Hemophilia A
Conditions
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.
Interventions
Pharmacokinetic (PK) analysis of ADVATE
BIOLOGICALPEGylated Recombinant Factor VIII
Pharmacokinetic (PK) analysis of BAX 855
Sponsors
Baxalta now part of Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 11 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII) | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 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
| Measure | Time frame | Description |
|---|---|---|
| Annualized Bleeding Rate (ABR) | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | 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 | 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 | — |
| Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 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 | 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 | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 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. |
| Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode | During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last | — |
| Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 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-∞) | (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 | 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) | (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) | (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 | 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) | (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 | 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) | (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 | 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) | (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 | 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) | (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 | 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 | Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination) | 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 | Baseline, Week 5 (or 10-15 Exposure Days [EDs], whichever occurs last), Week 12, and Month 6 (Completion/Termination) | 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. |
| Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | After first exposure to BAX 855 until completion of study - approx. 6 months per participant. | 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. |
Countries
Bulgaria, Hong Kong, Malaysia, Netherlands, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
52 sites participated in this study. 39 study sites enrolled participants and 13 sites were initiated but were inactive.
Pre-assignment details
73 participants enrolled and were screened for study participation. There were 9 screen failures. Among these, 2 participants were screen failures at first screening but entered the study later. 66 participants were dosed in the prophylactic part of the study, of whom 31 participants were also dosed in the PK part prior to prophylaxis.
Participants by arm
| Arm | Count |
|---|---|
| <6 Years Old | 32 |
| 6 to <12 Years Old | 34 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Sponsor | 0 | 1 |
Baseline characteristics
| Characteristic | <6 Years Old | 6 to <12 Years Old | Total |
|---|---|---|---|
| Age, Continuous | 3.7 Years STANDARD_DEVIATION 1.17 | 8.1 Years STANDARD_DEVIATION 1.92 | 6.0 Years STANDARD_DEVIATION 2.7 |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 32 Participants | 33 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 66 | 0 / 31 |
| serious Total, serious adverse events | 3 / 66 | 0 / 31 |
Outcome results
Primary
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 \[BU\].
Time frame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Population: Participants in the BAX 855 Safety Analysis Set who developed an inhibitor at any time plus participants who did not develop an inhibitor, had 50 or more exposure days (EDs) to BAX 855 and had FVIII Inhibitory test results after 50 EDs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| <6 Years Old | Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII) | 0 participants |
| 6 to <12 Years Old | Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII) | 0 participants |
| BAX 855 Safety Analysis Set | Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII) | 0 participants |
Secondary
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.
Time frame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Population: Full Analysis Set: All participants who received at least 1 dose of BAX 855 in either PK or prophylaxis part of study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Annualized Bleeding Rate (ABR) | Overall annualized bleeding rate | 2.37 bleeding episodes per year | 95% Confidence Interval 3.508 |
| <6 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of joint bleeds | 0.862 bleeding episodes per year | 95% Confidence Interval 2.622 |
| <6 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of target joint bleeds | 0 bleeding episodes per year | 95% Confidence Interval 0.354 |
| <6 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of non-target joint bleeds | 0.763 bleeding episodes per year | 95% Confidence Interval 2.618 |
| <6 Years Old | Annualized Bleeding Rate (ABR) | Annualized spontaneous bleeding rate | 1.018 bleeding episodes per year | 95% Confidence Interval 2.048 |
| <6 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of injury-related bleeds | 1.628 bleeding episodes per year | 95% Confidence Interval 2.308 |
| 6 to <12 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of injury-related bleeds | 2.586 bleeding episodes per year | 95% Confidence Interval 8.678 |
| 6 to <12 Years Old | Annualized Bleeding Rate (ABR) | Overall annualized bleeding rate | 3.75 bleeding episodes per year | 95% Confidence Interval 9.046 |
