Hemophilia A
Conditions
Brief summary
The goal of this study is to gather more information on safety and efficacy of Kovaltry for the prevention and treatment of bleeds in Chinese children, adolescents/adults with severe hemophilia A. In addition, pharmacokinetic parameters of Kovaltry will be assessed in a subset of patients.
Interventions
BIOLOGICALRecombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 1
25 to 50 IU of Kovaltry per kg body weight given via intravenous (IV) infusion twice weekly, three times weekly, or every other day according to individual requirements for 6 months. The dose decisions are at the discretion of the investigator.
BIOLOGICALRecombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 2
12 year-old: 25 to 50 IU of Kovaltry per kg body weight given via intravenous (IV) infusion twice weekly, three times weekly, or every other day for 6 months. \>12 year-old: 20 to 40 IU of Kovaltry per kg of body weight given via intravenous (IV) infusion two or three times per week for 6 months. The dose decisions are at the discretion of the investigator.
BIOLOGICALRecombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 3
15 to 50 IU of Kovaltry per kg body weight (minimum dose: 250 IU) given via intravenous (IV) infusions at least once a week. The dose decisions are at the discretion of the investigator.
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
0 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Part A (PTPs): * Chinese participants with severe hemophilia A (defined as Factor VIII (FVIII): C \< 1% with one- stage clotting assay documented at the time of screening) * Currently receiving on-demand or any type of prophylaxis treatment regimen with any FVIII product * For participants \< 12 years of age, ≥ 50 exposure days (ED); for participants ≥ 12 to 65 years of age, ≥ 150 ED with any FVIII product * No current evidence of inhibitor * No history of FVIII inhibitor formation * Signed informed consent Part B (PUPs/MTPs): * Participants must be \<6 years of age at the time of their parent or legal representative's signature of informed consent on the participant's behalf * Chinese participants with severe hemophilia A (defined as Factor VIII (FVIII): C \< 1% with one- stage clotting assay documented at the time of screening) * PUPs must have no previous exposure to any FVIII product. MTPs must have no more than 1 ED with any purified FVIII concentrate or 3 exposures with FFP or cryoprecipitate. * MTPs must have no current evidence of inhibitor antibody as measured by the Nijmegen-modified Bethesda assay (\<0.6 BU/mL) in 2 consecutive samples and must have absence of clinical signs or symptoms of decreased response to FVIII administration. Testing for the 2 negative samples must be performed by the central laboratory at least 1 week but not more than 2 weeks apart. Participants may not receive FVIII product within 72 hours prior to the collection of samples for inhibitor testing. * PUPs and MTPs must observe a 6-month washout period if they have received subcutaneous factor substitution therapy (emicizumab). * PUPs may be included if they will receive their first FVIII dose with KOVALTRY for treatment of first bleed and agree to start prophylaxis as part of their care. MTPs may be included if they agree to start prophylaxis as part of their care.
Exclusion criteria
Part A (PTPs): * Any other bleeding disease that is different from hemophilia A (e.g. von Willebrand disease, hemophilia B) * Platelet count \< 100 000/mm\^3 * Impaired renal function (serum creatinine \> 2.0 mg/dL) or active liver disease (alanine aminotransferase/aspartate aminotransferase \[ALT/AST\] \> 5x ULN) * Human immunodeficiency virus (HIV) positive with an absolute CD4 lymphocyte cell count \< 250 cells/μL * Known hypersensitivity to the active substance, mouse or hamster protein * Receiving chemotherapy, immune modulatory drugs other than anti-retroviral chemotherapy, or chronic use of oral or intravenous (IV) corticosteroids (\> 14 days) within the last 3 months. * Requiring any pre-medication to tolerate FVIII infusions (e.g. antihistamines) * Currently participating in another investigational drug study, or having previously participated in a clinical study involving an investigational drug within 30 days of signing informed consent or participated in completed interventional clinical studies with BAY81-8973 (Kovaltry) * Planned major surgery, defined as surgery with respiratory assistance and/or general anesthesia Part B (PUPs/MTPs): * Any other bleeding disease that is different from hemophilia A (e.g. von Willebrand disease, hemophilia B) * Platelet count \< 100 000/mm\^3 * Impaired renal function (serum creatinine \>2× upper limit of normal \[ULN\]) or active liver disease (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \>5× ULN) based on screening laboratory assessments * MTPs with history of FVIII inhibitor formation * Known hypersensitivity to the active substance, mouse or hamster protein * First treatment with KOVALTRY for high risk bleeding situations (e.g., surgery, intracranial bleed) or requiring intensive or prolonged treatment * Receiving chemotherapy, immune modulatory drugs other than anti-retroviral chemotherapy, or chronic use of oral or intravenous (IV) corticosteroids (\> 14 days) within the last 3 months. * Requiring any pre-medication to tolerate FVIII infusions (e.g. antihistamines) * Currently participating in another investigational drug study, or having previously participated in a clinical study involving an investigational drug within 30 days of signing informed consent or participated in completed interventional clinical studies with BAY 81-8973 (Kovaltry) * Planned major surgery, defined as surgery with respiratory assistance and/or general anesthesia * Unable to tolerate volume of blood draws required for study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part A | Up to 6 months | Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery. |
| Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part B | Up to 48 hours post-infusion during 6 months | Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Half-life (t1/2) of FVIII in Plasma in Part A | at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years | For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit. |
| Maximum Observed Concentration of FVIII in Plasma (Cmax) in Part A | at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years | For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit. |
| Area Under the Plasma Concentration of FVIII Versus Time Curve From Zero to Infinity (AUC) in Part A | at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years | For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit. |
| Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part A | Up to 48 hours post-infusion during 6 months | Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery. |
| Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part B | Up to 51 exposure days | Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery. |
| Number of Infusions Per Bleeding Episode | Part A: up to 6 months; Part B: up to 51 exposure days | The mean value of number of infusions for the treatment of one bleed to achieve hemostasis is reported. |
| Number of Surgeries Per Physician's Assessment of Adequacy of Hemostasis in Minor Surgery | Part A: up to 6 months; Part B: up to 51 exposure days | For participants who underwent minor surgeries during the study, investigators were ask to assess the adequacy of hemostasis during the surgeries as excellent, good, moderate or poor. Number of surgeries per assessment is reported. |
| FVIII In-vivo Recovery in Part B | At baseline, Visit 6 (ED 20), unscheduled visit and final visit, up to 51 exposure days | Incremental recovery of Factor VIII (FVIII) was determined by collecting blood samples pre-infusion and 15-30 minutes after the end of the infusion. Mean recovery values at different time points are reported. |
| Factor VIII Inhibitor Development by the Nijmegen Bethesda Assay | Part A: up to 6 months; Part B: up to 51 exposure days | Number of participants who developed a positive Factor VIII (FVIII) inhibitor level (≥0.6 Bethesda unit \[BU/mL\]) during the study is reported. |
| Number of Participants With Treatment-emergent Adverse Events | Part A: up to 6 months; Part B: up to 51 exposure days | An adverse event (AE) was any untoward medical occurrence in a participant, associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect; another medical important serious event as judged by the investigator. AEs or SAEs were considered to be treatment emergent (TEAEs or TESAEs) if they started after the first KOVALTRY infusion and up to 3 days after the last dose. |
| FVIII In-vivo Recovery in Part A | At baseline, Month 2 and final visit, up to 6 months | Incremental recovery of Factor VIII (FVIII) was determined by collecting blood samples pre-infusion and 15-30 minutes after the end of the infusion. Mean recovery values at different time points are reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Part A: up to 6 months; Part B: up to 51 exposure days | Participants or caregivers were asked to assess the response to treatment of bleeds as excellent, good, moderate or poor. Number of bleeds per assessment is reported. |
| Number of Participants Without Bleeding Episode | During prophylaxis treatment in Part A: up to 6 months; Part B: up to 51 exposure days | Number of participants who did not experience any bleed during the prophylaxis treatment period or within 48 hours of previous prophylaxis infusion is reported. |
Countries
China
Participant flow
Recruitment details
The Part A of study was conducted in multicenter in China between 22 SEP 2020 and 04 JAN 2022. The Part B of study was conducted in multicenter in China between 07 SEP 2021 and 15 MAR 2024.
Pre-assignment details
A total of 44 subjects were enrolled in Part A of the study. Of these, 2 subjects did not pass screening and 42 subjects participated in Part A. A total of 3 participants were enrolled in Part B of the study, and all of them passed screening.
