Death  

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Adverse Event
Grade Defining a TIE
Grade and Description
Cardiac arrest
4 or higher
1: Not defined
2: Not defined
3: Not defined
4: Life threatening consequences; urgent intervention 
indicated
5: Death
Myocardial infarction
3 or higher
1: Not defined
2: Asymptomatic and cardiac enzymes minimally 
abnormal and no evidence of ischemic ECG changes
3: Severe symptoms; cardiac enzymes abnormal; 
hemodynamically stable; ECG changes consistent with 
infarction
4: Life-threatening consequences;   hemodynamically 
unstable
5: Death 

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Adverse Event
Grade Defining a TIE
Grade and Description
Cardiac troponin I increased
3
1: Levels above the upper limit of normal and below the 
level of myocardial infraction as defined by the 
manufacturer
2: Not defined
3: Levels consistent with myocardial infarction as 
defined by the manufacturer
4: Not defined
5: Not defined
Ischemia cerebrovascular
1 or higher and associated 
with lesion(s) on CT/MRI 
not contiguous with the ICH 
lesion and in a discrete 
separate area of the brain
1: Asymptomatic; clinical or diagnostic observations 
only; intervention not indicated
2: Moderate symptoms
3: Not defined
4: Not defined
5: Not defined

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Adverse Event
Grade Defining a TIE
Grade and Description
Portal vein thrombosis
2 or higher
1: Not defined
2: Intervention not indicated
3: Medical intervention indicated
4:  Life-threatening consequences; urgent intervention 
indicated
5: Death
Ischemic stroke based upon CTCAE 
V4.03 toxicity criteria for stroke
1 or higher and associated 
with lesion(s) on CT/MRI 
not contiguous with the ICH 
lesion and in a discrete 
separate area of the brain
1: Asymptomatic or mild neurologic deficit; 
radiographic findings only
2: Moderate neurologic deficit
3: Severe neurologic deficit
4:  Life-threatening consequences; urgent intervention 
indicated
5: Death

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Adverse Event
Grade Defining a TIE
Grade and Description
Transient Ischemic attacks
2
1: Mild neurological deficit with or without imaging 
confirmation
2: Moderate neurologic deficit with or without imaging 
confirmation
3: Not defined
4: Not defined
5: Not defined
Purpura
2 or higher
1: Combined area of lesions covering <10% BSA
2: Combined areas of lesions covering 10-30% BSA; 
bleeding with trauma
3:  Combined areas of lesions covering >30% BSA; 
spontaneous bleeding
4: Not defined
5: Not defined

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Adverse Event
Grade Defining a TIE
Grade and Description
Superior vena cava syndrome
1 or higher
1. Asymptomatic; incidental finding of SVC thrombosis
2. Symptomatic; medical intervention indicated 
(eg, anticoagulation, radiation, or chemotherapy)
3: Severe symptoms; multi-modality intervention 
indicated (eg, anticoagulation, chemotherapy, radiation, 
stenting)
4: Life-threatening consequences; urgent multi-modality 
intervention indicated (eg, lysis, thrombectomy, 
surgery)
5: Death
Thromboembolic event
2 or higher
1: Venous thrombosis (eg, superficial thrombosis)
2: Venous thrombosis (eg, uncomplicated deep vein 
thrombosis), medical intervention indicated
3: Thrombosis (eg, uncomplicated pulmonary embolism 
[venous], non-embolic cardiac mural [arterial] 
thrombosis), medical intervention indicated
4: Life-threatening (eg, pulmonary embolism, 
cerebrovascular event, arterial insufficiency); 
hemodynamic or neurologic instability; urgent 
intervention indicated
5: Death

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Adverse Event
Grade Defining a TIE
Grade and Description
Visceral arterial ischemia
2 or higher
1: Not defined
2: Brief (<24 hours)episode of ischemia managed 
medically and without permanent deficit
3: Prolonged (>=24 hours) or recurring symptoms 
and/or invasive intervention indicated
4: Life-threatening consequences; evidence of end organ 
damage; urgent operative intervention indicated
5: Death
Peripheral arterial ischemia
3 or higher
1: Not defined
2: Brief (<24 hrs) episode of ischemia managed 
medically and without deficit
3: Prolonged (>=24 hours) or recurring symptoms 
and/or invasive intervention indicated
4: Life-threatening consequences; evidence of end organ 
damage; urgent operative intervention indicated
5: Death

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Appendix 2. Thrombosis Clinical Probability Scores15
Simplified Clinical Model for Assessment of DVT
Clinical variable
Score
Active cancer (treatment ongoing or within previous 6 months or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring 
general or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swelling
1
Calf swelling at least 3 cm larger than that on the asymptomatic leg (measured 10 cm below the 
tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (non-varicose)
1
Previously documented DVT
1
Alternative diagnosis at least as likely as DVT
-2
DVT, deep vein thrombosis. 2, probability of DVT is ‘likely’.  1, probability for DVT is ‘unlikely’.  
Alternatively, <1 is low probability, moderate is 1 or 2, and high is >2.
Variables Used to Determine Patient Pretest Probability for Pulmonary Embolism
Clinical variable
Score
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpitation of the 
deep veins)
3
PE as or more likely than an alternative diagnosis
3
Heart rate greater than 100
1.5
Immobilization or surgery in the previous 4 weeks
1.5
Previous DVT/PE
1.5
Hemoptysis
1
Malignancy (on treatment, treated in the last 6 month or palliative)
1
DVT, deep vein thrombosis; PE, pulmonary embolism. >4, probability of PE is ‘likely’.  4, probability for 
PE is ‘unlikely’.  Alternatively, <2 is low probability, moderate is 2-6, and high is >6. 

