severe Hemophilia A

Primary Objective 1. The primary objective is to compare two prophylactic dosing regimens of BAX 855 targeting two different FVIII trough levels, by comparing the proportions of subjects achieving a total annualized bleeding rate (ABR) of 0 in the second 6-month study period Secondary Objectives Efficacy:  To compare the two prophylactic dosing regimens of BAX 855 targeting two different FVIII trough levels with respect to the following:  The proportion of subjects in each prophylactic dosing arm achieving a spontaneous ABR and spontaneousi joint bleeding rate (AJBR) of 0 in the second 6-month study period  The proportion of subjects in each prophylactic dosing arm with a total, spontaneous ABR and AJBR <2  The total, spontaneous, and trauma-related ABRs in the 12-month study period  The reduction in ABR between the two treatment arms and the historical ABR prior to study enrollment  The total weight-adjusted consumption of BAX 855 for each prophylactic regimen  The joint status using the Hemophilia Joint Health Score (HJHS) and over time  HRQoL and pharmacoeconomic outcomes (including SF-36, EQ-5D, Haemo-SYM and healthcare resource utilization)  To determine the hemostatic efficacy of BAX 855 in the control of bleeding episodes  To evaluate the efficacy of BAX 855 for perioperative management, if surgery is required Safety:  To determine the immunogenicity of BAX 855  To determine the safety of BAX 855 Pharmacokinetics:  To determine the PK parameters of BAX 855 at baseline and steady state and the correlation with pre-infusion VWF antigen level  To determine IR over time Patient Reported Outcomes  To assess the difference in the SF-36 physical domain and component change scores from baseline to follow-up between patients in the 10% trough arm and patients in the 1-3% trough arm To assess the difference in the change of days of physical activity participation from baseline to follow-up between patients in the 10% trough arm and patients in the 1-3% trough arm

BAX 855

PEGylated recombinant human factor VIII

Injection of Lyophilized powder for solution

250, 500, 1000, 2000

Purpose
1. To compare the efficacy and safety of PK-guided treatment with BAX 855 targeting FVIII trough
levels of 1-3% and approximately 10% (8-12%)
2. To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855

Inclusion Criteria
Subjects Transitioning from another BAX 855 Study
Subjects transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study:
1. Subject has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study 261302.
2. Subject is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an ABR of ≥ 2 documented and treated during the past 12 months.
3. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm3 , as confirmed by central laboratory.
4. Subject is willing and able to comply with the requirements of the protocol.

Inclusion Criteria for Newly Recruited Subjects
Newly recruited subjects including BAX 855 naïve subjects who meet ALL of the
following criteria are eligible for this study:
1. Subject is 12 to 65 years old at the time of screening
2. Subject has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory or by historically documented FVIII clotting activity performed by a certified clinical laboratory and/or a FVIII gene mutation consistent with severe hemophilia A
3. Subject has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs)
4. Subject is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months.
5. Subject has a Karnofsky performance score of ≥ 60 at screening
6. Subject is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm3 , as confirmed by central laboratory at screening
7. Subject is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis
8. If female of childbearing potential, subject presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study
9. Subject is willing and able to comply with the requirements of the protocol.

Exclusion Criteria
Exclusion Criteria for Subjects Transitioning from Another BAX 855 Study Subjects transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study:
1. Subject has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study.
2. Subject has been diagnosed with an acquired hemostatic defect other than hemophilia A.
3. The subject’s weight is < 35 kg or > 100 kg.
4. Subject’s platelet count is < 100,000/mL.
5. Subject has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal).
6. Subject has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal.
7. Subject is scheduled to receive a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy during the study.
8. Subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject’s safety or compliance.
9. Subject is planning to take part in any other clinical study during the course of the study.
10. Subject is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include
close relatives (ie, children, partner/spouse, siblings, parents) as well as employees
of the investigator or site personnel conducting the study.
Exclusion Criteria for Newly Recruited Subjects
Newly recruited subjects who meet ANY of the following criteria are not eligible for this
study:
1. Subject has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen
modification of the Bethesda assay) as confirmed by central laboratory at screening
2. Subject has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 BU (as
determined by the Nijmegen modification of the Bethesda assay or the assay
employed with the respective cut-off in the local laboratory) at any time prior to
screening.
3. Subject has been diagnosed with an inherited or acquired hemostatic defect other
than hemophilia A (eg, qualitative platelet defect or von Willebrand’s disease).
4. The subject’s weight is < 35 kg or > 100 kg.
5. Subject’s platelet count is < 100,000/mL.
6. Subject has known hypersensitivity towards mouse or hamster proteins, PEG or
Tween 80.
7. Subject has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal
ALT and/or AST, as confirmed by central laboratory at screening, or a documented
INR > 1.5].
8. Subject has severe renal impairment (serum creatinine > 1.5 times the upper limit of
normal).
9. Subject has current or recent (< 30 days) use of other pegylated drugs prior to study
participation or is scheduled to use such drugs during study participation.
10. Subject is scheduled to receive during the course of the study, a systemic
immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to
hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral
chemotherapy.
11. Subject has participated in another clinical study involving an IP or investigational
device within 30 days prior to enrollment or is scheduled to participate in another
clinical study involving an IP or investigational device during the course of this
study.
12. Subject has a medical, psychiatric, or cognitive illness or recreational drug/alcohol
use that, in the opinion of the investigator, would affect subject safety or
compliance.
13. Subject is a member of the team conducting this study or is in a dependent
relationship with one of the study team members. Dependent relationships include
close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.