Haemophilia A
Conditions
Keywords
Recombinant factor VIII, Pediatric use
Brief summary
The primary objective was to evaluate the safety and efficacy of the treatment with BAY81-8973 for prophylaxis and treatment of breakthrough bleeds in children with severe hemophilia A. The secondary objectives were * To assess the safety and efficacy of BAY81-8973 during surgeries. * To assess incremental recovery of BAY81-8973. * To assess pharmacokinetic (PK) parameters in a subset of children (Previously treated patients \[PTPs\] and previously untreated patients \[PUPs\] / minimally treated patients \[MTPs\] - participation in PK sampling was voluntary and required consent).
Interventions
BIOLOGICALRecombinant Factor VIII (Kovaltry, BAY81-8973)
Main study: 25-50 IU/kg at least 2x/week for 6 months and at least 50 EDs, IV infusion; Extension study: 25-50 IU/kg at least 2x/week for at least 100 cumulative EDs (main study - Part A and extension study), IV infusion. Exposure day (ED): An ED is a unit of time (1 day) in which replacement treatment of Hemophilia is given to a patient.
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
0 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Male * PTPs (previously treated patients): aged \<= 12 years * PUPs (previously untreated patients) / MTPs (minimally treated patients): aged \< 6 years * Severe hemophilia A defined as \< 1% FVIII concentration (FVIII:C) * PTPs: \>= 50 exposure days (EDs) with any FVIII concentrate, no current evidence of inhibitory antibody, and no history of FVIII inhibitor formation * PUPs: no prior exposure to any FVIII product * MTPs: having no more than 3 EDs with any FVIII product, no current evidence of inhibitory antibody and no history of FVIII inhibitor formation
Exclusion criteria
* With another bleeding disorder that is different from Hemophilia A * With thrombocytopenia (platelet count \< 100 000/mm\^3) * Creatinine \> 2x upper limit of normal or Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) \> 5x upper limit of normal * Without a negative inhibitor testing at screening (except for PUPs) * Receiving chemotherapy, immune modulatory drugs, has received another investigational FVIII product within the last month, or received another experimental drug within the last 3 months * Requires any pre-medication to tolerate FVIII treatment * Known hypersensitivity to active substance, mouse, or hamster protein
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of Total Bleeds Within 48 h | Within 48 hours post infusion | Annualized number (mean +/- standard deviation) of total bleeds that occurred within 48 hours after all prophylaxis infusions (Part A: 6 months and at least 50 exposure days \[EDs\]; Part B: at least 50 EDs or until inhibitor development) was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other'). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hemostatic Control During Major and Minor Surgeries | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | For participants who underwent major or minor surgeries during the study, hemostasis during the surgeries was assessed as excellent, good, moderate or poor. Number of surgeries per assessment was summarized and reported. |
| Number of Participants With Inhibitor Development in Main Study | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | Number of participants with confirmed positive FVIII inhibitor titer (≥ 0.6 Bethesda unit \[BU/mL\]) during the main study was summarized and classified as participants developing low titer inhibitor (i.e. ≥ 0.6 to ≤ 5.0 BU/mL) and participants developing high titer inhibitor (i.e. \> 5.0 BU/mL). |
| Number of Participants With New Inhibitor Development in Extension Study | From start of extension study to at least 100 cumulative exposure days (EDs) (median 421 EDs; median 3.8 years) | Number of participants who had not developed an inhibitor during the main study but developed an inhibitor (confirmed positive FVIII inhibitor titer \[≥ 0.6 BU/mL\]) during the extension study was summarized and classified as participants developing low titer inhibitor (i.e. ≥ 0.6 to ≤ 5.0 BU/mL) and participants developing high titer inhibitor (i.e. \> 5.0 BU/mL). |
| Factor VIII Recovery Values | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | Incremental recovery of Factor VIII (FVIII) at 20-30 min after end of infusions was determined and mean recovery values were reported. |
| Consumption of Factor VIII in All Infusions | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | Factor VIII (FVIII) usage/consumption was summarized for all infusions. Consumption per participant's body weight per year was calculated and reported. |
| Annualized Number of Total Bleeds During Prophylaxis Treatment | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | Annualized number (mean +/- standard deviation) of total bleeds that occurred during prophylaxis treatment was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other'). |
| Consumption of FVIII in Infusions for the Treatment of Bleeds | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | Factor VIII (FVIII) usage/consumption was summarized for infusions used to treat breakthrough bleeds. Consumption per participant's body weight per year was calculated and reported. |
| Number of Infusions Per Bleed | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | The number of infusions used to treat a bleed was defined as the first infusion to treat the bleed plus all follow-up infusions to treat the same bleed, if any. The mean value of number of infusions for each bleed was calculated and reported. |
| Response to Treatment of Bleeds | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | Participants or caregivers were asked to assess the response to treatment of bleeds as excellent, good, moderate or poor. Percentage of bleeds per assessment was summarized and reported. |
| Half-life (t1/2) of BAY81-8973 in Plasma | Pre-infusion and until 24 hours post infusion | Half-life (t1/2) of BAY81-8973 in plasma was measured. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. |
| Consumption of FVIII in Infusions for Prophylaxis | Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months) | Factor VIII (FVIII) usage/consumption was summarized for prophylaxis infusions. Consumption per participant's body weight per year was calculated and reported. |
Countries
Argentina, Bulgaria, Canada, Denmark, Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Mexico, Norway, Poland, Romania, Russia, Spain, United States
Participant flow
Recruitment details
The study was conducted at multiple centers in 18 countries and consisted of: Part A - between 09-JUN-2011 (FPFV) and 02-JAN-2013 (LPLV); Part B - between 19-SEP-2012 (FPFV) and 09-SEP-2019 (LPLV); Extension study - between 21-DEC-2011 (FPFV) and 27-OCT-2020 (LPLV).
