Title

Phase 1 Safety, Pharmacokinetics And Pharmacodynamics Study Of Recombinant Factor VIIa Variant (813d) In Adult Subjects With Hemophilia
An Ascending Single Dose Study To Evaluate The Safety, Tolerability And Pharmacokinetics/Pharmacodynamics Of Pf-05280602, A Recombinant Factor Viia Variant (813d), In Adult Hemophilia A And B Subjects With Or Without Inhibitors
  • Phase

    Phase 1
  • Study Type

    Interventional
  • Intervention/Treatment

    pf-05280602 ...
  • Study Participants

    29
This study hypothesizes that the study drug, PF-05280602 (at the selected doses) will be safe to administer to subjects with severe Hemophilia A or B with or without inhibitors and will demonstrate evidence of hemostatic activity. This is supported by the preclinical findings in hemophilic animal models.
Study Started
Dec 31
2011
Primary Completion
Oct 31
2015
Study Completion
Oct 31
2015
Results Posted
Apr 06
2017
Last Update
May 12
2017

Biological PF-05280602

0.5 micrograms per kilogram of PF-05280602, IV infusion, single dose

Biological PF-05280602

4.5 micrograms per kilogram of PF-05280602, IV infusion, single dose

Biological PF-05280602

9.0 micrograms per kilogram of PF-05280602, IV infusion, single dose

Biological PF-05280602

18.0 micrograms per kilogram of PF-05280602, IV infusion, single dose

Biological PF-05280602

30.0 micrograms per kilogram of PF-05280602, IV infusion, single dose

1 Experimental

2 Experimental

3 Experimental

4 Experimental

5 Experimental

Criteria

Inclusion Criteria:

Male subjects 18 to <65 years old with severe hemophilia A or B with or without inhibitors to FVIII or FIX.
Subjects is willing and able to comply with the mandatory washout periods prior to screening and prior to dosing and through 48 hours post dosing. At screening this includes a washout of FIX for 96 hours and FVIII for 72 houts. At dosing this includes a washout of FIX for 96 hours and FVIII and other hemostatic agents for 72 hours through 48 hours post dosing.
Subjects must agree and commit to using a a highly effective method of birth control from the time of screening through four weeks after study drug administration.

Exclusion Criteria:

Presence of a bleeding disorder in addition to hemophilia A or B.
Regular, concomitant therapy with immunomodulating drugs (eg, intravenous immunoglobulin, and routine systemic corticosteroids).
History of coronary artery disease, thrombolic disease or diagnosis of prothrombic disorder.

Summary

PF-05280602 18.0 mcg/kg

PF-05280602 30.0 mcg/kg

PF-05280602 0.5 mcg/kg

PF-05280602 4.5 mcg/kg

PF-05280602 9.0 mcg/kg

All Events

Event Type Organ System Event Term PF-05280602 0.5 mcg/kg PF-05280602 4.5 mcg/kg PF-05280602 9.0 mcg/kg PF-05280602 18.0 mcg/kg PF-05280602 30.0 mcg/kg

Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Supine blood pressure (BP) was measured with the participant's arm supported at the level of the heart, and recorded to the nearest millimeters of mercury (mmHg) after 5 minutes of rest. The same arm (preferably the dominant arm) was to be used throughout the study.