Participants by arm
| Arm | Count |
|---|---|
| Part A: PTPs <12 Years Previously treated severe hemophilia A patients (PTPs) aged below 12 years received KOVALTRY prophylaxis and treatment. | 30 |
| Part A: PTPs ≥12 Years Previously treated severe hemophilia A patients (PTPs) aged 12 to 65 years received KOVALTRY for prophylaxis and treatment. | 12 |
| Part B: PUPs <6 Years Previously untreated severe hemophilia A patients (PUPs) aged below 6 years of age received KOVALTRY for prophylaxis and treatment. | 2 |
| Part B: MTPs <6 Years Minimally treated severe hemophilia A patients (MTPs) aged below 6 years received KOVALTRY for prophylaxis and treatment. | 1 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Patient/Guardian Decision | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A: PTPs <12 Years | Total | Part B: MTPs <6 Years | Part B: PUPs <6 Years | Part A: PTPs ≥12 Years |
|---|---|---|---|---|---|
| Age, Customized Adolescents (12-17 years) | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Age, Customized Adults (18-64 years) | 0 Participants | 7 Participants | 0 Participants | 0 Participants | 7 Participants |
| Age, Customized Children (2-11 years) | 30 Participants | 32 Participants | 1 Participants | 1 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 30 Participants | 45 Participants | 1 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 45 Participants | 1 Participants | 2 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 30 | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 3 / 12 | 8 / 30 | 1 / 2 | 1 / 1 |
| serious Total, serious adverse events | 0 / 12 | 2 / 30 | 0 / 2 | 0 / 1 |
Outcome results
Primary
Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part A
Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.
Time frame: Up to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part A | 1.86 Bleed per year | Standard Deviation 2.54 |
| Part A: PTPs <12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part A | 3.38 Bleed per year | Standard Deviation 4.17 |
Primary
Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part B
Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.
Time frame: Up to 48 hours post-infusion during 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part B | 0.00 Bleed per year | Standard Deviation 0 |
| Part A: PTPs <12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part B | 0.00 Bleed per year | Standard Deviation 0 |
Secondary
Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part B
Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred during the prophylaxis treatment period is reported for previously untreated/minimally treated patients (PUPs/MTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.
Time frame: Up to 51 exposure days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part B | 1.13 Bleed per year | Standard Deviation 1.6 |
| Part A: PTPs <12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes During Prophylaxis Treatment in Part B | 2.05 Bleed per year | Standard Deviation 0 |
Secondary
Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part A
Annualized number (mean +/- standard deviation) of all bleeding episodes that occurred within 48 hours of previous prophylaxis infusion is reported for previously treated patients (PTPs). All bleeding episodes: sum of spontaneous bleeds and trauma bleeds exclude bleeding due to surgery.
Time frame: Up to 48 hours post-infusion during 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part A | 2.26 Bleed per year | Standard Deviation 3.1 |
| Part A: PTPs <12 Years | Annualized Bleeding Rate (ABR) of All Bleeding Episodes Within 48 Hours of Previous Prophylaxis Infusion in Part A | 1.36 Bleed per year | Standard Deviation 2.19 |
Secondary
Area Under the Plasma Concentration of FVIII Versus Time Curve From Zero to Infinity (AUC) in Part A
For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit.
Time frame: at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years
Population: The number of analyzed participants in group Part A: PTPs \<12 years for category Final Visit/ Early is 0 because no evaluation was performed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: PTPs ≥12 Years | Area Under the Plasma Concentration of FVIII Versus Time Curve From Zero to Infinity (AUC) in Part A | Baseline | 1292.97 h*IU/dL | Geometric Coefficient of Variation 22.87 |
| Part A: PTPs <12 Years | Area Under the Plasma Concentration of FVIII Versus Time Curve From Zero to Infinity (AUC) in Part A | Baseline | 1519.38 h*IU/dL | Geometric Coefficient of Variation 32.38 |
| Part A: PTPs <12 Years | Area Under the Plasma Concentration of FVIII Versus Time Curve From Zero to Infinity (AUC) in Part A | Final Visit/ Early Termination | 1559.29 h*IU/dL | Geometric Coefficient of Variation 26.16 |
Secondary
Factor VIII Inhibitor Development by the Nijmegen Bethesda Assay
Number of participants who developed a positive Factor VIII (FVIII) inhibitor level (≥0.6 Bethesda unit \[BU/mL\]) during the study is reported.
Time frame: Part A: up to 6 months; Part B: up to 51 exposure days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: PTPs ≥12 Years | Factor VIII Inhibitor Development by the Nijmegen Bethesda Assay | 0 Participants |
| Part A: PTPs <12 Years | Factor VIII Inhibitor Development by the Nijmegen Bethesda Assay | 0 Participants |
| Part B: PUPs <6 Years | Factor VIII Inhibitor Development by the Nijmegen Bethesda Assay | 0 Participants |
| Part B: MTPs <6 Years | Factor VIII Inhibitor Development by the Nijmegen Bethesda Assay | 0 Participants |
Secondary
FVIII In-vivo Recovery in Part A
Incremental recovery of Factor VIII (FVIII) was determined by collecting blood samples pre-infusion and 15-30 minutes after the end of the infusion. Mean recovery values at different time points are reported.