| 6 to <12 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of non-target joint bleeds | 0.998 bleeding episodes per year | 95% Confidence Interval 2.253 |
| 6 to <12 Years Old | Annualized Bleeding Rate (ABR) | Annualized spontaneous bleeding rate | 1.316 bleeding episodes per year | 95% Confidence Interval 2.467 |
| 6 to <12 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of joint bleeds | 1.355 bleeding episodes per year | 95% Confidence Interval 2.59 |
| 6 to <12 Years Old | Annualized Bleeding Rate (ABR) | Annualized rate of target joint bleeds | 0 bleeding episodes per year | 95% Confidence Interval 1.146 |
| BAX 855 Safety Analysis Set | Annualized Bleeding Rate (ABR) | Annualized rate of joint bleeds | 1.103 bleeding episodes per year | 95% Confidence Interval 2.597 |
| BAX 855 Safety Analysis Set | Annualized Bleeding Rate (ABR) | Annualized rate of target joint bleeds | 0 bleeding episodes per year | 95% Confidence Interval 0.865 |
| BAX 855 Safety Analysis Set | Annualized Bleeding Rate (ABR) | Annualized rate of injury-related bleeds | 2.089 bleeding episodes per year | 95% Confidence Interval 6.471 |
| BAX 855 Safety Analysis Set | Annualized Bleeding Rate (ABR) | Annualized rate of non-target joint bleeds | 0.892 bleeding episodes per year | 95% Confidence Interval 2.42 |
| BAX 855 Safety Analysis Set | Annualized Bleeding Rate (ABR) | Overall annualized bleeding rate | 3.04 bleeding episodes per year | 95% Confidence Interval 6.988 |
| BAX 855 Safety Analysis Set | Annualized Bleeding Rate (ABR) | Annualized spontaneous bleeding rate | 1.164 bleeding episodes per year | 95% Confidence Interval 2.26 |
Secondary
Consumption of BAX 855: Number of Infusions Per Bleeding Episode
Time frame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Population: Participants in the BAX 855 Safety Analysis Set who had treated bleeding episodes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| <6 Years Old | Consumption of BAX 855: Number of Infusions Per Bleeding Episode | 1.17 infusions | Standard Deviation 0.362 |
| 6 to <12 Years Old | Consumption of BAX 855: Number of Infusions Per Bleeding Episode | 1.40 infusions | Standard Deviation 0.655 |
| BAX 855 Safety Analysis Set | Consumption of BAX 855: Number of Infusions Per Bleeding Episode | 1.30 infusions | Standard Deviation 0.551 |
Secondary
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
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| <6 Years Old | Consumption of BAX 855: Number of Prophylactic Infusions Per Month Per Participant | 8.07 infusions per month | Standard Deviation 0.245 |
| 6 to <12 Years Old | Consumption of BAX 855: Number of Prophylactic Infusions Per Month Per Participant | 7.72 infusions per month | Standard Deviation 0.974 |
| BAX 855 Safety Analysis Set | Consumption of BAX 855: Number of Prophylactic Infusions Per Month Per Participant | 7.89 infusions per month | Standard Deviation 0.736 |
Secondary
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
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| <6 Years Old | Consumption of BAX 855: Number of Prophylactic Infusions Per Year (Annualized) Per Participant | 96.82 infusions per year | Standard Deviation 2.942 |
| 6 to <12 Years Old | Consumption of BAX 855: Number of Prophylactic Infusions Per Year (Annualized) Per Participant | 92.61 infusions per year | Standard Deviation 11.693 |
| BAX 855 Safety Analysis Set | Consumption of BAX 855: Number of Prophylactic Infusions Per Year (Annualized) Per Participant | 94.65 infusions per year | Standard Deviation 8.834 |
Secondary
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
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| <6 Years Old | Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Month Per Participant | 458.93 IU/kg | Standard Deviation 46.161 |
| 6 to <12 Years Old | Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Month Per Participant | 455.86 IU/kg | Standard Deviation 76.101 |
| BAX 855 Safety Analysis Set | Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Month Per Participant | 457.35 IU/kg | Standard Deviation 62.919 |
Secondary
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
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| <6 Years Old | Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Year (Annualized) Per Participant | 5507.20 IU/kg | Standard Deviation 553.931 |
| 6 to <12 Years Old | Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Year (Annualized) Per Participant | 5470.32 IU/kg | Standard Deviation 913.21 |
| BAX 855 Safety Analysis Set | Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Year (Annualized) Per Participant | 5488.20 IU/kg | Standard Deviation 755.033 |
Secondary
Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode
Time frame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
Population: Participants in the BAX 855 Safety Analysis Set who had treated bleeding episodes.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode | Average dose to treat bleeding episode | 52.21 IU/kg | Standard Deviation 16.681 |
| <6 Years Old | Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode | Average dose per infusion per bleeding episode | 45.58 IU/kg | Standard Deviation 10.75 |
| 6 to <12 Years Old | Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode | Average dose to treat bleeding episode | 62.31 IU/kg | Standard Deviation 38.764 |
| 6 to <12 Years Old | Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode | Average dose per infusion per bleeding episode | 43.76 IU/kg | Standard Deviation 15.304 |
| BAX 855 Safety Analysis Set | Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode | Average dose to treat bleeding episode | 57.85 IU/kg | Standard Deviation 31.041 |
| BAX 855 Safety Analysis Set | Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode | Average dose per infusion per bleeding episode | 44.56 IU/kg | Standard Deviation 13.327 |
Secondary
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.
