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BAX 855 Pediatric Study

Primary Purpose

Hemophilia A

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method
PEGylated Recombinant Factor VIII
PEGylated Recombinant Factor VIII
Sponsored by
Baxalta now part of Shire
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia A

Eligibility Criteria

undefined - 11 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Phoenix Children's Hospital
  • University of Colorado
  • University of Florida College of Medicine
  • Ann & Robert H. Lurie Children's Hospital of Chicago
  • University of Louisville
  • Cornell University
  • New York Presbyterian Hospital-Weill
  • Cincinnati Childrens Hospital Medical Center
  • Nationwide Childrens Hospital
  • University of Oklahoma Health Sciences Center
  • University of Utah
  • Virginia Commonwealth University
  • UMHAP Sveti Georgi EAD
  • Specialized Hospital for Active Treatment of Oncohematological Diseases in Children
  • Multiprofile Hospital for Active Treatment "Sveta Marina"
  • The Chinese University of Hong Kong
  • Eulji University Hosptial
  • Ulsan University Hosptial
  • Severance Hospital
  • Hospital Pulau Pinang
  • Hospital Umum Sarawak
  • Hospital Sibu
  • Ampang Hospital
  • Tengku Ampian Rahimah (TAR) Hospital
  • Academic Medical Centre
  • Hospital Universitario La Paz
  • Hospital Universitario La Fe
  • Taichung Veterans General Hospital
  • China Medical University Hospital
  • Istanbul University Faculty of Medicine, Department of Pediatric Immunology
  • Ankara University Medical Faculty
  • Akdeniz Univesity Medical Faculty
  • Yuzuncu Yil University Medical Faculty
  • Institute of Blood Pathology and Transfusion Medicine of Academy of Medical Sciences of Ukraine
  • Birmingham Childrens Hospital NHS Trust
  • St. Thomas's Hospital
  • Great Ormond Street Hospital For Children
  • Royal Manchester Children's Hospital
  • Southampton General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

<6 years old

≥6 to <12 years

Arm Description

Outcomes

Primary Outcome Measures

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].

Secondary Outcome Measures

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.
Consumption of BAX 855: Number of Prophylactic Infusions Per Month Per Participant
Consumption of BAX 855: Number of Prophylactic Infusions Per Year (Annualized) Per Participant
Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Month Per Participant
Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Year (Annualized) Per Participant
Consumption of BAX 855: Number of Infusions Per Bleeding Episode
Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode
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.
Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855
Non-serious Adverse Events Possibly or Probably Related to BAX 855
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.
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.
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).
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.
Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion Per Dose, (AUC0-∞/Dose)
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
July 25, 2014
Last Updated
April 30, 2021
Sponsor
Baxalta now part of Shire
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1. Study Identification

Unique Protocol Identification Number
NCT02210091
Brief Title
BAX 855 Pediatric Study
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
October 31, 2014 (Actual)
Primary Completion Date
October 23, 2015 (Actual)
Study Completion Date
October 23, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Baxalta now part of Shire

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
75 (Actual)

8. Arms, Groups, and Interventions

Arm Title
<6 years old
Arm Type
Experimental
Arm Title
≥6 to <12 years
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method
Other Intervention Name(s)
ADVATE
Intervention Description
Pharmacokinetic (PK) analysis of ADVATE
Intervention Type
Biological
Intervention Name(s)
PEGylated Recombinant Factor VIII
Other Intervention Name(s)
BAX 855
Intervention Description
Pharmacokinetic (PK) analysis of BAX 855
Intervention Type
Biological
Intervention Name(s)
PEGylated Recombinant Factor VIII
Other Intervention Name(s)
BAX 855
Intervention Description
Prophylaxis treatment
Primary Outcome Measure Information:
Title
Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII)
Description
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].
Time Frame
After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Secondary Outcome Measure Information:
Title
Annualized Bleeding Rate (ABR)
Description
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.
Time Frame
During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Title
Consumption of BAX 855: Number of Prophylactic Infusions Per Month Per Participant
Time Frame
During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Title
Consumption of BAX 855: Number of Prophylactic Infusions Per Year (Annualized) Per Participant
Time Frame
During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Title
Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Month Per Participant
Time Frame
During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Title
Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Year (Annualized) Per Participant
Time Frame
During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Title
Consumption of BAX 855: Number of Infusions Per Bleeding Episode
Time Frame
During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Title
Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode
Time Frame
During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Title
Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed
Description
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.
Time Frame
After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Title
Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855
Time Frame
After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Title
Non-serious Adverse Events Possibly or Probably Related to BAX 855
Time Frame
After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Title
Number of Participants With Clinically Significant Changes in Vital Signs
Description
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.
Time Frame
After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Title
Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids)
Description
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.
Time Frame
After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Title
Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins
Description
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).
Time Frame
After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Title
Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞)
Description
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.
Time Frame
(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
Title
Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion Per Dose, (AUC0-∞/Dose)
Time Frame
(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
Title
Pharmacokinetics (PK): Mean Residence Time (MRT)
Description
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.
Time Frame
(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
Title
Pharmacokinetics (PK): Clearance (CL)
Description
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.
Time Frame
(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
Title
Pharmacokinetics (PK): Plasma Half-life (T1/2)
Description
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.
Time Frame
(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
Title
Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss)
Description
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.
Time Frame
(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
Title
Pharmacokinetics (PK): Incremental Recovery (IR)
Description
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.
Time Frame
(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
Title
Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay
Description
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.
Time Frame
Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination)
Title
Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay
Description
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.
Time Frame
Baseline, Week 5 (or 10-15 Exposure Days [EDs], whichever occurs last), Week 12, and Month 6 (Completion/Termination)

