BAX 855 Pediatric Study

Inhibitory antibodies to FVIII were measured using the Nijmegen modification of the Bethesda assay. Incidence of an FVIII inhibitory antibody was defined as an inhibitor level ≥0.6 Bethesda units [BU].

The annualized bleeding rate (ABR) during the prophylaxis period was assessed based upon each individual bleeding episode, spontaneous or traumatic, recorded in the participant´s diary and/or recorded in the physician/nurse/study site notes. The annualized bleeding rate was analyzed using a generalized linear model framework assuming a negative binomial distribution with a logarithmic link function and presence or absence of target joints and age cohort as covariates and duration of the observation period in years as offset. Point estimates for the mean and 95% confidence intervals are presented.

Rating Scale for Treatment of Bleeding Episodes (BEs) (4-point ordinal scale): Excellent: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion required for the control of bleeding. Administration of further infusions to maintain hemostasis did not affect this scoring. Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion. Possibly requires more than 1 infusion for complete resolution. Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after single infusion. Required more than 1 infusion for complete resolution. None: No improvement or condition worsens.

Vital signs: body temperature (°C), respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood pressure (mmHg). For each vital sign value that changed from normal at baseline to abnormal at any subsequent study visit, the Investigator determined if the value was clinically significant (i.e. and adverse event), or not.

The HEMATOLOGY PANEL consisted of complete blood count: hemoglobin, hematocrit, erythrocytes (ie, red blood cell count), leukocytes (ie, white blood cell count) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, and neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration, and platelet count. The CLINICAL CHEMISTRY PANEL consisted of sodium, potassium, chloride, bicarbonate, total protein, albumin, ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose. The LIPID PANEL consisted of cholesterol, very low density lipoprotein, low density lipoprotein, high density lipoprotein, and triglycerides. For each laboratory parameter value that changed from normal at baseline to abnormal at any subsequent study visit, the Investigator determined if the value was clinically significant, or not.

Binding antibodies to FVIII and PEG-FVIII, as well as to PEG, were measured using enzyme-linked immunosorbent assay (ELISA). Both immunoglobulin G (IgG) and immunoglobulin M (IgM) binding antibodies for FVIII, BAX 855, and PEG were tested at each study visit. Testing for binding antibodies to CHO was performed on citrate-anti-coagulated plasma using an ELISA employing polyclonal anti-human IgG antibodies. This outcome measure includes antibodies that were transient (antibody developed after exposure to BAX 855 but not present at study termination/completion) and pre-existent (antibody originally present before exposure to BAX 855).

The first PK infusion was ADVATE and the second PK infusion was BAX 855. All participants undergoing PK assessment had a 72-hour washout period before administration of ADVATE and BAX 855. There were 4 blood draws for PK analysis-1 pre-infusion and 3 post infusion. The timing of the infusion (morning [am] or afternoon [pm]) and the timing of Blood Draws 3 and 4 (3 groups for each blood draw) were determined at randomization. The sequence was as follows:- Blood Draw 1. within 30 minutes pre-infusion [Day 0]; PK INFUSION - am or pm [Day 0]; Blood Draw 2. 15-30 minutes post-infusion [Day 0]; Blood Draw 3. 3 groups:- 7 hours post-infusion (if am PK infusion) or 4 hours post-infusion (if pm PK infusion) [Day 0], Day 1 am or Day 1 pm; Blood Draw 4. 3 groups:- Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data. A one-stage clotting assay was used as the primary assay and a chromogenic assay was used to provide supportive data.

The first PK infusion was ADVATE and the second PK infusion was BAX 855. All participants undergoing PK assessment had a 72-hour washout period before administration of ADVATE and BAX 855. There were 4 blood draws for PK analysis-1 pre-infusion and 3 post infusion. The timing of the infusion (morning [am] or afternoon [pm]) and the timing of Blood Draws 3 and 4 (3 groups for each blood draw) were determined at randomization. The sequence was as follows:- Blood Draw 1. within 30 minutes pre-infusion [Day 0]; PK INFUSION - am or pm [Day 0]; Blood Draw 2. 15-30 minutes post-infusion [Day 0]; Blood Draw 3. 3 groups:- 7 hours post-infusion (if am PK infusion) or 4 hours post-infusion (if pm PK infusion) [Day 0], Day 1 am or Day 1 pm; Blood Draw 4. 3 groups:- Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data. A one-stage clotting assay was used as the primary assay and a chromogenic assay was used to provide supportive data.