Time frame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Population: Participants in the Full Analysis Set who had treated bleeding episodes.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| <6 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Excellent | 15 bleeding episodes |
| <6 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Good | 9 bleeding episodes |
| <6 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Fair | 1 bleeding episodes |
| <6 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Not reported | 0 bleeding episodes |
| 6 to <12 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Not reported | 3 bleeding episodes |
| 6 to <12 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Excellent | 19 bleeding episodes |
| 6 to <12 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Fair | 3 bleeding episodes |
| 6 to <12 Years Old | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Good | 20 bleeding episodes |
| BAX 855 Safety Analysis Set | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Not reported | 3 bleeding episodes |
| BAX 855 Safety Analysis Set | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Good | 29 bleeding episodes |
| BAX 855 Safety Analysis Set | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Fair | 4 bleeding episodes |
| BAX 855 Safety Analysis Set | Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed | Excellent | 34 bleeding episodes |
Secondary
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.
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| <6 Years Old | Non-serious Adverse Events Possibly or Probably Related to BAX 855 | Investigator Assessment | 1 adverse events |
| <6 Years Old | Non-serious Adverse Events Possibly or Probably Related to BAX 855 | Sponsor Assessment | 0 adverse events |
| 6 to <12 Years Old | Non-serious Adverse Events Possibly or Probably Related to BAX 855 | Investigator Assessment | 0 adverse events |
| 6 to <12 Years Old | Non-serious Adverse Events Possibly or Probably Related to BAX 855 | Sponsor Assessment | 0 adverse events |
| BAX 855 Safety Analysis Set | Non-serious Adverse Events Possibly or Probably Related to BAX 855 | Investigator Assessment | 0 adverse events |
| BAX 855 Safety Analysis Set | Non-serious Adverse Events Possibly or Probably Related to BAX 855 | Sponsor Assessment | 0 adverse events |
Secondary
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.
Time frame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| <6 Years Old | Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | Hematology-CS Rise in Eosinophils | 1 clinically significant findings |
| <6 Years Old | Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | Clin. Chemistry-CS Rise in Alkaline Phosphatase | 1 clinically significant findings |
| 6 to <12 Years Old | Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | Hematology-CS Rise in Eosinophils | 0 clinically significant findings |
| 6 to <12 Years Old | Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | Clin. Chemistry-CS Rise in Alkaline Phosphatase | 0 clinically significant findings |
| BAX 855 Safety Analysis Set | Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | Hematology-CS Rise in Eosinophils | 1 clinically significant findings |
| BAX 855 Safety Analysis Set | Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids) | Clin. Chemistry-CS Rise in Alkaline Phosphatase | 1 clinically significant findings |
Secondary
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.
Time frame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| <6 Years Old | Number of Participants With Clinically Significant Changes in Vital Signs | 1 participants |
| 6 to <12 Years Old | Number of Participants With Clinically Significant Changes in Vital Signs | 0 participants |
| BAX 855 Safety Analysis Set | Number of Participants With Clinically Significant Changes in Vital Signs | 0 participants |
Secondary
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.