PF-05280602 0.5 mcg/kg

DBP: Baseline

78.0
mmHg (Mean)
Standard Deviation: NA

DBP: Change at Day 15

-9.0
mmHg (Mean)
Standard Deviation: NA

DBP: Change at Day 2

2.0
mmHg (Mean)
Standard Deviation: NA

DBP: Change at Day 3

-3.0
mmHg (Mean)
Standard Deviation: NA

SBP: Baseline

122.0
mmHg (Mean)
Standard Deviation: NA

SBP: Change at Day 15

-10.0
mmHg (Mean)
Standard Deviation: NA

SBP: Change at Day 2

SBP: Change at Day 3

5.0
mmHg (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

DBP: Baseline

73.7
mmHg (Mean)
Standard Deviation: 6.35

DBP: Change at Day 15

-3.5
mmHg (Mean)
Standard Deviation: 11.41

DBP: Change at Day 2

-2.8
mmHg (Mean)
Standard Deviation: 6.43

DBP: Change at Day 3

-6.5
mmHg (Mean)
Standard Deviation: 6.57

SBP: Baseline

130.2
mmHg (Mean)
Standard Deviation: 7.14

SBP: Change at Day 15

-5.5
mmHg (Mean)
Standard Deviation: 12.18

SBP: Change at Day 2

-8.7
mmHg (Mean)
Standard Deviation: 8.24

SBP: Change at Day 3

-7.0
mmHg (Mean)
Standard Deviation: 6.99

PF-05280602 9.0 mcg/kg

DBP: Baseline

70.5
mmHg (Mean)
Standard Deviation: 10.97

DBP: Change at Day 15

6.0
mmHg (Mean)
Standard Deviation: 13.11

DBP: Change at Day 2

2.7
mmHg (Mean)
Standard Deviation: 6.28

DBP: Change at Day 3

3.3
mmHg (Mean)
Standard Deviation: 6.56

SBP: Baseline

120.2
mmHg (Mean)
Standard Deviation: 25.41

SBP: Change at Day 15

4.7
mmHg (Mean)
Standard Deviation: 18.00

SBP: Change at Day 2

-0.2
mmHg (Mean)
Standard Deviation: 14.41

SBP: Change at Day 3

2.2
mmHg (Mean)
Standard Deviation: 19.30

PF-05280602 18.0 mcg/kg

DBP: Baseline

75.8
mmHg (Mean)
Standard Deviation: 4.67

DBP: Change at Day 15

-4.3
mmHg (Mean)
Standard Deviation: 11.15

DBP: Change at Day 2

-0.8
mmHg (Mean)
Standard Deviation: 5.12

DBP: Change at Day 3

-2.2
mmHg (Mean)
Standard Deviation: 8.11

SBP: Baseline

124.2
mmHg (Mean)
Standard Deviation: 7.68

SBP: Change at Day 15

-4.5
mmHg (Mean)
Standard Deviation: 14.92

SBP: Change at Day 2

-3.0
mmHg (Mean)
Standard Deviation: 6.51

SBP: Change at Day 3

-5.5
mmHg (Mean)
Standard Deviation: 7.66

PF-05280602 30.0 mcg/kg

DBP: Baseline

77.0
mmHg (Mean)
Standard Deviation: 6.87

DBP: Change at Day 15

-4.5
mmHg (Mean)
Standard Deviation: 5.65

DBP: Change at Day 2

-3.3
mmHg (Mean)
Standard Deviation: 5.50

DBP: Change at Day 3

4.3
mmHg (Mean)
Standard Deviation: 10.41

SBP: Baseline

125.5
mmHg (Mean)
Standard Deviation: 8.53

SBP: Change at Day 15

1.8
mmHg (Mean)
Standard Deviation: 11.84

SBP: Change at Day 2

-1.5
mmHg (Mean)
Standard Deviation: 5.58

SBP: Change at Day 3

Change From Baseline in Body Weight

PF-05280602 0.5 mcg/kg

Baseline

72.7
kilograms (kg) (Mean)
Standard Deviation: NA

Change at Day 15

-0.5
kilograms (kg) (Mean)
Standard Deviation: NA

Change at Day 2

-0.9
kilograms (kg) (Mean)
Standard Deviation: NA

Change at Day 3

-0.8
kilograms (kg) (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

Baseline

75.0
kilograms (kg) (Mean)
Standard Deviation: 12.65

Change at Day 15

0.4
kilograms (kg) (Mean)
Standard Deviation: 1.09

Change at Day 2

-1.0
kilograms (kg) (Mean)
Standard Deviation: 0.98

Change at Day 3

-0.6
kilograms (kg) (Mean)
Standard Deviation: 0.85

PF-05280602 9.0 mcg/kg

Baseline

78.7
kilograms (kg) (Mean)
Standard Deviation: 10.73

Change at Day 15

0.6
kilograms (kg) (Mean)
Standard Deviation: 1.55

Change at Day 2

-0.6
kilograms (kg) (Mean)
Standard Deviation: 0.72

Change at Day 3

-0.5
kilograms (kg) (Mean)
Standard Deviation: 0.60

PF-05280602 18.0 mcg/kg

Baseline

78.0
kilograms (kg) (Mean)
Standard Deviation: 11.31

Change at Day 15

0.6
kilograms (kg) (Mean)
Standard Deviation: 1.26

Change at Day 2

-0.8
kilograms (kg) (Mean)
Standard Deviation: 1.31

Change at Day 3

-0.8
kilograms (kg) (Mean)
Standard Deviation: 1.39

PF-05280602 30.0 mcg/kg

Baseline

73.4
kilograms (kg) (Mean)
Standard Deviation: 6.88

Change at Day 15

0.2
kilograms (kg) (Mean)
Standard Deviation: 0.59

Change at Day 2

-0.4
kilograms (kg) (Mean)
Standard Deviation: 0.83

Change at Day 3

-0.3
kilograms (kg) (Mean)
Standard Deviation: 0.56

Change From Baseline in Body Temperature

Body temperature was measured by mouth (oral) or ear (tympanic). A temperature greater than 38.5 degree Celsius was considered a fever.