The first PK infusion was ADVATE and the second PK infusion was BAX 855. All participants undergoing PK assessment had a 72-hour washout period before administration of ADVATE and BAX 855. There were 4 blood draws for PK analysis-1 pre-infusion and 3 post infusion. The timing of the infusion (morning [am] or afternoon [pm]) and the timing of Blood Draws 3 and 4 (3 groups for each blood draw) were determined at randomization. The sequence was as follows:- Blood Draw 1. within 30 minutes pre-infusion [Day 0]; PK INFUSION - am or pm [Day 0]; Blood Draw 2. 15-30 minutes post-infusion [Day 0]; Blood Draw 3. 3 groups:- 7 hours post-infusion (if am PK infusion) or 4 hours post-infusion (if pm PK infusion) [Day 0], Day 1 am or Day 1 pm; Blood Draw 4. 3 groups:- Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data. A one-stage clotting assay was used as the primary assay and a chromogenic assay was used to provide supportive data.

The first PK infusion was ADVATE and the second PK infusion was BAX 855. All participants undergoing PK assessment had a 72-hour washout period before administration of ADVATE and BAX 855. There were 4 blood draws for PK analysis-1 pre-infusion and 3 post infusion. The timing of the infusion (morning [am] or afternoon [pm]) and the timing of Blood Draws 3 and 4 (3 groups for each blood draw) were determined at randomization. The sequence was as follows:- Blood Draw 1. within 30 minutes pre-infusion [Day 0]; PK INFUSION - am or pm [Day 0]; Blood Draw 2. 15-30 minutes post-infusion [Day 0]; Blood Draw 3. 3 groups:- 7 hours post-infusion (if am PK infusion) or 4 hours post-infusion (if pm PK infusion) [Day 0], Day 1 am or Day 1 pm; Blood Draw 4. 3 groups:- Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data. A one-stage clotting assay was used as the primary assay and a chromogenic assay was used to provide supportive data.

The first PK infusion was ADVATE and the second PK infusion was BAX 855. All participants undergoing PK assessment had a 72-hour washout period before administration of ADVATE and BAX 855. There were 4 blood draws for PK analysis-1 pre-infusion and 3 post infusion. The timing of the infusion (morning [am] or afternoon [pm]) and the timing of Blood Draws 3 and 4 (3 groups for each blood draw) were determined at randomization. The sequence was as follows:- Blood Draw 1. within 30 minutes pre-infusion [Day 0]; PK INFUSION - am or pm [Day 0]; Blood Draw 2. 15-30 minutes post-infusion [Day 0]; Blood Draw 3. 3 groups:- 7 hours post-infusion (if am PK infusion) or 4 hours post-infusion (if pm PK infusion) [Day 0], Day 1 am or Day 1 pm; Blood Draw 4. 3 groups:- Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data. A one-stage clotting assay was used as the primary assay and a chromogenic assay was used to provide supportive data.

The first PK infusion was ADVATE and the second PK infusion was BAX 855. All participants undergoing PK assessment had a 72-hour washout period before administration of ADVATE and BAX 855. There were 4 blood draws for PK analysis-1 pre-infusion and 3 post infusion. The timing of the infusion (morning [am] or afternoon [pm]) and the timing of Blood Draws 3 and 4 (3 groups for each blood draw) were determined at randomization. The sequence was as follows:- Blood Draw 1. within 30 minutes pre-infusion [Day 0]; PK INFUSION - am or pm [Day 0]; Blood Draw 2. 15-30 minutes post-infusion [Day 0]; Blood Draw 3. 3 groups:- 7 hours post-infusion (if am PK infusion) or 4 hours post-infusion (if pm PK infusion) [Day 0], Day 1 am or Day 1 pm; Blood Draw 4. 3 groups:- Day 2, Day 3 or Day 4. A non-compartmental model approach was implemented to analyze IR data. A one-stage clotting assay was used as the primary assay and a chromogenic assay was used to provide supportive data.

Pre- and post-infusion levels of Factor VIII (FVIII) following infusion of BAX 855 were used to determine IR. For participants who underwent PK evaluation, baseline IR was determined from the IR measurement used in the PK analysis. Refer to data in Outcome measure 21- "Pharmacokinetics (PK): Incremental Recovery (IR)", for the category "One stage clotting assay - BAX 855" For participants who did not undergo a PK evaluation, baseline IR was determined at the baseline visit prior to the prophylactic treatment phase and is included in this outcome measure. Category title includes number of participants [n] < 6 yrs; ≥6 to <12 yrs and the Full Analysis Set, respectively.

Pre- and post-infusion levels of Factor VIII (FVIII) following infusion of BAX 855 were used to determine IR. For participants who underwent PK evaluation, baseline IR was determined from the IR measurement used in the PK analysis. Refer to data in Outcome measure 21- "Pharmacokinetics (PK): Incremental Recovery (IR)", for the category "Chromogenic assay - BAX 855" For participants who did not undergo a PK evaluation, baseline IR was determined at the baseline visit prior to the prophylactic treatment phase and is included in this outcome measure. Category title includes number of participants [n] < 6 yrs; ≥6 to <12 yrs and the Full Analysis Set, respectively.