Hemophilia A
Conditions
Brief summary
1. To compare the efficacy and safety of pharmacokinetic (PK)-guided treatment with BAX 855 targeting FVIII trough levels of 1-3% and approximately 10% (8-12%) 2. To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855
Interventions
BIOLOGICALPEGylated Recombinant Factor VIII
Pharmacokinetic (PK) evaluation
Sponsors
Baxalta Innovations GmbH, now part of Shire
Baxalta now part of Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participants transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study: 1. Participant has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study 261302. 2. Participant is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an Annual Bleed Rate (ABR) of ≥ 2 documented and treated during the past 12 months. 3. Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm\^3, as confirmed by central laboratory. 4. Participant is willing and able to comply with the requirements of the protocol. * Newly recruited participants (ie not transitioning from another BAX 855 study) including BAX855 naïve participants who meet ALL of the following criteria are eligible for this study: 1. Participant has severe hemophilia A (FVIII clotting activity \< 1%) as confirmed by central laboratory OR by historically documented FVIII clotting activity performed by a certified clinical laboratory, optionally supported by a FVIII gene mutation consistent with severe hemophilia A 2. Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs) 3. Participant is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months. 4. Participant has a Karnofsky performance score of ≥ 60 at screening 5. Participant is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm\^3, as confirmed by central laboratory at screening 6. Participant is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis 7. If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study 8. Participant is willing and able to comply with the requirements of the protocol.
Exclusion criteria
* Participants transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study: 1. Participant has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study. 2. Participant has been diagnosed with an acquired hemostatic defect other than hemophilia A. 3. The participant's weight is \< 35 kg or \> 100 kg. 4. Participant's platelet count is \< 100,000/mL. 5. Participant has an abnormal renal function (serum creatinine \> 1.5 times the upper limit of normal). 6. Participant has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal. 7. Participant is scheduled to receive a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy during the study. 8. Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant's safety or compliance. 9. Participant is planning to take part in any other clinical study during the course of the study. 10. Participant 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. Newly recruited participants (ie not transitioning from another BAX 855 study) who meet ANY of the following criteria are not eligible for this study: 1. Participant has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening. 2. Participant has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) at any time prior to screening. 3. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease). 4. The participant's weight is \< 35 kg or \> 100 kg. 5. Participant's platelet count is \< 100,000/mL. 6. Participant has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80. 7. Participant has severe chronic hepatic dysfunction \[eg, ≥ 5 times upper limit of normal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as confirmed by central laboratory at screening, or a documented INR \> 1.5\]. 8. Participant has severe renal impairment (serum creatinine \> 1.5 times the upper limit of normal). 9. 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. 10. Participant is scheduled to receive during the course of the study, a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy. 11. Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study. 12. 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. 13. Participant 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 |
|---|---|---|
| Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months | Day 183 to Day 364 (6 months) | Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Spontaneous Bleeding Rate for Second Six Months | Day 183 to Day 364 (6 months) | Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma. |
| Annualized Traumatic Bleeding Rate for Second Six Months | Day 183 to Day 364 (6 months) | Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma. |
| Annualized Joint Bleeding Rate (AJBR) for Second Six Months | Day 183 to Day 364 (6 months) | Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: 'aura', pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function. |
| Total Weight-adjusted Consumption of BAX 855 | From start of study treatment up to 12 months (completion or termination) | Total weight-adjusted consumption of BAX 855 were reported. |
| Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | 8 hours after study drug administration | The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. |
| Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | From start of study treatment up to bleed resolution (up to 12 months) | The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. |
| Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution | From start of study treatment up to 12 months (completion or termination) | Infusions of BAX 855 that were required until bleed resolution were reported. |
| Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score | Baseline, Month 12 | HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the participant. |
| Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Day 0 through discharge or 14 days post-surgery | The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first). |
| Blood Loss Per Participant in Case of Surgery | Day 0 through discharge or 14 days post-surgery | The intraoperative blood loss was measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Postoperatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. In cases where no drain was present, blood loss was determined by the surgeon's clinical judgment, as applicable or entered as not available. Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first). |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From start of study treatment up to 12 months (completion or termination) | An AE was any unfavorable and unintended sign (an abnormal laboratory finding), symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the participant or required medical or surgical intervention to prevent any of the above outcomes. |
| Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events | From start of study treatment up to 12 months (completion or termination) | Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature. |
| Total Annualized Bleeding Rate for Second Six Months | Day 183 to Day 364 (6 months) | Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years. |
| Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | From start of study treatment up to 12 months (completion or termination) | Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here. |
| Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey | Baseline, Month 12 (completion or termination) | Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores. |
| Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf) | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 were reported. |
| Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855 | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | IR at Cmax of BAX 855 were reported. |
| Plasma Half-life (T1/2) of BAX 855 | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | T1/2 of BAX 855 in plasma were reported. |
| Mean Residence Time (MRT) of BAX 855 | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | MRT of BAX 855 were reported. |
| Maximum Plasma Concentration (Cmax) of BAX 855 | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | Cmax of BAX 855 were reported. |
| Time to Maximum Concentration of BAX 855 in Plasma (Tmax) | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | Tmax of BAX 855 were reported. |
| Total Body Clearance (CL) of BAX 855 | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | Total body clearance of BAX 855 from blood by the kidney were reported. |
| Volume of Distribution at Steady State (Vss) | Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion | Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate. |
| Incremental Recovery (IR) Over Time | Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination) | Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg). |
| Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events | From start of study treatment up to 12 months (completion or termination) | Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology. |
Countries
Australia, Austria, Bulgaria, France, Germany, Hong Kong, Hungary, Israel, Italy, Malaysia, Norway, Poland, Romania, Singapore, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 62 study centers in 19 countries between 23 November 2015 (first participant first visit) and 05 August 2018 (last participant last visit).