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
Population: Pharmacokinetic (PK) Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | One stage clotting assay - ADVATE | 14000 IU•hr/L | Standard Deviation 3070 |
| <6 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | Chromogenic assay - ADVATE | 11600 IU•hr/L | Standard Deviation 3070 |
| <6 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | One stage clotting assay - BAX 855 | 19500 IU•hr/L | Standard Deviation 7580 |
| <6 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | Chromogenic assay - BAX 855 | 21900 IU•hr/L | Standard Deviation 15900 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | Chromogenic assay - BAX 855 | 22600 IU•hr/L | Standard Deviation 5140 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | One stage clotting assay - ADVATE | 14400 IU•hr/L | Standard Deviation 1800 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | One stage clotting assay - BAX 855 | 20100 IU•hr/L | Standard Deviation 4930 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | Chromogenic assay - ADVATE | 16600 IU•hr/L | Standard Deviation 3290 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | Chromogenic assay - BAX 855 | 22300 IU•hr/L | Standard Deviation 11200 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | Chromogenic assay - ADVATE | 14400 IU•hr/L | Standard Deviation 4040 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | One stage clotting assay - BAX 855 | 19800 IU•hr/L | Standard Deviation 6160 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞) | One stage clotting assay - ADVATE | 14200 IU•hr/L | Standard Deviation 2420 |
Secondary
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
Population: The PK parameters were derived using a non-compartmental estimation approach using a flexible sampling design to provide point and interval estimates for summary PK parameter using a batch method. AUC/Dose is not a standard output parameter so this calculation was not done.
Secondary
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.
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
Population: Pharmacokinetic (PK) Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Clearance (CL) | One stage clotting assay - ADVATE | 0.0775 L/hr | Standard Deviation 0.0132 |
| <6 Years Old | Pharmacokinetics (PK): Clearance (CL) | Chromogenic assay - ADVATE | 0.0933 L/hr | Standard Deviation 0.0106 |
| <6 Years Old | Pharmacokinetics (PK): Clearance (CL) | One stage clotting assay - BAX 855 | 0.0596 L/hr | Standard Deviation 0.019 |
| <6 Years Old | Pharmacokinetics (PK): Clearance (CL) | Chromogenic assay - BAX 855 | 0.0574 L/hr | Standard Deviation 0.0174 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Clearance (CL) | Chromogenic assay - BAX 855 | 0.0812 L/hr | Standard Deviation 0.0248 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Clearance (CL) | One stage clotting assay - ADVATE | 0.1250 L/hr | Standard Deviation 0.042 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Clearance (CL) | One stage clotting assay - BAX 855 | 0.0913 L/hr | Standard Deviation 0.0276 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Clearance (CL) | Chromogenic assay - ADVATE | 0.1040 L/hr | Standard Deviation 0.00875 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Clearance (CL) | Chromogenic assay - BAX 855 | 0.0704 L/hr | Standard Deviation 0.0246 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Clearance (CL) | Chromogenic assay - ADVATE | 0.0994 L/hr | Standard Deviation 0.011 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Clearance (CL) | One stage clotting assay - BAX 855 | 0.0770 L/hr | Standard Deviation 0.0286 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Clearance (CL) | One stage clotting assay - ADVATE | 0.1030 L/hr | Standard Deviation 0.0398 |
Secondary
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.
