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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
29
0.5 micrograms per kilogram of PF-05280602, IV infusion, single dose
4.5 micrograms per kilogram of PF-05280602, IV infusion, single dose
9.0 micrograms per kilogram of PF-05280602, IV infusion, single dose
University of California San Diego Medical Center
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.
Time frame: Baseline, Day 2, Day 3, and Day 15
Change From Baseline in Body Weight
Time frame: Baseline, Day 2, Day 3, and Day 15
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.
Time frame: Baseline, Day 2, Day 3, and Day 15
Change From Baseline in Respiration Rate
Respiration rate measured as respirations per minute (resp/min).
Time frame: Baseline, Day 2, Day 3, and Day 15
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.
Time frame: Baseline, Day 2, Day 3, and Day 15
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.
Time frame: Baseline (Day 0), Day 1, Day 2, Day 3, Day 15
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18.0 micrograms per kilogram of PF-05280602, IV infusion, single dose
30.0 micrograms per kilogram of PF-05280602, IV infusion, single dose
San Diego, California, United States
New Haven Clinical Research Unit
New Haven, Connecticut, United States
Rush University Medical Center
Chicago, Illinois, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Doernbecher Children's Hospital
Portland, Oregon, United States
OHSU Investigational Pharmacy
Portland, Oregon, United States
Oregon Health & Science University
Portland, Oregon, United States
CTRC
Philadelphia, Pennsylvania, United States
Penn Comprehensive Hemophilia Program - Center for Blood Disorders
Philadelphia, Pennsylvania, United States
Pfizer Clinical Research Unit
Brussels, Belgium
...and 13 more locations
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.
Time frame: Baseline through Day 15
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.
Time frame: Baseline through Day 60
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.
Time frame: Baseline through Day 60
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.
Time frame: Baseline through Day 60
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.
Time frame: Baseline through Day 60
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.
Time frame: Baseline through Day 15
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.
Time frame: Baseline through Day 3
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.
Time frame: Baseline through Day 3
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).
Time frame: Baseline through Day 15
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.
Time frame: Baseline through Day 15
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.
Time frame: Baseline through Day 60
Maximum Observed Plasma Concentration (Cmax)
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
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)
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
Terminal Elimination Half-Life (t1/2)
t1/2 is the time measured for the plasma concentration to decrease by one half.
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
Incremental Recovery (IncRec)
IncRec is the maximum rise in plasma concentration per administered dose.
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
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.
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
Mean Residence Time (MRT)
MRT is AUMCinf/AUCinf, where AUMC is the area under the first moment curve.
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
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.
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
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.
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose)
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.
Time frame: Baseline through Day 15
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.
Time frame: Baseline through Day 15
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.
Time frame: Baseline through Day 3
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.
Time frame: Baseline through Day 3
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.
Time frame: Baseline through Day 15
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.
Time frame: Baseline through Day 3
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.
Time frame: Baseline through Day 3
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.
Time frame: Baseline through Day 3