Pre-assignment details
A total of 135 participants were enrolled in the study. Of them,14 participants were dropped out and did not receive any treatment 121 participants underwent initial pharmacokinetic(PK) assessment with a single administration of BAX 855 and based on their individual PK values, 115 participants were randomized to any one of the prophylactic regimen.
Participants by arm
| Arm | Count |
|---|---|
| BAX 855-Low Level Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of \> 80 IU/kg were required or regular FVIII peak levels of 200% were reached. | 57 |
| BAX 855-High Level Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels. | 58 |
| BAX 855-Non-randomized Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments. | 6 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| PK/Safety Assessment Period | Non-compliance to study procedures | 0 | 2 | 0 |
| PK/Safety Assessment Period | Other | 4 | 4 | 0 |
| PK/Safety Assessment Period | Physician Decision | 0 | 1 | 0 |
| PK/Safety Assessment Period | Screen Failure | 0 | 0 | 1 |
| PK/Safety Assessment Period | Withdrawal by Subject | 1 | 2 | 5 |
| PK/Safety Assessment Period | Withdrawn by sponsor | 0 | 1 | 0 |
| Prophylactic Treatment Period | Major protocol deviation | 0 | 4 | 0 |
| Prophylactic Treatment Period | Subject less than 75% exposed to BAX 855 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | BAX 855-Low Level | BAX 855-High Level | BAX 855-Non-randomized | Total |
|---|---|---|---|---|
| Age, Continuous | 31.1 Years STANDARD_DEVIATION 13.76 | 31.2 Years STANDARD_DEVIATION 12.22 | 25.8 Years STANDARD_DEVIATION 10.03 | 30.9 Years STANDARD_DEVIATION 12.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 53 Participants | 4 Participants | 110 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 14 Participants | 18 Participants | 2 Participants | 34 Participants |
| Race/Ethnicity, Customized Mestizo | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Latin American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 40 Participants | 36 Participants | 4 Participants | 80 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 57 Participants | 58 Participants | 6 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 58 | 0 / 6 |
| other Total, other adverse events | 25 / 57 | 25 / 58 | 0 / 6 |
| serious Total, serious adverse events | 5 / 57 | 5 / 58 | 0 / 6 |
Outcome results
Primary
Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months
Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.
Time frame: Day 183 to Day 364 (6 months)
Population: Full analysis set (FAS) included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BAX 855-Low Level | Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months | 42.1 Percentage of participants |
| BAX 855-High Level | Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months | 62.1 Percentage of participants |
Comparison: The proportion of participants with an ABR of 0 during the second 6-month period on BAX 855 prophylaxis, was compared between the 2 prophylaxis arms using a chi-square test with continuity correction at a 2-sided 5% level of significance.p-value: 0.054595% CI: [-0.038, 3.958]Chi-squared
Secondary
Annualized Joint Bleeding Rate (AJBR) for Second Six Months
Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: 'aura', pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function.
Time frame: Day 183 to Day 364 (6 months)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Annualized Joint Bleeding Rate (AJBR) for Second Six Months | 2.617 Bleeds per year | Standard Deviation 7.361 |
| BAX 855-High Level | Annualized Joint Bleeding Rate (AJBR) for Second Six Months | 1.079 Bleeds per year | Standard Deviation 2.553 |
Secondary
Annualized Spontaneous Bleeding Rate for Second Six Months
Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma.