PF-05280602 0.5 mcg/kg

Baseline

36.1
degree Celcius (Mean)
Standard Deviation: NA

Change at Day 15

0.3
degree Celcius (Mean)
Standard Deviation: NA

Change at Day 2

0.4
degree Celcius (Mean)
Standard Deviation: NA

Change at Day 3

0.3
degree Celcius (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

Baseline

36.5
degree Celcius (Mean)
Standard Deviation: 0.29

Change at Day 15

0.1
degree Celcius (Mean)
Standard Deviation: 0.39

Change at Day 2

-0.4
degree Celcius (Mean)
Standard Deviation: 0.62

Change at Day 3

-0.2
degree Celcius (Mean)
Standard Deviation: 0.60

PF-05280602 9.0 mcg/kg

Baseline

36.5
degree Celcius (Mean)
Standard Deviation: 0.34

Change at Day 15

0.1
degree Celcius (Mean)
Standard Deviation: 0.36

Change at Day 2

-0.1
degree Celcius (Mean)
Standard Deviation: 0.30

Change at Day 3

0.1
degree Celcius (Mean)
Standard Deviation: 0.15

PF-05280602 18.0 mcg/kg

Baseline

36.6
degree Celcius (Mean)
Standard Deviation: 0.30

Change at Day 15

0.1
degree Celcius (Mean)
Standard Deviation: 0.24

Change at Day 2

0.1
degree Celcius (Mean)
Standard Deviation: 0.34

Change at Day 3

PF-05280602 30.0 mcg/kg

Baseline

36.4
degree Celcius (Mean)
Standard Deviation: 0.43

Change at Day 15

0.2
degree Celcius (Mean)
Standard Deviation: 0.60

Change at Day 2

0.2
degree Celcius (Mean)
Standard Deviation: 0.29

Change at Day 3

0.2
degree Celcius (Mean)
Standard Deviation: 0.13

Change From Baseline in Respiration Rate

Respiration rate measured as respirations per minute (resp/min).

PF-05280602 0.5 mcg/kg

Baseline

12.0
resp/min (Mean)
Standard Deviation: NA

Change at Day 15

2.0
resp/min (Mean)
Standard Deviation: NA

Change at Day 2

Change at Day 3

PF-05280602 4.5 mcg/kg

Baseline

15.0
resp/min (Mean)
Standard Deviation: 2.76

Change at Day 15

0.7
resp/min (Mean)
Standard Deviation: 4.32

Change at Day 2

0.5
resp/min (Mean)
Standard Deviation: 1.76

Change at Day 3

0.2
resp/min (Mean)
Standard Deviation: 3.37

PF-05280602 9.0 mcg/kg

Baseline

15.2
resp/min (Mean)
Standard Deviation: 2.04

Change at Day 15

-0.2
resp/min (Mean)
Standard Deviation: 2.14

Change at Day 2

0.3
resp/min (Mean)
Standard Deviation: 3.50

Change at Day 3

0.3
resp/min (Mean)
Standard Deviation: 3.50

PF-05280602 18.0 mcg/kg

Baseline

15.7
resp/min (Mean)
Standard Deviation: 1.97

Change at Day 15

1.2
resp/min (Mean)
Standard Deviation: 3.49

Change at Day 2

2.2
resp/min (Mean)
Standard Deviation: 2.56

Change at Day 3

1.7
resp/min (Mean)
Standard Deviation: 1.63

PF-05280602 30.0 mcg/kg

Baseline

16.0
resp/min (Mean)
Standard Deviation: 2.83

Change at Day 15

-0.3
resp/min (Mean)
Standard Deviation: 1.97

Change at Day 2

0.5
resp/min (Mean)
Standard Deviation: 1.22

Change at Day 3

0.2
resp/min (Mean)
Standard Deviation: 2.23

Change From Baseline in Supine Pulse Rate

Change from baseline is the vital sign value at Day 2, Day 3, and Day 15 minus vital sign value at baseline.

PF-05280602 0.5 mcg/kg

Baseline

62.0
beats per minute (bpm) (Mean)
Standard Deviation: NA

Change at Day 15

2.0
beats per minute (bpm) (Mean)
Standard Deviation: NA

Change at Day 2

1.0
beats per minute (bpm) (Mean)
Standard Deviation: NA

Change at Day 3

PF-05280602 4.5 mcg/kg

Baseline

64.8
beats per minute (bpm) (Mean)
Standard Deviation: 6.21

Change at Day 15

8.3
beats per minute (bpm) (Mean)
Standard Deviation: 12.68

Change at Day 2

-1.3
beats per minute (bpm) (Mean)
Standard Deviation: 3.56

Change at Day 3

1.3
beats per minute (bpm) (Mean)
Standard Deviation: 6.80

PF-05280602 9.0 mcg/kg

Baseline

69.3
beats per minute (bpm) (Mean)
Standard Deviation: 10.65

Change at Day 15

4.5
beats per minute (bpm) (Mean)
Standard Deviation: 12.68

Change at Day 2

3.7
beats per minute (bpm) (Mean)
Standard Deviation: 6.89

Change at Day 3

2.5
beats per minute (bpm) (Mean)
Standard Deviation: 7.89

PF-05280602 18.0 mcg/kg

Baseline

60.7
beats per minute (bpm) (Mean)
Standard Deviation: 10.69

Change at Day 15

10.2
beats per minute (bpm) (Mean)
Standard Deviation: 12.22

Change at Day 2

8.8
beats per minute (bpm) (Mean)
Standard Deviation: 7.88

Change at Day 3

10.7
beats per minute (bpm) (Mean)
Standard Deviation: 5.65

PF-05280602 30.0 mcg/kg

Baseline

66.5
beats per minute (bpm) (Mean)
Standard Deviation: 8.22

Change at Day 15

3.0
beats per minute (bpm) (Mean)
Standard Deviation: 5.33

Change at Day 2

2.0
beats per minute (bpm) (Mean)
Standard Deviation: 5.69

Change at Day 3

3.3
beats per minute (bpm) (Mean)
Standard Deviation: 3.56

Number of Participants With Changes Since Previous Physical Examination

Physical examinations were conducted by a physician, trained physician's assistant, or nurse practitioner. A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, genitourinary, gastrointestinal, musculoskeletal, and neurological systems. The limited or abbreviated physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.