Pre-assignment details
Overall, 58 participants were screened in Part A, of which 7 participants were screening failures and 51 participants received the study drug; 52 participants were screened in Part B, of which 9 participants were screening failures and 43 participants received the study drug. 46 participants from Part A and 36 from Part B entered the optional extension study.
Participants by arm
| Arm | Count |
|---|---|
| Main Study - Part A: PTPs 0-<6 Years Previously treated patients (PTPs) aged below 6 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED) in main study - Part A. | 25 |
| Main Study - Part A: PTPs 6-12 Years Previously treated patients (PTPs) aged 6 to 12 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED) in main study - Part A. | 26 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years Previously untreated patients (PUPs) or minimally treated patients (MTPs, patients who had no more then 3 exposure days (EDs) with any FVIII product) received BAY81-8973 15-50 IU/kg at least 1x/week for 50 EDs or until inhibitor development in main study - Part B. | 43 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Study | Diagnosed with von Willebrand disease | 1 | 0 |
| Extension Study | Failure of ITI therapy | 0 | 3 |
| Extension Study | Family's decision | 0 | 1 |
| Extension Study | Incorrect visit planning | 0 | 1 |
| Extension Study | Inhibitor management | 0 | 2 |
| Extension Study | ITI therapy with marketed product | 0 | 1 |
| Extension Study | Long travel | 0 | 1 |
| Extension Study | Physician Decision | 0 | 1 |
| Extension Study | Withdrawal by Subject | 0 | 1 |
| Main Study | Adverse Event | 0 | 1 |
| Main Study | Inhibitor management | 0 | 17 |
| Main Study | Protocol Violation | 0 | 1 |
| Main Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Main Study - Part A: PTPs 0-<6 Years | Main Study - Part A: PTPs 6-12 Years | Main Study - Part B: PUPs/MTPs 0-<6 Years | Total |
|---|---|---|---|---|
| Age, Continuous | 3.8 Years STANDARD_DEVIATION 1.3 | 8.8 Years STANDARD_DEVIATION 1.8 | 1.1 Years STANDARD_DEVIATION 0.8 | 3.9 Years STANDARD_DEVIATION 3.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 9 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 25 Participants | 34 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 24 Participants | 24 Participants | 37 Participants | 85 Participants |
| Race/Ethnicity, Customized White, American Indian or Alaska native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 25 Participants | 26 Participants | 43 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 26 | 0 / 43 | 0 / 46 | 0 / 36 |
| other Total, other adverse events | 16 / 25 | 19 / 26 | 28 / 43 | 41 / 46 | 24 / 36 |
| serious Total, serious adverse events | 0 / 25 | 5 / 26 | 26 / 43 | 23 / 46 | 14 / 36 |
Outcome results
Primary
Annualized Number of Total Bleeds Within 48 h
Annualized number (median \[inter-quartile range (Q1-Q3)\]) of total bleeds that occurred within 48 hours after all prophylaxis infusions (Part A: 6 months and at least 50 exposure days \[EDs\]; Part B: at least 50 EDs or until inhibitor development) was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
Time frame: Within 48 hours post infusion
Population: Intent-to-treat (ITT) analysis set - main study: all participants of the SAF in main study who had infusion/bleeding data from the electronic patient diary (EPD)
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Annualized Number of Total Bleeds Within 48 h | 1.88 Bleeds | Inter-Quartile Range 0 |
| Main Study - Part A: PTPs 6-12 Years | Annualized Number of Total Bleeds Within 48 h | 0.00 Bleeds | Inter-Quartile Range 0 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Annualized Number of Total Bleeds Within 48 h | 0.0 Bleeds | Inter-Quartile Range 0 |
Primary
Annualized Number of Total Bleeds Within 48 h
Annualized number (mean +/- standard deviation) of total bleeds that occurred within 48 hours after all prophylaxis infusions (Part A: 6 months and at least 50 exposure days \[EDs\]; Part B: at least 50 EDs or until inhibitor development) was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
Time frame: Within 48 hours post infusion
Population: Intent-to-treat (ITT) analysis set - main study: all participants of the SAF in main study who had infusion/bleeding data from the electronic patient diary (EPD)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Annualized Number of Total Bleeds Within 48 h | 2.23 Bleeds | Standard Deviation 2.77 |