10. Eligibility

Sex
All
Maximum Age & Unit of Time
11 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
Facility Name
Phoenix Children's Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80220
Country
United States
Facility Name
University of Florida College of Medicine
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Louisville
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
Cornell University
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11040
Country
United States
Facility Name
New York Presbyterian Hospital-Weill
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Cincinnati Childrens Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Nationwide Childrens Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
UMHAP Sveti Georgi EAD
City
Plovdiv
ZIP/Postal Code
4000
Country
Bulgaria
Facility Name
Specialized Hospital for Active Treatment of Oncohematological Diseases in Children
City
Sofia
ZIP/Postal Code
1527
Country
Bulgaria
Facility Name
Multiprofile Hospital for Active Treatment "Sveta Marina"
City
Varna
ZIP/Postal Code
9010
Country
Bulgaria
Facility Name
The Chinese University of Hong Kong
City
Shatin
State/Province
New Territories
Country
Hong Kong
Facility Name
Eulji University Hosptial
City
Seo-gu
State/Province
Daejeon
ZIP/Postal Code
302-799
Country
Korea, Republic of
Facility Name
Ulsan University Hosptial
City
Dong-gu
State/Province
Ulsan
ZIP/Postal Code
682-714
Country
Korea, Republic of
Facility Name
Severance Hospital
City
Seoul
ZIP/Postal Code
134-727
Country
Korea, Republic of
Facility Name
Hospital Pulau Pinang
City
George Town
State/Province
Penang
ZIP/Postal Code
10450
Country
Malaysia
Facility Name
Hospital Umum Sarawak
City
Kuching
State/Province
Sarawak
ZIP/Postal Code
93586
Country
Malaysia
Facility Name
Hospital Sibu
City
Sibu
State/Province
Sarawak
ZIP/Postal Code
96000
Country
Malaysia
Facility Name
Ampang Hospital
City
Ampang
State/Province
Selangor
ZIP/Postal Code
68000
Country
Malaysia
Facility Name
Tengku Ampian Rahimah (TAR) Hospital
City
Klang
State/Province
Selangor
ZIP/Postal Code
41200
Country
Malaysia
Facility Name
Academic Medical Centre
City
Amsterdam
ZIP/Postal Code
1105 NZ
Country
Netherlands
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Hospital Universitario La Fe
City
Valencia
ZIP/Postal Code
460026
Country
Spain
Facility Name
Taichung Veterans General Hospital
City
Taichung City
State/Province
Xitun District
ZIP/Postal Code
40705
Country
Taiwan
Facility Name
China Medical University Hospital
City
Taichung
ZIP/Postal Code
40447
Country
Taiwan
Facility Name
Istanbul University Faculty of Medicine, Department of Pediatric Immunology
City
Cerrahpasa
State/Province
Istanbul
ZIP/Postal Code
34098
Country
Turkey
Facility Name
Ankara University Medical Faculty
City
Ankara
ZIP/Postal Code
06560
Country
Turkey
Facility Name
Akdeniz Univesity Medical Faculty
City
Antalya
ZIP/Postal Code
07059
Country
Turkey
Facility Name
Yuzuncu Yil University Medical Faculty
City
Van
ZIP/Postal Code
65000
Country
Turkey
Facility Name
Institute of Blood Pathology and Transfusion Medicine of Academy of Medical Sciences of Ukraine
City
Lviv
ZIP/Postal Code
79044
Country
Ukraine
Facility Name
Birmingham Childrens Hospital NHS Trust
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
Facility Name
St. Thomas's Hospital
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
Great Ormond Street Hospital For Children
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
Facility Name
Royal Manchester Children's Hospital
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
Facility Name
Southampton General Hospital
City
Southampton
ZIP/Postal Code
SO16 6YD
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
IPD Sharing Access Criteria
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
IPD Sharing URL
https://vivli.org/ourmember/takeda/
Citations:
PubMed Identifier
27891721
Citation
Mullins ES, Stasyshyn O, Alvarez-Roman MT, Osman D, Liesner R, Engl W, Sharkhawy M, Abbuehl BE. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia. 2017 Mar;23(2):238-246. doi: 10.1111/hae.13119. Epub 2016 Nov 27.
Results Reference
result

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BAX 855 Pediatric Study

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