BAX 855 Pediatric Study

Study Overview
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Brief Summary
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The study purpose is: To assess the incidence of FVIII inhibitory antibodies during 6 months of twice weekly prophylactic treatment with BAX 855 or 50 exposure days (EDs), whichever occurs last. To compare pharmacokinetic (PK) parameters to ADVATE. To assess hemostatic efficacy in prophylaxis and the treatment of bleeding episodes. To evaluate safety and immunogenicity.

Official Title
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A Phase 3 Prospective, Uncontrolled, Multicenter Study Evaluating Pharmacokinetics, Efficacy, Safety, and Immunogenicity of BAX 855 (PEGylated Full-length Recombinant FVIII) in Previously Treated Pediatric Patients With Severe Hemophilia A

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method
* Biological: PEGylated Recombinant Factor VIII
* Biological: PEGylated Recombinant Factor VIII


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe hemophilia A (Factor VIII (FVIII) <1%) determined by central laboratory. <12 years old at the time of screening. Participants aged ≥6 to <12 years of age have been previously treated with plasma-derived and/or recombinant Factor VIII (rFVIII) concentrate(s) for a minimum of 150 exposure days (EDs) (based on the participant's medical records). Participants <6 years of age have been previously treated with plasma-derived and/or rFVIII concentrate(s) for at least 50 EDs (based on the participant's medical records). Participant is human immunodeficiency virus (HIV) negative; or HIV positive with stable disease and CD4+ count of ≥200 cells/mm^3, as confirmed by central laboratory. Participant and/or legal representative accepts prophylactic treatment over a period of 6 months. Participant and/or the legal representative is willing and able to comply with the requirements of the protocol. Exclusion Criteria: Participant has detectable FVIII inhibitory antibodies (≥0.4 Bethesda Units (BU) using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening. Participant has a history of FVIII inhibitory antibodies (≥0.4 BU using the Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay) at any time prior to screening. Participant has known hypersensitivity towards mouse or hamster proteins, polyethylene glycol (PEG), or Tween 80. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease). Participant's platelet count is <100,000/μL. Participant has severe chronic hepatic dysfunction (eg, ≥5 times upper limit of normal (ULN) alanine aminotransferase (ALT), as confirmed by central laboratory at screening, or a documented international normalized ratio (INR) >1.5). Participant has severe renal impairment (serum creatinine >1.5 times ULN). Participant is scheduled to receive during the course of the study, an immunomodulating drug (eg, corticosteroid agents at a dose equivalent to hydrocortisone >10 mg/day, or α-interferon) other than anti-retroviral chemotherapy. Participant 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. Participant has participated in another clinical study involving an investigational product (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. Participant has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the Investigator, would affect participant safety or compliance. Participant's legal representative 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.

Ages Eligible for Study
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Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: <6 years old<br> | Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method<br>* Pharmacokinetic (PK) analysis of ADVATE<br>* Other names: ADVATE;Biological: PEGylated Recombinant Factor VIII<br>* Pharmacokinetic (PK) analysis of BAX 855<br>* Other names: BAX 855;Biological: PEGylated Recombinant Factor VIII<br>* Prophylaxis treatment<br>* Other names: BAX 855;|
| Experimental: ≥6 to <12 years<br> | Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method<br>* Pharmacokinetic (PK) analysis of ADVATE<br>* Other names: ADVATE;Biological: PEGylated Recombinant Factor VIII<br>* Pharmacokinetic (PK) analysis of BAX 855<br>* Other names: BAX 855;Biological: PEGylated Recombinant Factor VIII<br>* Prophylaxis treatment<br>* Other names: BAX 855;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII) | 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]. | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Bleeding Rate (ABR) | 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. | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 
| Consumption of BAX 855: Number of Prophylactic Infusions Per Month Per Participant |  | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 
| Consumption of BAX 855: Number of Prophylactic Infusions Per Year (Annualized) Per Participant |  | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 
| Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Month Per Participant |  | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 
| Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Year (Annualized) Per Participant |  | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 
| Consumption of BAX 855: Number of Infusions Per Bleeding Episode |  | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 
| Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode |  | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 
| Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | 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. | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 
| Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855 |  | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 
| Non-serious Adverse Events Possibly or Probably Related to BAX 855 |  | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 
| Number of Participants With Clinically Significant Changes in Vital Signs | 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. | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 
| Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | 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. | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 
| Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | 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). | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 
| Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | 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. | (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4 | 
| Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion Per Dose, (AUC0-∞/Dose) |  | (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4 | 
| Pharmacokinetics (PK): Mean Residence Time (MRT) | 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. | (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4 | 
| Pharmacokinetics (PK): Clearance (CL) | 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. | (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4 | 
| Pharmacokinetics (PK): Plasma Half-life (T1/2) | 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. | (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4 | 
| Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | 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. | (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4 | 
| Pharmacokinetics (PK): Incremental Recovery (IR) | 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. | (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4 | 
| Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | 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. | Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination) | 
| Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | 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. | Baseline, Week 5 (or 10-15 Exposure Days [EDs], whichever occurs last), Week 12, and Month 6 (Completion/Termination) |