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Appendix 3. ABC/216
ABC/2 formula: A is the greatest hemorrhage diameter by CT, B is the diameter 90to A, 
and C is the approximate number of CT slides with hemorrhage multiplied by the slide 
thickness. 
The derivation of the ABC/2 formula is as follows: The volume of an ellipsoid is 
4/3π(A/2)(B/2)(C/2), where A, B, and C are the three diameters. If π is estimated to be 3, 
then the volume of an ellipsoid becomes ABC/2.

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Appendix 4. National Institute of Health Stroke Scale17
Online certification and reference for the NIHSS can be found at 
https://secure.trainingcampus.net/uas/modules/trees/windex.aspx?rx=nihss-
english.trainingcampus.net
A copy of the NIHSS assessment forms will be supplied to the site with the B2341002 study 
documentation. 
Summary of the assessment from http://www.nihstrokescale.org/ is detailed below:
The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of 
acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, 
extraocular movement, motor strength, ataxia, dysarthria, and sensory loss.  A trained 
observer rates the patient’s ability to answer questions and perform activities.  Ratings for 
each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for 
untestable items.  The single patient assessment requires less than 10 minutes to complete. 
The evaluation of stroke severity depends upon the ability of the observer to accurately and 
consistently assess the patient.

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Appendix 5. Glasgow Coma Scale18
Component
Rating
Score
Eyes Open
Spontaneous
4
To sound
3
To pressure
2
None
1
Verbal Response
Oriented
5
Confused
4
Words
3
Sounds
2
None
1
Motor Response
Obeys commands
6
Localising
5
Normal flexion
4
Abnormal flexion
3
Extension
2
None
1

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Appendix 6. Modified Rankin Scale (mRS)19
The following link should be used to access the training module for the mRS: 
https://secure.trainingcampus.net/uas/modules/trees/windex.aspx?rx=rankin-
english.trainingcampus.net

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Appendix 7. Abbreviations 
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ADA
anti-drug antibody
ADE
adaptive design explorer
AE
adverse event
AHA/ASA
American Heart Association/American Stroke Association
ALT
alanine aminotransferase
Anti-CHO
anti-Chinese hamster ovary
Anti-PACE
anti-paired basic amino acid cleaving enzyme
APC
activated protein C
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATIII
antithrombin III
BID
twice daily
BP
blood pressure
CA
Competent Authority
CDS
core data sheet
CRF
case report form
CRM
continual reassessment method
CSA
clinical study agreement
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CT 
computed tomography 
CV
coefficient of variation
DNA
deoxyribonucleic acid
DU
dispensable unit
DVT
deep vein thrombosis
EC
effective concentration
EC
ethics committee
ECG
electrocardiogram
ED
effective dose
eDMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
ELISAs
Enzyme-linked immunosorbent assays
EMS
emergency medical services 
ESO
European Stroke Organisation 
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
FIH
first in human
FSH
follicle-stimulating hormone
FVa
factor Va
FX
factor X
GCP
good clinical practice
GCS
Glasgow coma scale
GLP
good laboratory practice
HEENT
head, eyes, ears, nose and throat
IB
investigator’s brochure
ICH
intracerebral hemorrhage 
ICH
International Conference on Harmonisation
ICU
intensive care unit
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
IVH
intraventricular hemorrhage 
IVR
interactive voice response
IWR
interactive web response
kg
kilogram
LFT
liver function test
LMWH
low molecular-weight heparin
LRP
lipoprotein receptor-related protein
LSLV
last subject last visit 
MCMC
Markov Chain Monte Carlo
mCRM
modified continual reassessment method
MED
minimum effective dose
MR or MRI
magnetic resonance imaging
mRS
modified Rankin score
MTD
maximum tolerated dose
NAb
neutralizing antibody
N/A
not applicable
NCI
National Cancer Institute 
NIHSS
National Institute of Health Stroke Scale
NOAL
no observed effects level
NOAEL
no observed adverse effect level
OBU
Oncology Business Unit
PD
pharmacodynamic
PE
pulmonary embolism 

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Abbreviation
Term
PF1+2
prothrombin fragment 1+2
PK
pharmacokinetic 
PT
prothrombin time
PWRD
Pfizer Worldwide Research and Development 
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
SAP
statistical analysis plan
SCL
Supply Chain Lead
SoA
schedule of activities
SOP
standard operating procedure
SPC
summary of product characteristics
SRSD
single reference safety document
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAT
thrombin-antithrombin
TEAE
treatment emergent adverse event
TIE
thromboembolic and/or ischemic event
TFPI
tissue factor pathway inhibitor
TX
toxicokinetics
VISTA
virtual international stroke trial archive
WBC
white blood cell
ULN
upper limit of normal
US
United States
USPI
United States package insert

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Appendix 8. Definition for Subjects Capable of Providing Consent in Sweden
Enrollment of subjects in Sweden is limited to individuals who are able to provide their 
personal informed consent.  Individuals conscious, oriented and able to follow commands are 
considered able to provide their own consent and in Sweden these individuals are 
operationally defined by the following criteria:
Inclusion Criteria

Glasgow Coma Scale score 14.
Exclusion Criteria

Individuals with aphasia (verbal Glasgow Coma Scale score <5 and NIH Stroke Scale 
Score >0 in item 9).

Individuals with dementia.

Individuals with a reduced level of consciousness (NIH Stroke Scale score 1 in item 1).