Time frame: Day 183 to Day 364 (6 months)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Annualized Spontaneous Bleeding Rate for Second Six Months | 2.489 Bleeds per year | Standard Deviation 6.554 |
| BAX 855-High Level | Annualized Spontaneous Bleeding Rate for Second Six Months | 0.737 Bleeds per year | Standard Deviation 1.738 |
Secondary
Annualized Traumatic Bleeding Rate for Second Six Months
Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma.
Time frame: Day 183 to Day 364 (6 months)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Annualized Traumatic Bleeding Rate for Second Six Months | 1.114 Bleeds per year | Standard Deviation 2.037 |
| BAX 855-High Level | Annualized Traumatic Bleeding Rate for Second Six Months | 0.912 Bleeds per year | Standard Deviation 2.647 |
Secondary
Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf)
Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 were reported.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: Pharmacokinetic analysis set (PKAS) included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf) | 2673 International units*hour per deciliter | Standard Deviation 877.3 |
| BAX 855-High Level | Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf) | 2659 International units*hour per deciliter | Standard Deviation 1041 |
| BAX 855-Non-randomized | Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf) | 2214 International units*hour per deciliter | Standard Deviation 355.8 |
Secondary
Blood Loss Per Participant in Case of Surgery
The intraoperative blood loss was measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Postoperatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. In cases where no drain was present, blood loss was determined by the surgeon's clinical judgment, as applicable or entered as not available. Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).
Time frame: Day 0 through discharge or 14 days post-surgery
Population: Surgery analysis set included all participants in the FAS (randomized to one of the two prophylactic arms and treated prophylactically for any period of time) who underwent some form of surgery (including dental) during the course of study participation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAX 855-Low Level | Blood Loss Per Participant in Case of Surgery | Intra-operative: Predicted Maximum | 20.800 Milliliters (mL) | Standard Deviation 18.089 |
| BAX 855-Low Level | Blood Loss Per Participant in Case of Surgery | Post-operative: Predicted Average | 10.000 Milliliters (mL) | Standard Deviation 9.129 |
| BAX 855-Low Level | Blood Loss Per Participant in Case of Surgery | Intra-operative: Predicted Average | 10.600 Milliliters (mL) | Standard Deviation 9.227 |
| BAX 855-Low Level | Blood Loss Per Participant in Case of Surgery | Post-operative: Predicted Maximum | 20.200 Milliliters (mL) | Standard Deviation 17.987 |
| BAX 855-Low Level | Blood Loss Per Participant in Case of Surgery | Intra-operative: Observed | 4.400 Milliliters (mL) | Standard Deviation 4.017 |
| BAX 855-High Level | Blood Loss Per Participant in Case of Surgery | Post-operative: Predicted Average | 145.000 Milliliters (mL) | Standard Deviation 320.967 |
| BAX 855-High Level | Blood Loss Per Participant in Case of Surgery | Post-operative: Predicted Maximum | 230.000 Milliliters (mL) | Standard Deviation 475.563 |
| BAX 855-High Level | Blood Loss Per Participant in Case of Surgery | Intra-operative: Observed | 72.000 Milliliters (mL) | Standard Deviation 160.741 |
| BAX 855-High Level | Blood Loss Per Participant in Case of Surgery | Intra-operative: Predicted Average | 65.833 Milliliters (mL) | Standard Deviation 139.29 |
| BAX 855-High Level | Blood Loss Per Participant in Case of Surgery | Intra-operative: Predicted Maximum | 128.333 Milliliters (mL) | Standard Deviation 231.79 |
| BAX 855-High Level | Blood Loss Per Participant in Case of Surgery | Post-operative: Observed | 820.000 Milliliters (mL) | — |
Secondary
Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score
HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the participant.
Time frame: Baseline, Month 12
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score | -1.9 Score on a scale | Standard Deviation 5.25 |
| BAX 855-High Level | Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score | -1.1 Score on a scale | Standard Deviation 7.77 |
Secondary
Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey
Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores.