| Main Study - Part A: PTPs 6-12 Years | Annualized Number of Total Bleeds Within 48 h | 1.86 Bleeds | Standard Deviation 3.08 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Annualized Number of Total Bleeds Within 48 h | 1.9 Bleeds | Standard Deviation 3.3 |
Secondary
Annualized Number of Total Bleeds During Prophylaxis Treatment
Annualized number (median \[inter-quartile range (Q1-Q3)\]) of total bleeds that occurred during prophylaxis treatment was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Intent-to-treat (ITT) analysis set - main study: all participants of the SAF in main study who had infusion/bleeding data from the electronic patient diary (EPD)
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Annualized Number of Total Bleeds During Prophylaxis Treatment | 2.03 Bleeds | Inter-Quartile Range 0 |
| Main Study - Part A: PTPs 6-12 Years | Annualized Number of Total Bleeds During Prophylaxis Treatment | 0.93 Bleeds | Inter-Quartile Range 0 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Annualized Number of Total Bleeds During Prophylaxis Treatment | 4.7 Bleeds | Inter-Quartile Range 2.1 |
Secondary
Annualized Number of Total Bleeds During Prophylaxis Treatment
Annualized number (mean +/- standard deviation) of total bleeds that occurred during prophylaxis treatment was summarized and reported. Total bleeds: sum of spontaneous bleeds, trauma bleeds (only treated bleeds were classified as spontaneous or trauma), untreated bleeds and 'other' bleeds ('other' bleeds were infusions with reason given as 'other').
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Intent-to-treat (ITT) analysis set - main study: all participants of the SAF in main study who had infusion/bleeding data from the electronic patient diary (EPD)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Annualized Number of Total Bleeds During Prophylaxis Treatment | 4.16 Bleeds | Standard Deviation 5.02 |
| Main Study - Part A: PTPs 6-12 Years | Annualized Number of Total Bleeds During Prophylaxis Treatment | 3.37 Bleeds | Standard Deviation 5.01 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Annualized Number of Total Bleeds During Prophylaxis Treatment | 7.1 Bleeds | Standard Deviation 8.6 |
Secondary
Consumption of Factor VIII in All Infusions
Factor VIII (FVIII) usage/consumption was summarized for all infusions. Consumption per participant's body weight per year was calculated and reported.
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Intent-to-treat (ITT) analysis set - main study: all participants of the SAF in main study who had infusion/bleeding data from the electronic patient diary (EPD)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Consumption of Factor VIII in All Infusions | 5499.1 international units/kilogram/year | Standard Deviation 1996.2 |
| Main Study - Part A: PTPs 6-12 Years | Consumption of Factor VIII in All Infusions | 4679.1 international units/kilogram/year | Standard Deviation 1688.7 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Consumption of Factor VIII in All Infusions | 2195.8 international units/kilogram/year | Standard Deviation 1903.6 |
Secondary
Consumption of FVIII in Infusions for Prophylaxis
Factor VIII (FVIII) usage/consumption was summarized for prophylaxis infusions. Consumption per participant's body weight per year was calculated and reported.
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Participants in intent-to-treat (ITT) analysis set in main study with at least one dose of prophylaxis treatment with study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Consumption of FVIII in Infusions for Prophylaxis | 5224.8 international units/kilogram/year | Standard Deviation 1760.2 |
| Main Study - Part A: PTPs 6-12 Years | Consumption of FVIII in Infusions for Prophylaxis | 4492.7 international units/kilogram/year | Standard Deviation 1667.6 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Consumption of FVIII in Infusions for Prophylaxis | 1486.6 international units/kilogram/year | Standard Deviation 963.3 |
Secondary
Consumption of FVIII in Infusions for the Treatment of Bleeds
Factor VIII (FVIII) usage/consumption was summarized for infusions used to treat breakthrough bleeds. Consumption per participant's body weight per year was calculated and reported.
