Study of PF-05208756, Moroctocog Alfa (AF-CC), Xyntha For Male Chinese Subjects With Hemophilia A

Study Overview
=================
Brief Summary
-----------------
An open-label, single dose pharmacokinetic study of Xyntha (Moroctocog Alfa (AF-CC), Recombinant Factor VIII) in male Chinese subjects with hemophilia A

Detailed Description
-----------------
The purpose of this study is to obtain pharmacokinetic profiles of FVIII:C after Xyntha administration in Chinese patients with severe hemophilia A, which is in support of the continued registration of Xyntha in China

Official Title
-----------------
An Open-label, Single Dose Pharmacokinetic Study Of Xyntha (Moroctocog Alfa (Af-cc), Recombinant Factor Viii) In Male Chinese Subjects With Hemophilia A

Conditions
-----------------
Hemophilia A

Intervention / Treatment
-----------------
* Drug: Intravenous infusions of Xyntha


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study: Male Chinese subjects 6 years or older (weight >20 kg) with severe hemophilia A (factor VIII activity <1%) previously treated with > 150 exposure days to any FVIII-containing products. Subjects should not have received an infusion of any FVIII products for at least 3 days (at least 72 hours) before the administration of Xyntha on Day 1. Subjects must be in a non bleeding state before the administration of Xyntha on Day 1. Evidence of a personally or legally acceptable representative (legally acceptable representative is only applicable to pediatric subjects) signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria: Subjects with any of the following characteristics/conditions will not be included in the study: Current FVIII inhibitor or history of FVIII inhibitor (defined as > upper limit of normal (ULN) of the local reporting laboratory). Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) or clinical findings at Screening. Diagnosed with any other bleeding disorder in addition to hemophilia A. Documented Human Immunodeficiency Virus (HIV). Subjects anticipating elective surgery or other invasive procedure within 1 month following study entry. Treatment with immunomodulatory therapy within 30 days or 5 half lives whichever is longer, prior to study entry or planned use for the duration of study participation. Subjects with known hypersensitivity to the active substance or to any of the excipients of Xyntha. Subjects with a known hypersensitivity to Chinese Hamster Ovary cell (CHO cell) proteins. Subjects with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat, if deemed necessary: significant hepatic or renal impairment (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x ULN, or total bilirubin >2 x ULN or serum creatinine >2 x ULN), prothrombin time >1.5 x ULN, platelet count <80,000 L. Subjects with Gilbert's disease may be enrolled. Unwilling or unable to follow the terms of the protocol. Any condition which may compromise the subject's ability to comply with and/or perform study related activities or that poses a clinical contraindication to study participation, in the opinion of the investigator or sponsor. A positive urine drug screen. History of regular alcohol consumption exceeding 14 drinks/week (1 drink = 5 ounces (150 mL) of wine, 12 ounces (360 mL) of beer, or 1.5 ounces (45 mL) of hard liquor) within 6 months of screening. Treatment with an investigational drug within 30 days or 5 half lives preceding Day 1, whichever is longer. Screening supine blood pressure 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at least 5 minutes of supine rest. If blood pressure (BP) is 140 mm Hg (systolic) or 90 mm Hg (diastolic), the BP should be repeated two more times and the average of the three BP values should be used to determine the subject's eligibility. Screening supine 12 lead ECG demonstrating QTcF >450 or a QRS interval >120 msec msec. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTcF values should be used to determine the subject's eligibility. Blood donation (excluding plasma donations) of approximately 500 mL or more within 56 days prior to dosing. History of sensitivity to heparin or heparin induced thrombocytopenia. Unwilling or unable to comply with the Lifestyle Guidelines described in this protocol. 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. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. Subjects with history of infection within 1 week prior to study entry. Male subjects with partners currently pregnant and 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 study and for at least 28 days after the last dose of investigational product.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous infusion of Xyntha<br>observation arm | Drug: Intravenous infusions of Xyntha<br>* A single dose 50IU/kg dose of Xyntha administered by intravenous infusion within 10 minutes on Day 1<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma FVIII Activity (Cmax) |  | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Area Under the Plasma FVIII Activity-Time Profile From Time 0 to Time of the Last Quantifiable Concentration (AUClast) |  | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Area Under the Plasma FVIII Activity-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) |  | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Clearance (CL) | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Volume of Distribution at Steady-State (Vss) | Volume of distribution is 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. Vss is the volume of distribution at steady-state. | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Terminal Phase Rate Constant (Kel) | Terminal phase rate constant is the absolute value of the slope of a linear regression during the terminal phase of the natural--logarithm transformed concentration--time profile. | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Terminal Elimination Half-Life (t1/2) | Terminal half-life is the time measured for the plasma concentration to decrease by one half. | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Mean Residence Time (MRT) | MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from zero time to infinity calculated as AUMCinf = AUMCt + ((t x Ct) / kel) + (Ct / kel^2). AUMCt is the area under the first moment curve from zero time to time t calculated using the trapezoidal method. | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 
| Incremental Recovery (INCREC) | Incremental recovery is the increase in circulating FVIII activity for every IU of Xyntha administered per kilogram of body weight. | Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
FVIII activity