Time frame: Baseline, Month 12 (completion or termination)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey | 3.551 Score on a scale | Standard Deviation 8.351 |
| BAX 855-High Level | Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey | 2.846 Score on a scale | Standard Deviation 8.658 |
Secondary
Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855
IR at Cmax of BAX 855 were reported.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855 | 2.227 (IU/dL) / (IU/kg) | Standard Deviation 0.5201 |
| BAX 855-High Level | Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855 | 2.231 (IU/dL) / (IU/kg) | Standard Deviation 0.5451 |
| BAX 855-Non-randomized | Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855 | 2.478 (IU/dL) / (IU/kg) | Standard Deviation 0.2016 |
Secondary
Incremental Recovery (IR) Over Time
Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg).
Time frame: Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination)
Population: PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAX 855-Low Level | Incremental Recovery (IR) Over Time | Month 6 | 2.62 IU/dL per IU/kg | Standard Deviation 0.585 |
| BAX 855-Low Level | Incremental Recovery (IR) Over Time | Month 9 | 2.65 IU/dL per IU/kg | Standard Deviation 0.511 |
| BAX 855-Low Level | Incremental Recovery (IR) Over Time | Month 3 | 2.68 IU/dL per IU/kg | Standard Deviation 0.515 |
| BAX 855-Low Level | Incremental Recovery (IR) Over Time | Month 10.5 | 2.61 IU/dL per IU/kg | Standard Deviation 0.467 |
| BAX 855-Low Level | Incremental Recovery (IR) Over Time | Month 7.5 | 2.53 IU/dL per IU/kg | Standard Deviation 0.36 |
| BAX 855-Low Level | Incremental Recovery (IR) Over Time | Completion/ Termination | 2.71 IU/dL per IU/kg | Standard Deviation 0.553 |
| BAX 855-Low Level | Incremental Recovery (IR) Over Time | Baseline | 2.68 IU/dL per IU/kg | Standard Deviation 0.513 |
| BAX 855-High Level | Incremental Recovery (IR) Over Time | Completion/ Termination | 2.73 IU/dL per IU/kg | Standard Deviation 0.689 |
| BAX 855-High Level | Incremental Recovery (IR) Over Time | Baseline | 2.70 IU/dL per IU/kg | Standard Deviation 0.45 |
| BAX 855-High Level | Incremental Recovery (IR) Over Time | Month 3 | 2.66 IU/dL per IU/kg | Standard Deviation 0.459 |
| BAX 855-High Level | Incremental Recovery (IR) Over Time | Month 6 | 2.76 IU/dL per IU/kg | Standard Deviation 0.552 |
| BAX 855-High Level | Incremental Recovery (IR) Over Time | Month 7.5 | 2.71 IU/dL per IU/kg | Standard Deviation 0.545 |
| BAX 855-High Level | Incremental Recovery (IR) Over Time | Month 9 | 2.68 IU/dL per IU/kg | Standard Deviation 0.545 |
| BAX 855-High Level | Incremental Recovery (IR) Over Time | Month 10.5 | 2.58 IU/dL per IU/kg | Standard Deviation 0.584 |
Secondary
Maximum Plasma Concentration (Cmax) of BAX 855
Cmax of BAX 855 were reported.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Maximum Plasma Concentration (Cmax) of BAX 855 | 132.54 International units per deciliter(IU/dL) | Standard Deviation 31.83 |
| BAX 855-High Level | Maximum Plasma Concentration (Cmax) of BAX 855 | 135.65 International units per deciliter(IU/dL) | Standard Deviation 33.1 |
| BAX 855-Non-randomized | Maximum Plasma Concentration (Cmax) of BAX 855 | 149.18 International units per deciliter(IU/dL) | Standard Deviation 12.86 |
Secondary
Mean Residence Time (MRT) of BAX 855
MRT of BAX 855 were reported.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: Pharmacokinetic analysis set (PKAS) included all participants in the SAS (participants enrolled who had at least 1 BAX 855 infusion) that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAX 855-Low Level | Mean Residence Time (MRT) of BAX 855 | 22.77 hour (h) |
| BAX 855-High Level | Mean Residence Time (MRT) of BAX 855 | 21.50 hour (h) |
| BAX 855-Non-randomized | Mean Residence Time (MRT) of BAX 855 | 16.18 hour (h) |
Secondary
Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution
The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.