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Participants in intent-to-treat (ITT) analysis set in main study with at least one bleed treated with study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Consumption of FVIII in Infusions for the Treatment of Bleeds | 457.07 international units/kilogram/year | Standard Deviation 526.87 |
| Main Study - Part A: PTPs 6-12 Years | Consumption of FVIII in Infusions for the Treatment of Bleeds | 391.64 international units/kilogram/year | Standard Deviation 219.61 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Consumption of FVIII in Infusions for the Treatment of Bleeds | 835.4 international units/kilogram/year | Standard Deviation 1926.4 |
Secondary
Factor VIII Recovery Values
Incremental recovery of Factor VIII (FVIII) at 20-30 min after end of infusions was determined and mean recovery values were reported.
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Participants in intent-to-treat (ITT) analysis set in main study with valid FVIII recovery values
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Factor VIII Recovery Values | Participants without inhibitor | 1.63 International unit (IU)/dL per IU/kg | Standard Deviation 0.31 |
| Main Study - Part A: PTPs 6-12 Years | Factor VIII Recovery Values | Participants without inhibitor | 1.72 International unit (IU)/dL per IU/kg | Standard Deviation 0.46 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Factor VIII Recovery Values | Participants without inhibitor | 1.76 International unit (IU)/dL per IU/kg | Standard Deviation 0.55 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Factor VIII Recovery Values | Participants with low titer inhibitor | 0.86 International unit (IU)/dL per IU/kg | Standard Deviation 0.56 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Factor VIII Recovery Values | Participants with high titer inhibitor | 0.38 International unit (IU)/dL per IU/kg | Standard Deviation 0.42 |
Secondary
Half-life (t1/2) of BAY81-8973 in Plasma
Half-life (t1/2) of BAY81-8973 in plasma was measured. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Time frame: Pre-infusion and until 24 hours post infusion
Population: Participants in PK analysis set (PKS) - A with evaluable data for this endpoint (PKS - A: all participants who entered main study - Part A and received at least one infusion of study medication with evaluable pharmacokinetic data)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Half-life (t1/2) of BAY81-8973 in Plasma | 13.2 Hours | Geometric Coefficient of Variation 39.7 |
| Main Study - Part A: PTPs 6-12 Years | Half-life (t1/2) of BAY81-8973 in Plasma | 12.1 Hours | Geometric Coefficient of Variation 16.3 |
Secondary
Hemostatic Control During Major and Minor Surgeries
For participants who underwent major or minor surgeries during the study, hemostasis during the surgeries was assessed as excellent, good, moderate or poor. Number of surgeries per assessment was summarized and reported.
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Participants in SAF in main study who underwent major or minor surgeries during the study
| Arm | Measure | Group | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Good | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Excellent | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Moderate | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Moderate | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Poor | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Not available | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Poor | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Not available | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Good | 0 Surgeries |
| Main Study - Part A: PTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Excellent | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Good | 1 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Poor | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Moderate | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Moderate | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Excellent | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Not available | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Poor | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Excellent | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Not available | 0 Surgeries |
| Main Study - Part A: PTPs 6-12 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Good | 0 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Not available | 0 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Excellent | 3 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Good | 1 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Moderate | 0 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Poor | 0 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Minor surgery | Not available | 1 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Excellent | 0 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Good | 1 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Moderate | 0 Surgeries |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Hemostatic Control During Major and Minor Surgeries | Major surgery | Poor | 0 Surgeries |
Secondary
Number of Infusions Per Bleed
The number of infusions used to treat a bleed was defined as the first infusion to treat the bleed plus all follow-up infusions to treat the same bleed, if any. The mean value of number of infusions for each bleed was calculated and reported.
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Participants in intent-to-treat (ITT) analysis set in main study with at least one bleed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Number of Infusions Per Bleed | 1.3 Infusions | Standard Deviation 1.8 |
| Main Study - Part A: PTPs 6-12 Years | Number of Infusions Per Bleed | 1.4 Infusions | Standard Deviation 1.7 |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Number of Infusions Per Bleed | 1.7 Infusions | Standard Deviation 8.7 |
Secondary
Number of Participants With Inhibitor Development in Main Study
Number of participants with confirmed positive FVIII inhibitor titer (≥ 0.6 Bethesda unit \[BU/mL\]) during the main study was summarized and classified as participants developing low titer inhibitor (i.e. ≥ 0.6 to ≤ 5.0 BU/mL) and participants developing high titer inhibitor (i.e. \> 5.0 BU/mL).