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
Population: Pharmacokinetic (PK) Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | One stage clotting assay - ADVATE | 1.8563 IU/dL : IU/kg | Standard Deviation 0.76004 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | Chromogenic assay - ADVATE | 1.7374 IU/dL : IU/kg | Standard Deviation 0.2911 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | One stage clotting assay - BAX 855 | 1.8809 IU/dL : IU/kg | Standard Deviation 0.48894 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | Chromogenic assay - BAX 855 | 1.8813 IU/dL : IU/kg | Standard Deviation 0.27069 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | Chromogenic assay - BAX 855 | 2.1710 IU/dL : IU/kg | Standard Deviation 0.38472 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | One stage clotting assay - ADVATE | 1.8696 IU/dL : IU/kg | Standard Deviation 0.25856 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | One stage clotting assay - BAX 855 | 1.9342 IU/dL : IU/kg | Standard Deviation 0.47451 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) | Chromogenic assay - ADVATE | 2.0458 IU/dL : IU/kg | Standard Deviation 0.31739 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) | Chromogenic assay - BAX 855 | 2.0402 IU/dL : IU/kg | Standard Deviation 0.36355 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) | Chromogenic assay - ADVATE | 1.9065 IU/dL : IU/kg | Standard Deviation 0.33879 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) | One stage clotting assay - BAX 855 | 1.9101 IU/dL : IU/kg | Standard Deviation 0.47371 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) | One stage clotting assay - ADVATE | 1.8636 IU/dL : IU/kg | Standard Deviation 0.53481 |
Secondary
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.
Time frame: Baseline, Week 5 (or 10-15 Exposure Days [EDs], whichever occurs last), Week 12, and Month 6 (Completion/Termination)
Population: Participants from the Full Analysis Set who provided at least data from baseline, Week 5 (or 10-15 EDs, whichever occurred last), Week 12 or Month 6.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Baseline [n= 15; 16; 31] | 1.7675 IU/dL : IU/kg | Standard Deviation 0.34998 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Week 5 (or after 10-15 EDs) [n= 27; 30; 57] | 1.9273 IU/dL : IU/kg | Standard Deviation 0.324 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Week 12 [n= 26; 31; 57] | 1.8794 IU/dL : IU/kg | Standard Deviation 0.24281 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Month 6 (Termination/Completion) [n= 27; 28; 55] | 1.8359 IU/dL : IU/kg | Standard Deviation 0.29188 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Month 6 (Termination/Completion) [n= 27; 28; 55] | 2.0659 IU/dL : IU/kg | Standard Deviation 0.45723 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Baseline [n= 15; 16; 31] | 1.9334 IU/dL : IU/kg | Standard Deviation 0.3 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Week 12 [n= 26; 31; 57] | 1.9869 IU/dL : IU/kg | Standard Deviation 0.423 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Week 5 (or after 10-15 EDs) [n= 27; 30; 57] | 1.9960 IU/dL : IU/kg | Standard Deviation 0.39258 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Month 6 (Termination/Completion) [n= 27; 28; 55] | 1.9530 IU/dL : IU/kg | Standard Deviation 0.39876 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Week 5 (or after 10-15 EDs) [n= 27; 30; 57] | 1.9635 IU/dL : IU/kg | Standard Deviation 0.36021 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Week 12 [n= 26; 31; 57] | 1.9379 IU/dL : IU/kg | Standard Deviation 0.35368 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay | Baseline [n= 15; 16; 31] | 1.8532 IU/dL : IU/kg | Standard Deviation 0.33055 |
Secondary
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.
Time frame: Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination)
Population: Participants from the Full Analysis Set who provided at least data from baseline, Week 5 (or 10-15 EDs, whichever occurred last), Week 12 or Month 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Baseline [n=15, 16, 31] | 1.6889 IU/dL : IU/kg | Standard Deviation 0.2761 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Week 5 (or after 10-15 EDs) [n= 27, 30, 57] | 1.8952 IU/dL : IU/kg | Standard Deviation 0.55483 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Week 12 [n= 26, 31, 57] | 1.6818 IU/dL : IU/kg | Standard Deviation 0.23069 |
| <6 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Month 6 (Termination/Completion) [n=27, 28, 55] | 1.5801 IU/dL : IU/kg | Standard Deviation 0.31568 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Month 6 (Termination/Completion) [n=27, 28, 55] | 1.7120 IU/dL : IU/kg | Standard Deviation 0.36588 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Baseline [n=15, 16, 31] | 1.7843 IU/dL : IU/kg | Standard Deviation 0.35942 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Week 12 [n= 26, 31, 57] | 1.9212 IU/dL : IU/kg | Standard Deviation 0.42496 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Week 5 (or after 10-15 EDs) [n= 27, 30, 57] | 1.8661 IU/dL : IU/kg | Standard Deviation 0.49785 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Month 6 (Termination/Completion) [n=27, 28, 55] | 1.6472 IU/dL : IU/kg | Standard Deviation 0.34546 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Week 5 (or after 10-15 EDs) [n= 27, 30, 57] | 1.8799 IU/dL : IU/kg | Standard Deviation 0.52105 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Week 12 [n= 26, 31, 57] | 1.8120 IU/dL : IU/kg | Standard Deviation 0.36738 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay | Baseline [n=15, 16, 31] | 1.7381 IU/dL : IU/kg | Standard Deviation 0.32017 |
Secondary
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.