Time frame: From start of study treatment up to bleed resolution (up to 12 months)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Excellent: Bleeds treated with 1 infusion | 50 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Excellent: Bleeds treated with 2 infusions | 4 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with 1 infusion | 47 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with 2 infusions | 19 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with 3 infusions | 6 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with >= 4 infusions | 3 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with 1 infusion | 3 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with 2 infusions | 5 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with 3 infusions | 7 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with >= 4 infusions | 3 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | None:Bleeds treated with 2 infusions | 1 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | None:Bleeds treated with 3 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | None:Bleeds treated with 2 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Excellent: Bleeds treated with 1 infusion | 34 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with 1 infusion | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Excellent: Bleeds treated with 2 infusions | 2 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with >= 4 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with 1 infusion | 24 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with 2 infusions | 1 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with 2 infusions | 7 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | None:Bleeds treated with 3 infusions | 1 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with 3 infusions | 3 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Fair:Bleeds treated with 3 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution | Good:Bleeds treated with >= 4 infusions | 6 Treated Bleeds |
Secondary
Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions
The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.
Time frame: 8 hours after study drug administration
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with >= 4 infusion | 2 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with 1 infusion | 19 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with 1 infusion | 2 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with 1 infusion | 36 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with 2 infusions | 7 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with 3 infusions | 0 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with 3 infusions | 4 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with 2 infusions | 16 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with >= 4 infusions | 1 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with 2 infusions | 3 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with 1 infusion | 1 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with 3 infusions | 5 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with 2 infusions | 1 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with 3 infusions | 0 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with >= 4 infusions | 0 Treated Bleeds |
| BAX 855-Low Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with >= 4 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with >= 4 infusions | 1 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with 1 infusion | 17 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with 2 infusions | 1 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with 3 infusions | 1 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Excellent: Bleeds treated with >= 4 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with 1 infusion | 16 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with 2 infusions | 6 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with 3 infusions | 1 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Good: Bleeds treated with >= 4 infusion | 2 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with 1 infusion | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with 2 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with 3 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | Fair: Bleeds treated with >= 4 infusions | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with 1 infusion | 0 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with 3 infusions | 1 Treated Bleeds |
| BAX 855-High Level | Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions | None: Bleeds treated with 2 infusions | 0 Treated Bleeds |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any unfavorable and unintended sign (an abnormal laboratory finding), symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the participant or required medical or surgical intervention to prevent any of the above outcomes.
Time frame: From start of study treatment up to 12 months (completion or termination)
Population: SAS included all participants enrolled who had at least one BAX 855 infusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BAX 855-Low Level | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with SAE | 5 Participants |
| BAX 855-Low Level | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with AE | 35 Participants |
| BAX 855-High Level | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with SAE | 5 Participants |
| BAX 855-High Level | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with AE | 38 Participants |
| BAX 855-Non-randomized | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with SAE | 0 Participants |
| BAX 855-Non-randomized | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with AE | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events
Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology.
Time frame: From start of study treatment up to 12 months (completion or termination)
Population: SAS included all participants enrolled who had at least one BAX 855 infusion.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BAX 855-Low Level | Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events | 2 Participants |
| BAX 855-High Level | Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events | 1 Participants |
| BAX 855-Non-randomized | Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events
Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature.
Time frame: From start of study treatment up to 12 months (completion or termination)
Population: SAS included all participants enrolled who had at least one BAX 855 infusion.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BAX 855-Low Level | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events | 0 Participants |
| BAX 855-High Level | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events | 0 Participants |
| BAX 855-Non-randomized | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events | 0 Participants |
Secondary
Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds
The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).
Time frame: Day 0 through discharge or 14 days post-surgery
Population: Surgery analysis set included all participants in the FAS (randomized to one of the two prophylactic arms and treated prophylactically for any period of time) who underwent some form of surgery (including dental) during the course of study participation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Good: Post-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Fair: Peri-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | None: Post-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Excellent: Post-operative | 3 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | None: Intra-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Good: Peri-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Good: Intra-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | None: Peri-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Fair: Intra-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Unknown: Intra-operative | 2 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Excellent: Peri-operative | 2 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Unknown: Post-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Fair: Post-operative | 0 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Unknown: Peri-operative | 1 Participants |
| BAX 855-Low Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Excellent: Intra-operative | 1 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Unknown: Peri-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Excellent: Intra-operative | 3 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Excellent: Post-operative | 4 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Excellent: Peri-operative | 4 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Good: Intra-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Good: Post-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Good: Peri-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Fair: Intra-operative | 1 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Fair: Post-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Fair: Peri-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | None: Intra-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | None: Post-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | None: Peri-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Unknown: Intra-operative | 0 Participants |
| BAX 855-High Level | Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds | Unknown: Post-operative | 0 Participants |
Secondary
Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein
Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here.