PF-05280602 0.5 mcg/kg

Baseline

Day 1

Day 15

Day 2

Day 3

PF-05280602 4.5 mcg/kg

Baseline

Day 1

Day 15

1.0
participants

Day 2

Day 3

PF-05280602 9.0 mcg/kg

Baseline

Day 1

Day 15

Day 2

1.0
participants

Day 3

1.0
participants

PF-05280602 18.0 mcg/kg

Baseline

Day 1

Day 15

1.0
participants

Day 2

Day 3

1.0
participants

PF-05280602 30.0 mcg/kg

Baseline

Day 1

Day 15

Day 2

Day 3

Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings

ECG findings of potential clinical concern were: PR interval greater than or equal to (>=)300 milliseconds (msec), >=25% increase from baseline for baseline values >200 msec, >=50% increase from baseline for baseline values less than or equal to (<=)200 msec; QRS complex >=140 msec or >=50% increase from baseline; QTcF interval (Fridericia's correction) >=450 msec or >=30 msec increase from baseline.

PF-05280602 0.5 mcg/kg

PR Interval >=25/50% Increase From Baseline

PR Interval >=300 msec

QRS Complex >=140 msec

QRS Complex >=50% Increase From Baseline

QTcF Interval 30-<60 msec Increase From Baseline

QTcF Interval >=450 msec

QTcF Interval >=60 msec Increase From Baseline

PF-05280602 4.5 mcg/kg

PR Interval >=25/50% Increase From Baseline

PR Interval >=300 msec

QRS Complex >=140 msec

QRS Complex >=50% Increase From Baseline

QTcF Interval 30-<60 msec Increase From Baseline

1.0
participants

QTcF Interval >=450 msec

QTcF Interval >=60 msec Increase From Baseline

PF-05280602 9.0 mcg/kg

PR Interval >=25/50% Increase From Baseline

PR Interval >=300 msec

QRS Complex >=140 msec

QRS Complex >=50% Increase From Baseline

QTcF Interval 30-<60 msec Increase From Baseline

QTcF Interval >=450 msec

QTcF Interval >=60 msec Increase From Baseline

PF-05280602 18.0 mcg/kg

PR Interval >=25/50% Increase From Baseline

PR Interval >=300 msec

QRS Complex >=140 msec

QRS Complex >=50% Increase From Baseline

QTcF Interval 30-<60 msec Increase From Baseline

QTcF Interval >=450 msec

QTcF Interval >=60 msec Increase From Baseline

PF-05280602 30.0 mcg/kg

PR Interval >=25/50% Increase From Baseline

PR Interval >=300 msec

QRS Complex >=140 msec

QRS Complex >=50% Increase From Baseline

QTcF Interval 30-<60 msec Increase From Baseline

QTcF Interval >=450 msec

QTcF Interval >=60 msec Increase From Baseline

Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Withdrawals Due to AEs (Except Hemophilia AEs)

An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Day 15 that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.

PF-05280602 0.5 mcg/kg

AEs

1.0
participants

SAEs

Withdrawals Due to AEs

PF-05280602 4.5 mcg/kg

AEs

4.0
participants

SAEs

Withdrawals Due to AEs

PF-05280602 9.0 mcg/kg

AEs

4.0
participants

SAEs

Withdrawals Due to AEs

PF-05280602 18.0 mcg/kg

AEs

3.0
participants

SAEs

Withdrawals Due to AEs

PF-05280602 30.0 mcg/kg

AEs

2.0
participants

SAEs

Withdrawals Due to AEs

Number of Participants With Treatment-Emergent Hemophilia AEs and Withdrawals Due to Hemophilia AEs

Hemophilia AEs included spontaneous (no known contributing factor) and traumatic (known or presumed contributing factor/reason) bleeding episodes.

PF-05280602 0.5 mcg/kg

Hemophilia AEs

1.0
participants

Hemophilia SAEs

Withdrawals Due to Hemophilia AEs

PF-05280602 4.5 mcg/kg

Hemophilia AEs

1.0
participants

Hemophilia SAEs

Withdrawals Due to Hemophilia AEs

PF-05280602 9.0 mcg/kg

Hemophilia AEs

1.0
participants

Hemophilia SAEs

Withdrawals Due to Hemophilia AEs

PF-05280602 18.0 mcg/kg

Hemophilia AEs

1.0
participants

Hemophilia SAEs

Withdrawals Due to Hemophilia AEs

PF-05280602 30.0 mcg/kg

Hemophilia AEs

2.0
participants

Hemophilia SAEs

Withdrawals Due to Hemophilia AEs

Number of Treatment-Emergent AEs and SAEs by Severity (Except Hemophilia AEs)

AE severity were graded as mild, moderate, or severe. Mild severity AEs do not interfere with the participant's usual function. Moderate AEs interfere to some extent with the participant's usual function. Severe AEs interfere significantly with the participant's usual function.