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Participants in main study - safety analysis set (SAF, all participants who entered Study Part A or Part B and received at least one infusion of study medication) with inhibitor measurements done
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Number of Participants With Inhibitor Development in Main Study | Low titer inhibitor | 0 Participants |
| Main Study - Part A: PTPs 0-<6 Years | Number of Participants With Inhibitor Development in Main Study | High titer inhibitor | 0 Participants |
| Main Study - Part A: PTPs 6-12 Years | Number of Participants With Inhibitor Development in Main Study | Low titer inhibitor | 0 Participants |
| Main Study - Part A: PTPs 6-12 Years | Number of Participants With Inhibitor Development in Main Study | High titer inhibitor | 0 Participants |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Number of Participants With Inhibitor Development in Main Study | Low titer inhibitor | 6 Participants |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Number of Participants With Inhibitor Development in Main Study | High titer inhibitor | 17 Participants |
Secondary
Number of Participants With New Inhibitor Development in Extension Study
Number of participants who had not developed an inhibitor during the main study but developed an inhibitor (confirmed positive FVIII inhibitor titer \[≥ 0.6 BU/mL\]) during the extension study was summarized and classified as participants developing low titer inhibitor (i.e. ≥ 0.6 to ≤ 5.0 BU/mL) and participants developing high titer inhibitor (i.e. \> 5.0 BU/mL).
Time frame: From start of extension study to at least 100 cumulative exposure days (EDs) (median 421 EDs; median 3.8 years)
Population: All participants who entered the extension study and had not developed inhibitors during the main study Part A or Part B
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Number of Participants With New Inhibitor Development in Extension Study | Low titer inhibitor (incl. false-positive) | 1 Participants |
| Main Study - Part A: PTPs 0-<6 Years | Number of Participants With New Inhibitor Development in Extension Study | High titer inhibitor | 0 Participants |
| Main Study - Part A: PTPs 6-12 Years | Number of Participants With New Inhibitor Development in Extension Study | Low titer inhibitor (incl. false-positive) | 0 Participants |
| Main Study - Part A: PTPs 6-12 Years | Number of Participants With New Inhibitor Development in Extension Study | High titer inhibitor | 0 Participants |
Secondary
Response to Treatment of Bleeds
Participants or caregivers were asked to assess the response to treatment of bleeds as excellent, good, moderate or poor. Percentage of bleeds per assessment was summarized and reported.
Time frame: Part A: 6 months and at least 50 exposure days (EDs) (median 73 EDs; median 6 months); Part B: at least 50 EDs or until inhibitor development (median 46 EDs; median 8 months)
Population: Participants in intent-to-treat (ITT) analysis set in main study with at least one bleed
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Main Study - Part A: PTPs 0-<6 Years | Response to Treatment of Bleeds | Excellent | 20 Bleeds assessed for the response |
| Main Study - Part A: PTPs 0-<6 Years | Response to Treatment of Bleeds | Good | 23 Bleeds assessed for the response |
| Main Study - Part A: PTPs 0-<6 Years | Response to Treatment of Bleeds | Moderate | 0 Bleeds assessed for the response |
| Main Study - Part A: PTPs 0-<6 Years | Response to Treatment of Bleeds | Poor | 1 Bleeds assessed for the response |
| Main Study - Part A: PTPs 6-12 Years | Response to Treatment of Bleeds | Poor | 0 Bleeds assessed for the response |
| Main Study - Part A: PTPs 6-12 Years | Response to Treatment of Bleeds | Excellent | 12 Bleeds assessed for the response |
| Main Study - Part A: PTPs 6-12 Years | Response to Treatment of Bleeds | Moderate | 7 Bleeds assessed for the response |
| Main Study - Part A: PTPs 6-12 Years | Response to Treatment of Bleeds | Good | 18 Bleeds assessed for the response |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Response to Treatment of Bleeds | Poor | 6 Bleeds assessed for the response |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Response to Treatment of Bleeds | Good | 56 Bleeds assessed for the response |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Response to Treatment of Bleeds | Moderate | 16 Bleeds assessed for the response |
| Main Study - Part B: PUPs/MTPs 0-<6 Years | Response to Treatment of Bleeds | Excellent | 27 Bleeds assessed for the response |