Time frame: From start of study treatment up to 12 months (completion or termination)
Population: SAS included all participants enrolled who had at least one BAX 855 infusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgG antibodies to FVIII | 0 Participants |
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgM antibodies to FVIII | 0 Participants |
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgG antibodies to PEG-FVIII | 2 Participants |
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgM antibodies to PEG-FVIII | 0 Participants |
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgG antibodies to PEG | 0 Participants |
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgM antibodies to PEG | 1 Participants |
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding Ig antibodies to CHO | 0 Participants |
| BAX 855-Low Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Inhibitory antibodies to FVIII | 0 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Inhibitory antibodies to FVIII | 1 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgG antibodies to FVIII | 3 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgG antibodies to PEG | 0 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgM antibodies to FVIII | 0 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding Ig antibodies to CHO | 0 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgG antibodies to PEG-FVIII | 7 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgM antibodies to PEG | 3 Participants |
| BAX 855-High Level | Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein | Binding IgM antibodies to PEG-FVIII | 1 Participants |
Secondary
Plasma Half-life (T1/2) of BAX 855
T1/2 of BAX 855 in plasma were reported.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAX 855-Low Level | Plasma Half-life (T1/2) of BAX 855 | 15.28 hour (h) |
| BAX 855-High Level | Plasma Half-life (T1/2) of BAX 855 | 14.66 hour (h) |
| BAX 855-Non-randomized | Plasma Half-life (T1/2) of BAX 855 | 10.97 hour (h) |
Secondary
Time to Maximum Concentration of BAX 855 in Plasma (Tmax)
Tmax of BAX 855 were reported.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAX 855-Low Level | Time to Maximum Concentration of BAX 855 in Plasma (Tmax) | 0.467 hour (h) |
| BAX 855-High Level | Time to Maximum Concentration of BAX 855 in Plasma (Tmax) | 0.475 hour (h) |
| BAX 855-Non-randomized | Time to Maximum Concentration of BAX 855 in Plasma (Tmax) | 0.417 hour (h) |
Secondary
Total Annualized Bleeding Rate for Second Six Months
Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.
Time frame: Day 183 to Day 364 (6 months)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants evaluable for this outcome at specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Total Annualized Bleeding Rate for Second Six Months | 3.603 Bleeds per year | Standard Deviation 7.512 |
| BAX 855-High Level | Total Annualized Bleeding Rate for Second Six Months | 1.649 Bleeds per year | Standard Deviation 3.433 |
Secondary
Total Body Clearance (CL) of BAX 855
Total body clearance of BAX 855 from blood by the kidney were reported.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Total Body Clearance (CL) of BAX 855 | 0.02477 Deciliters per kilogram * hour (dL/kg*h) | Standard Deviation 0.00958 |
| BAX 855-High Level | Total Body Clearance (CL) of BAX 855 | 0.02624 Deciliters per kilogram * hour (dL/kg*h) | Standard Deviation 0.009333 |
| BAX 855-Non-randomized | Total Body Clearance (CL) of BAX 855 | 0.02774 Deciliters per kilogram * hour (dL/kg*h) | Standard Deviation 0.004385 |
Secondary
Total Weight-adjusted Consumption of BAX 855
Total weight-adjusted consumption of BAX 855 were reported.
Time frame: From start of study treatment up to 12 months (completion or termination)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Total Weight-adjusted Consumption of BAX 855 | 3984.593 International units per kilogram (IU/kg) | Standard Deviation 1678.461 |
| BAX 855-High Level | Total Weight-adjusted Consumption of BAX 855 | 7030.714 International units per kilogram (IU/kg) | Standard Deviation 3208.049 |
Secondary
Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution
Infusions of BAX 855 that were required until bleed resolution were reported.
Time frame: From start of study treatment up to 12 months (completion or termination)
Population: FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here Number of participants analyzed refer to number of participants with treated bleeds.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution | 1.6 Infusions | Standard Deviation 1.19 |
| BAX 855-High Level | Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution | 1.6 Infusions | Standard Deviation 1.36 |
Secondary
Volume of Distribution at Steady State (Vss)
Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate.
Time frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
Population: PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAX 855-Low Level | Volume of Distribution at Steady State (Vss) | 0.5147 Deciliters per kilogram (dL/kg) | Standard Deviation 0.1209 |
| BAX 855-High Level | Volume of Distribution at Steady State (Vss) | 0.5158 Deciliters per kilogram (dL/kg) | Standard Deviation 0.1062 |
| BAX 855-Non-randomized | Volume of Distribution at Steady State (Vss) | 149.18 Deciliters per kilogram (dL/kg) | Standard Deviation 12.86 |