PF-05280602 0.5 mcg/kg

Mild AEs

2.0
adverse events

Moderate AEs

1.0
adverse events

Severe AEs

PF-05280602 4.5 mcg/kg

Mild AEs

6.0
adverse events

Moderate AEs

1.0
adverse events

Severe AEs

PF-05280602 9.0 mcg/kg

Mild AEs

5.0
adverse events

Moderate AEs

5.0
adverse events

Severe AEs

PF-05280602 18.0 mcg/kg

Mild AEs

7.0
adverse events

Moderate AEs

2.0
adverse events

Severe AEs

PF-05280602 30.0 mcg/kg

Mild AEs

1.0
adverse events

Moderate AEs

1.0
adverse events

Severe AEs

Number of Treatment-Emergent Hemophilia AEs by Severity

Mild severity AEs do not interfere with the participant's usual function. Moderate AEs interfere to some extent with the participant's usual function. Severe AEs interfere significantly with the participant's usual function.

PF-05280602 0.5 mcg/kg

Mild Hemophilia AEs

1.0
adverse events

Moderate Hemophilia AEs

1.0
adverse events

Severe Hemophilia AEs

PF-05280602 4.5 mcg/kg

Mild Hemophilia AEs

Moderate Hemophilia AEs

1.0
adverse events

Severe Hemophilia AEs

PF-05280602 9.0 mcg/kg

Mild Hemophilia AEs

Moderate Hemophilia AEs

2.0
adverse events

Severe Hemophilia AEs

PF-05280602 18.0 mcg/kg

Mild Hemophilia AEs

Moderate Hemophilia AEs

1.0
adverse events

Severe Hemophilia AEs

PF-05280602 30.0 mcg/kg

Mild Hemophilia AEs

Moderate Hemophilia AEs

2.0
adverse events

Severe Hemophilia AEs

Number of Participants With Treatment-Emergent Abnormal Troponin-T Levels by Magnitude

Troponin-T is a cardiac marker for the evaluation of possible cardiovascular injury. Troponin-T levels of potential clinical concern are values >1.5 times the upper limit of normal (1.5X ULN) or >=2.5X ULN.

PF-05280602 4.5 mcg/kg

>1.5X ULN

<1X lower limit of normal (LLN)

>1X ULN

>=2.5X ULN

PF-05280602 9.0 mcg/kg

>1.5X ULN

<1X lower limit of normal (LLN)

>1X ULN

>=2.5X ULN

PF-05280602 18.0 mcg/kg

>1.5X ULN

<1X lower limit of normal (LLN)

>1X ULN

>=2.5X ULN

PF-05280602 30.0 mcg/kg

>1.5X ULN

<1X lower limit of normal (LLN)

>1X ULN

>=2.5X ULN

PF-05280602 0.5 mcg/kg

>1.5X ULN

<1X lower limit of normal (LLN)

>1X ULN

>=2.5X ULN

Number of Participants With Treatment-Emergent Abnormal Anti-Thrombin III (ATIII) Levels by Magnitude

ATIII is a protein in the blood that blocks abnormal blood clots from forming. Low levels of ATIII can cause abnormal blood clots. ATIII levels of potential clinical concern are values <1X LLN and >1X ULN.

PF-05280602 0.5 mcg/kg

<1X LLN

>1X ULN

PF-05280602 4.5 mcg/kg

<1X LLN

>1X ULN

PF-05280602 9.0 mcg/kg

<1X LLN

>1X ULN

PF-05280602 18.0 mcg/kg

<1X LLN

>1X ULN

1.0
participants

PF-05280602 30.0 mcg/kg

<1X LLN

2.0
participants

>1X ULN

Number of Participants With Treatment-Emergent Abnormal Tissue Factor Pathway Inhibitor (TFPI) Levels by Magnitude

TFPI is a polypeptide that can regulate blood coagulation. TFPI levels of potential clinical concern are values <1X LLN and >1X ULN.

PF-05280602 0.5 mcg/kg

<1X LLN

>1X ULN

1.0
participants

PF-05280602 4.5 mcg/kg

<1X LLN

1.0
participants

>1X ULN

PF-05280602 9.0 mcg/kg

<1X LLN

2.0
participants

>1X ULN

PF-05280602 18.0 mcg/kg

<1X LLN

>1X ULN

PF-05280602 30.0 mcg/kg

<1X LLN

>1X ULN

1.0
participants

Number of Participants With Treatment-Emergent Laboratory Test Abnormalities (Normal Baseline)

The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, platelets, leukocytes, total neutrophils, eosinophils, basophils, lymphocytes, monocytes); chemistry (total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], glucose, uric acid, sodium, potassium, chloride, bicarbonate, calcium, albumin, total protein, creatine kinase); urinalysis (urine white blood cell [WBC], urine RBC); other (troponin T).

PF-05280602 0.5 mcg/kg

PF-05280602 4.5 mcg/kg

PF-05280602 9.0 mcg/kg

2.0
participants

PF-05280602 18.0 mcg/kg

1.0
participants

PF-05280602 30.0 mcg/kg

2.0
participants

Number of Participants With Clinically Significant Laboratory Abnormalities Meeting Stopping Criteria

Clinically significant findings for stopping rules are: hemoglobin <8 grams/deciliter (g/dL) or >20% decrease from normal baseline; WBC >20,000 cells/mm^3 or <1,500 decrease with normal baseline; platelets <100,000/mm^3 or >33% decrease from baseline; total bilirubin >1.5X ULN; AST or ALT >2.5X ULN; alkaline phosphatase >3X ULN; creatinine >1.5X baseline; BUN >31.0 mg/dL; glucose <0.6 or >1.5X reference range; uric acid > ULN; sodium >150 or <130 mEq/L; potassium >5.5 or <3.0 mEq/L; calcium >11.5 or <8.0 mg/dL; albumin <2.0 g/L; total protein <5.0 g/L; positive D-dimer at Day 15; PT prolonged by 3 seconds above baseline; ATIII < LLN and >20% decrease from baseline; troponin-T values above the reference range; fibrinogen <0.75X LLN or >25% decrease from baseline.