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
Population: Pharmacokinetic (PK) Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | One stage clotting assay - ADVATE | 13.3 hours (hr) | Standard Deviation 3.95 |
| <6 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | One stage clotting assay - BAX 855 | 17.0 hours (hr) | Standard Deviation 3.51 |
| <6 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | Chromogenic assay - ADVATE | 12.5 hours (hr) | Standard Deviation 2.52 |
| <6 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | Chromogenic assay - BAX 855 | 18.7 hours (hr) | Standard Deviation 12.6 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | One stage clotting assay - ADVATE | 14.2 hours (hr) | Standard Deviation 2.64 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | Chromogenic assay - BAX 855 | 17.2 hours (hr) | Standard Deviation 3.72 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | One stage clotting assay - BAX 855 | 17.8 hours (hr) | Standard Deviation 2.4 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Mean Residence Time (MRT) | Chromogenic assay - ADVATE | 11.6 hours (hr) | Standard Deviation 1.2 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Mean Residence Time (MRT) | Chromogenic assay - BAX 855 | 17.9 hours (hr) | Standard Deviation 8.76 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Mean Residence Time (MRT) | One stage clotting assay - BAX 855 | 17.5 hours (hr) | Standard Deviation 2.93 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Mean Residence Time (MRT) | Chromogenic assay - ADVATE | 12.0 hours (hr) | Standard Deviation 1.93 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Mean Residence Time (MRT) | One stage clotting assay - ADVATE | 13.8 hours (hr) | Standard Deviation 3.27 |
Secondary
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.
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
Population: Pharmacokinetic (PK) Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | One stage clotting assay - BAX 855 | 11.8 hours (hr) | Standard Deviation 2.43 |
| <6 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | Chromogenic assay - BAX 855 | 13.0 hours (hr) | Standard Deviation 8.74 |
| <6 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | One stage clotting assay - ADVATE | 9.24 hours (hr) | Standard Deviation 2.74 |
| <6 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | Chromogenic assay - ADVATE | 8.68 hours (hr) | Standard Deviation 1.75 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | One stage clotting assay - ADVATE | 9.82 hours (hr) | Standard Deviation 1.83 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | Chromogenic assay - BAX 855 | 11.9 hours (hr) | Standard Deviation 2.58 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | One stage clotting assay - BAX 855 | 12.4 hours (hr) | Standard Deviation 1.67 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Plasma Half-life (T1/2) | Chromogenic assay - ADVATE | 8.04 hours (hr) | Standard Deviation 0.83 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Plasma Half-life (T1/2) | Chromogenic assay - BAX 855 | 12.4 hours (hr) | Standard Deviation 6.07 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Plasma Half-life (T1/2) | Chromogenic assay - ADVATE | 8.33 hours (hr) | Standard Deviation 1.34 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Plasma Half-life (T1/2) | One stage clotting assay - BAX 855 | 12.1 hours (hr) | Standard Deviation 2.03 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Plasma Half-life (T1/2) | One stage clotting assay - ADVATE | 9.56 hours (hr) | Standard Deviation 2.26 |
Secondary
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.