PF-05280602 0.5 mcg/kg

Albumin

Alkaline Phosphatase

ALT

Anti-Thrombin III

AST

BUN

Calcium

Creatinine

D-Dimer

Fibrinogen

Glucose

Hemoglobin

Platelets

Potassium

Prothrombin Time

Sodium

Total Bilirubin

Total Protein

Troponin-T

Uric Acid

WBC

PF-05280602 4.5 mcg/kg

Albumin

Alkaline Phosphatase

ALT

Anti-Thrombin III

AST

BUN

Calcium

Creatinine

1.0
participants

D-Dimer

Fibrinogen

Glucose

Hemoglobin

Platelets

Potassium

Prothrombin Time

Sodium

Total Bilirubin

Total Protein

Troponin-T

Uric Acid

WBC

PF-05280602 9.0 mcg/kg

Albumin

Alkaline Phosphatase

ALT

Anti-Thrombin III

AST

BUN

Calcium

Creatinine

D-Dimer

Fibrinogen

Glucose

1.0
participants

Hemoglobin

Platelets

Potassium

1.0
participants

Prothrombin Time

Sodium

Total Bilirubin

Total Protein

Troponin-T

Uric Acid

WBC

PF-05280602 18.0 mcg/kg

Albumin

Alkaline Phosphatase

ALT

Anti-Thrombin III

AST

BUN

Calcium

Creatinine

D-Dimer

Fibrinogen

Glucose

1.0
participants

Hemoglobin

Platelets

Potassium

Prothrombin Time

Sodium

Total Bilirubin

Total Protein

Troponin-T

Uric Acid

WBC

PF-05280602 30.0 mcg/kg

Albumin

Alkaline Phosphatase

ALT

Anti-Thrombin III

AST

BUN

Calcium

Creatinine

D-Dimer

1.0
participants

Fibrinogen

1.0
participants

Glucose

Hemoglobin

Platelets

Potassium

Prothrombin Time

Sodium

Total Bilirubin

Total Protein

Troponin-T

Uric Acid

WBC

Number of Participants With Positive Immune Response (Anti-Drug Antibodies [ADA], PF-05280602 Inhibitor, Factor VIIa Inhibitor, Factor VII Inhibitor, and Depletion of Factor VII Activity)

Assays for the determination of a positive immune response was performed. An antibody immune response was defined as a confirmed post-treatment positive ELISA result in combination with a negative baseline sample ELISA result. Positive antibody immune responses to PF-05280602 by ELISA was evaluated for cross reactivity to NovoSeven RT and to Factor VII.

PF-05280602 0.5 mcg/kg

ADA

Depletion of Factor VII Activity

Factor VIIa Inhibitor

Factor VII Inhibitor

PF-05280602 Inhibitor

PF-05280602 4.5 mcg/kg

ADA

Depletion of Factor VII Activity

Factor VIIa Inhibitor

Factor VII Inhibitor

PF-05280602 Inhibitor

PF-05280602 9.0 mcg/kg

ADA

Depletion of Factor VII Activity

Factor VIIa Inhibitor

Factor VII Inhibitor

PF-05280602 Inhibitor

PF-05280602 18.0 mcg/kg

ADA

1.0
participants

Depletion of Factor VII Activity

Factor VIIa Inhibitor

Factor VII Inhibitor

PF-05280602 Inhibitor

PF-05280602 30.0 mcg/kg

ADA

Depletion of Factor VII Activity

Factor VIIa Inhibitor

Factor VII Inhibitor

PF-05280602 Inhibitor

Maximum Observed Plasma Concentration (Cmax)

PF-05280602 0.5 mcg/kg

1.68
ng/mL (Geometric Mean)
Geometric Coefficient of Variation: NA

PF-05280602 4.5 mcg/kg

84.78
ng/mL (Geometric Mean)
Geometric Coefficient of Variation: 20

PF-05280602 9.0 mcg/kg

183.1
ng/mL (Geometric Mean)
Geometric Coefficient of Variation: 28

PF-05280602 18.0 mcg/kg

496.2
ng/mL (Geometric Mean)
Geometric Coefficient of Variation: 14

PF-05280602 30.0 mcg/kg

814.8
ng/mL (Geometric Mean)
Geometric Coefficient of Variation: 23

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)

Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)

PF-05280602 0.5 mcg/kg

3.82
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: NA

PF-05280602 4.5 mcg/kg

300.7
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 15

PF-05280602 9.0 mcg/kg

638.9
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 21

PF-05280602 18.0 mcg/kg

1557.0
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 19

PF-05280602 30.0 mcg/kg

2788.0
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 31

Terminal Elimination Half-Life (t1/2)

t1/2 is the time measured for the plasma concentration to decrease by one half.