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
Population: Pharmacokinetic (PK) Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | One stage clotting assay - ADVATE | 1.02 litre (L) | Standard Deviation 0.302 |
| <6 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | Chromogenic assay - ADVATE | 1.14 litre (L) | Standard Deviation 0.107 |
| <6 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | One stage clotting assay - BAX 855 | 0.97 litre (L) | Standard Deviation 0.23 |
| <6 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | Chromogenic assay - BAX 855 | 0.907 litre (L) | Standard Deviation 0.124 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | Chromogenic assay - BAX 855 | 1.33 litre (L) | Standard Deviation 0.233 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | One stage clotting assay - ADVATE | 1.69 litre (L) | Standard Deviation 0.35 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | One stage clotting assay - BAX 855 | 1.59 litre (L) | Standard Deviation 0.343 |
| 6 to <12 Years Old | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | Chromogenic assay - ADVATE | 1.20 litre (L) | Standard Deviation 0.0548 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | Chromogenic assay - BAX 855 | 1.14 litre (L) | Standard Deviation 0.285 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | Chromogenic assay - ADVATE | 1.18 litre (L) | Standard Deviation 0.0857 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | One stage clotting assay - BAX 855 | 1.31 litre (L) | Standard Deviation 0.427 |
| BAX 855 Safety Analysis Set | Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | One stage clotting assay - ADVATE | 1.39 litre (L) | Standard Deviation 0.47 |
Secondary
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).
Time frame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Population: BAX 855 Safety Analysis Set: Data not available for 1 participant in the 6 to \<12 years group as participant was prematurely withdrawn from study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| <6 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to FVIII | 0 participants |
| <6 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to PEG | 0 participants |
| <6 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to PEG-FVIII | 3 participants |
| <6 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding Ig antibodies to CHO | 0 participants |
| <6 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to FVIII | 0 participants |
| <6 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to PEG | 0 participants |
| <6 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to PEG-FVIII | 0 participants |
| 6 to <12 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to PEG-FVIII | 4 participants |
| 6 to <12 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to PEG-FVIII | 0 participants |
| 6 to <12 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to PEG | 0 participants |
| 6 to <12 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to PEG | 0 participants |
| 6 to <12 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding Ig antibodies to CHO | 0 participants |
| 6 to <12 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to FVIII | 0 participants |
| 6 to <12 Years Old | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to FVIII | 0 participants |
| BAX 855 Safety Analysis Set | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to PEG | 0 participants |
| BAX 855 Safety Analysis Set | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to FVIII | 0 participants |
| BAX 855 Safety Analysis Set | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to FVIII | 0 participants |
| BAX 855 Safety Analysis Set | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to PEG-FVIII | 0 participants |
| BAX 855 Safety Analysis Set | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgM antibodies to PEG | 0 participants |
| BAX 855 Safety Analysis Set | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding IgG antibodies to PEG-FVIII | 7 participants |
| BAX 855 Safety Analysis Set | Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins | Positive binding Ig antibodies to CHO | 0 participants |
Secondary
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.
Population: BAX 855 Safety Analysis Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| <6 Years Old | Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855 | Investigator Assessment | 0 serious adverse events |
| <6 Years Old | Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855 | Sponsor Assessment | 0 serious adverse events |
| 6 to <12 Years Old | Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855 | Investigator Assessment | 0 serious adverse events |
| 6 to <12 Years Old | Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855 | Sponsor Assessment | 0 serious adverse events |
| BAX 855 Safety Analysis Set | Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855 | Investigator Assessment | 0 serious adverse events |
| BAX 855 Safety Analysis Set | Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855 | Sponsor Assessment | 0 serious adverse events |
Post Hoc
Pharmacokinetics (PK): Plasma Half-life Ratio of BAX 855 to ADVATE
This is a descriptive summary of the ratio of plasma half-life in the same subject for BAX 855 compared to ADVATE based on the final covariate model (first observation tabulation).
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
Population: Pharmacokinetic (PK) Analysis Set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| <6 Years Old | Pharmacokinetics (PK): Plasma Half-life Ratio of BAX 855 to ADVATE | One stage clotting assay | 1.30 hours (hr) |
| <6 Years Old | Pharmacokinetics (PK): Plasma Half-life Ratio of BAX 855 to ADVATE | Chromogenic assay | 1.50 hours (hr) |