PF-05280602 0.5 mcg/kg

PF-05280602 4.5 mcg/kg

3.533
hour (Mean)
Standard Deviation: 0.560

PF-05280602 9.0 mcg/kg

3.637
hour (Mean)
Standard Deviation: 0.803

PF-05280602 18.0 mcg/kg

3.303
hour (Mean)
Standard Deviation: 0.638

PF-05280602 30.0 mcg/kg

3.58
hour (Mean)
Standard Deviation: 0.564

Incremental Recovery (IncRec)

IncRec is the maximum rise in plasma concentration per administered dose.

PF-05280602 0.5 mcg/kg

3.48
ng/mL/mcg/kg (Geometric Mean)
Geometric Coefficient of Variation: NA

PF-05280602 4.5 mcg/kg

18.49
ng/mL/mcg/kg (Geometric Mean)
Geometric Coefficient of Variation: 20

PF-05280602 9.0 mcg/kg

20.06
ng/mL/mcg/kg (Geometric Mean)
Geometric Coefficient of Variation: 28

PF-05280602 18.0 mcg/kg

27.67
ng/mL/mcg/kg (Geometric Mean)
Geometric Coefficient of Variation: 16

PF-05280602 30.0 mcg/kg

26.87
ng/mL/mcg/kg (Geometric Mean)
Geometric Coefficient of Variation: 24

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)

AUCinf is area under the plasma concentration-time curve from time 0 extrapolated to infinite time.

PF-05280602 0.5 mcg/kg

PF-05280602 4.5 mcg/kg

300.7
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 15

PF-05280602 9.0 mcg/kg

638.9
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 21

PF-05280602 18.0 mcg/kg

1557.0
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 19

PF-05280602 30.0 mcg/kg

2788.0
ng*hr/mL (Geometric Mean)
Geometric Coefficient of Variation: 31

Mean Residence Time (MRT)

MRT is AUMCinf/AUCinf, where AUMC is the area under the first moment curve.

PF-05280602 0.5 mcg/kg

PF-05280602 4.5 mcg/kg

7.948
hours (Mean)
Standard Deviation: 1.786

PF-05280602 9.0 mcg/kg

5.697
hours (Mean)
Standard Deviation: 0.727

PF-05280602 18.0 mcg/kg

4.963
hours (Mean)
Standard Deviation: 0.741

PF-05280602 30.0 mcg/kg

5.087
hours (Mean)
Standard Deviation: 0.649

Volume of Distribution at Steady State (Vss)

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.

PF-05280602 0.5 mcg/kg

PF-05280602 4.5 mcg/kg

0.1168
L/kg (Geometric Mean)
Geometric Coefficient of Variation: 35

PF-05280602 9.0 mcg/kg

0.0806
L/kg (Geometric Mean)
Geometric Coefficient of Variation: 24

PF-05280602 18.0 mcg/kg

0.05651
L/kg (Geometric Mean)
Geometric Coefficient of Variation: 21

PF-05280602 30.0 mcg/kg

0.05494
L/kg (Geometric Mean)
Geometric Coefficient of Variation: 32

Clearance (CL)

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes). Clearance obtained after intravenous infusion dose is influenced by the fraction of the dose absorbed.

PF-05280602 0.5 mcg/kg

PF-05280602 4.5 mcg/kg

0.01502
L/hr/kg (Geometric Mean)
Geometric Coefficient of Variation: 15

PF-05280602 9.0 mcg/kg

0.01423
L/hr/kg (Geometric Mean)
Geometric Coefficient of Variation: 21

PF-05280602 18.0 mcg/kg

0.01149
L/hr/kg (Geometric Mean)
Geometric Coefficient of Variation: 20

PF-05280602 30.0 mcg/kg

0.01089
L/hr/kg (Geometric Mean)
Geometric Coefficient of Variation: 31

Time to Reach Maximum Observed Plasma Concentration (Tmax)

PF-05280602 0.5 mcg/kg

0.167
hours (Median)
Full Range: NA

PF-05280602 4.5 mcg/kg

0.167
hours (Median)
Full Range: 15

PF-05280602 9.0 mcg/kg

0.242
hours (Median)
Full Range: 21

PF-05280602 18.0 mcg/kg

0.142
hours (Median)
Full Range: 20

PF-05280602 30.0 mcg/kg

0.15
hours (Median)
Full Range: 31

Maximum Mean Decrease From Baseline in Prothrombin Time (PT)

PT measures how long it takes blood to clot. Maximum mean decrease from baseline at any time point was reported.

PF-05280602 0.5 mcg/kg

-0.7
seconds (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

-3.37
seconds (Mean)
Standard Deviation: 0.372

PF-05280602 9.0 mcg/kg

-3.8
seconds (Mean)
Standard Deviation: 0.629

PF-05280602 18.0 mcg/kg

-3.85
seconds (Mean)
Standard Deviation: 0.409

PF-05280602 30.0 mcg/kg

-4.45
seconds (Mean)
Standard Deviation: 0.493

Maximum Mean Decrease From Baseline in Activated Partial Thromboplastin Time (aPTT)

aPTT is a blood test that characterizes blood coagulation. Maximum mean decrease from baseline at any time point was reported.

PF-05280602 0.5 mcg/kg

-1.3
seconds (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

-17.93
seconds (Mean)
Standard Deviation: 8.944

PF-05280602 9.0 mcg/kg

-24.47
seconds (Mean)
Standard Deviation: 12.273

PF-05280602 18.0 mcg/kg

-43.02
seconds (Mean)
Standard Deviation: 16.541

PF-05280602 30.0 mcg/kg

-46.85
seconds (Mean)
Standard Deviation: 12.281

Maximum Mean Increase From Baseline in Thrombin Anti-Thrombin (TAT) Complexes

TAT complex is a parameter of coagulation and fibrinolysis. The normal reference range of values for TAT is 1 to 4.1 mcg/L. Elevated TAT concentrations may signify predisposition to thrombosis. Maximum mean increase from baseline at any time point was reported.

PF-05280602 0.5 mcg/kg

3.7
mcg/L (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

23.82
mcg/L (Mean)
Standard Deviation: 51.130

PF-05280602 9.0 mcg/kg

4.72
mcg/L (Mean)
Standard Deviation: 5.282

PF-05280602 18.0 mcg/kg

5.52
mcg/L (Mean)
Standard Deviation: 6.530

PF-05280602 30.0 mcg/kg

22.47
mcg/L (Mean)
Standard Deviation: 28.010

Maximum Mean Increase From Baseline in Prothrombin Fragments 1+2

Prothrombin fragment 1+2 is a coagulation factor, released when prothrombin is cleaved by activated Factor X. Elevated plasma levels of prothrombin fragment 1+2 indicate high risk of thrombosis. Maximum mean increase from baseline at any time point was reported.

PF-05280602 0.5 mcg/kg

38.0
picomoles per liter (pmol/L) (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

31.8
picomoles per liter (pmol/L) (Mean)
Standard Deviation: 30.56

PF-05280602 9.0 mcg/kg

66.4
picomoles per liter (pmol/L) (Mean)
Standard Deviation: 84.73

PF-05280602 18.0 mcg/kg

76.7
picomoles per liter (pmol/L) (Mean)
Standard Deviation: 28.27

PF-05280602 30.0 mcg/kg

238.3
picomoles per liter (pmol/L) (Mean)
Standard Deviation: 162.22

Maximum Mean Increase From Baseline in D-Dimers

D-dimer is an indicator of fibrin formation and its subsequent lysis and is a useful biomarker representing overall activation of blood coagulation. Maximum mean increase from baseline at any time point was reported.

PF-05280602 18.0 mcg/kg

88.3
ng/mL (Mean)
Standard Deviation: 123.36

PF-05280602 30.0 mcg/kg

238.3
ng/mL (Mean)
Standard Deviation: 285.06

PF-05280602 0.5 mcg/kg

240.0
ng/mL (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

75.0
ng/mL (Mean)
Standard Deviation: 103.68

PF-05280602 9.0 mcg/kg

28.3
ng/mL (Mean)
Standard Deviation: 173.60

Maximum Mean Increase From Baseline in Endogenous Thrombin Potential (ETP)

ETP was evaluated using a Thrombin Generation Assay (TGA), a validated automated ex-vivo assay that measures the ability of plasma to generate thrombin. Thrombin generation curves are generated and calculated using dedicated software. ETP is the area under the thrombin generation curve and represents the total amount of generated thrombin. Maximum mean increase from baseline at any time point was reported.

PF-05280602 0.5 mcg/kg

13.4
nanomolar*minute (nM*min) (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

212.643
nanomolar*minute (nM*min) (Mean)
Standard Deviation: 77.3337

PF-05280602 9.0 mcg/kg

186.196
nanomolar*minute (nM*min) (Mean)
Standard Deviation: 147.6925

PF-05280602 18.0 mcg/kg

287.173
nanomolar*minute (nM*min) (Mean)
Standard Deviation: 421.1883

PF-05280602 30.0 mcg/kg

522.758
nanomolar*minute (nM*min) (Mean)
Standard Deviation: 94.0122

Maximum Mean Decrease From Baseline in Thrombin Generation Lag Time

The lag time is defined as the time to reach one sixth of the peak height and is a measure of the initiation phase. It is equivalent to the clotting time. Maximum mean decrease from baseline at any time point was reported.

PF-05280602 0.5 mcg/kg

-0.54
minutes (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

-6.235
minutes (Mean)
Standard Deviation: 5.7141

PF-05280602 9.0 mcg/kg

-7.088
minutes (Mean)
Standard Deviation: 7.9294

PF-05280602 18.0 mcg/kg

-13.4
minutes (Mean)
Standard Deviation: 14.6902

PF-05280602 30.0 mcg/kg

-2.425
minutes (Mean)
Standard Deviation: 0.9507

Maximum Mean Increase From Baseline in Peak Thrombin Generation

The peak height is defined as the maximum thrombin concentration produced. Maximum mean increase from baseline at any time point was reported.

PF-05280602 0.5 mcg/kg

-0.62
Nanomolar (nM) (Mean)
Standard Deviation: NA

PF-05280602 4.5 mcg/kg

17.982
Nanomolar (nM) (Mean)
Standard Deviation: 6.0924

PF-05280602 9.0 mcg/kg

16.568
Nanomolar (nM) (Mean)
Standard Deviation: 12.9124

PF-05280602 18.0 mcg/kg

23.362
Nanomolar (nM) (Mean)
Standard Deviation: 28.4618