Time frame: At baseline, Month 2 and final visit, up to 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: PTPs ≥12 Years | FVIII In-vivo Recovery in Part A | Baseline | 1.82 IU/dL per IU/kg | Standard Deviation 0.26 |
| Part A: PTPs ≥12 Years | FVIII In-vivo Recovery in Part A | Month 2 | 1.86 IU/dL per IU/kg | Standard Deviation 0.32 |
| Part A: PTPs ≥12 Years | FVIII In-vivo Recovery in Part A | Final visit | 1.85 IU/dL per IU/kg | Standard Deviation 0.33 |
| Part A: PTPs <12 Years | FVIII In-vivo Recovery in Part A | Baseline | 2.03 IU/dL per IU/kg | Standard Deviation 0.46 |
| Part A: PTPs <12 Years | FVIII In-vivo Recovery in Part A | Month 2 | 2.12 IU/dL per IU/kg | Standard Deviation 0.42 |
| Part A: PTPs <12 Years | FVIII In-vivo Recovery in Part A | Final visit | 2.06 IU/dL per IU/kg | Standard Deviation 0.37 |
Secondary
FVIII In-vivo Recovery in Part B
Incremental recovery of Factor VIII (FVIII) was determined by collecting blood samples pre-infusion and 15-30 minutes after the end of the infusion. Mean recovery values at different time points are reported.
Time frame: At baseline, Visit 6 (ED 20), unscheduled visit and final visit, up to 51 exposure days
Population: The Part B PUP participant who discontinued didn't have any measurements for recovery calculation and therefore wasn't included in recovery analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: PTPs ≥12 Years | FVIII In-vivo Recovery in Part B | Baseline (Unscheduled visit for PUP) | 1.90 IU/dL per IU/kg | Standard Deviation 0 |
| Part A: PTPs ≥12 Years | FVIII In-vivo Recovery in Part B | Visit 6 (ED 20) | 0.91 IU/dL per IU/kg | Standard Deviation 0 |
| Part A: PTPs ≥12 Years | FVIII In-vivo Recovery in Part B | Final visit | 1.55 IU/dL per IU/kg | Standard Deviation 0 |
| Part A: PTPs <12 Years | FVIII In-vivo Recovery in Part B | Baseline (Unscheduled visit for PUP) | 1.86 IU/dL per IU/kg | Standard Deviation 0 |
| Part A: PTPs <12 Years | FVIII In-vivo Recovery in Part B | Visit 6 (ED 20) | 1.22 IU/dL per IU/kg | Standard Deviation 0 |
Secondary
Half-life (t1/2) of FVIII in Plasma in Part A
For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit.
Time frame: at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years
Population: The number of analyzed participants in group Part A: PTPs \<12 years for category Final Visit/ Early is 0 because no evaluation was performed
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: PTPs ≥12 Years | Half-life (t1/2) of FVIII in Plasma in Part A | Baseline | 10.3655 Hour | Geometric Coefficient of Variation 21.22 |
| Part A: PTPs <12 Years | Half-life (t1/2) of FVIII in Plasma in Part A | Baseline | 11.8605 Hour | Geometric Coefficient of Variation 19.25 |
| Part A: PTPs <12 Years | Half-life (t1/2) of FVIII in Plasma in Part A | Final Visit/ Early Termination | 11.2630 Hour | Geometric Coefficient of Variation 17.29 |
Secondary
Maximum Observed Concentration of FVIII in Plasma (Cmax) in Part A
For the assessment, participants were administered a dose of 50 IU/kg KOVALTRY. Participants must have no signs or symptoms of an acute bleeding episode. For participants below 12 years, the evaluation was only performed once at baseline. For adolescents/adult participants 12 years or older, the evaluation was performed twice at baseline and at final visit.
Time frame: at baseline for PTPs < 12 Years and at baseline and final visit (month 6) for PTPs >= 12 Years
Population: The number of analyzed participants in group Part A: PTPs \<12 years for category Final Visit/ Early is 0 because no evaluation was performed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: PTPs ≥12 Years | Maximum Observed Concentration of FVIII in Plasma (Cmax) in Part A | Baseline | 95.20 IU/dL | Geometric Coefficient of Variation 15.24 |
| Part A: PTPs <12 Years | Maximum Observed Concentration of FVIII in Plasma (Cmax) in Part A | Baseline | 114.64 IU/dL | Geometric Coefficient of Variation 15.77 |
| Part A: PTPs <12 Years | Maximum Observed Concentration of FVIII in Plasma (Cmax) in Part A | Final Visit/ Early Termination | 115.95 IU/dL | Geometric Coefficient of Variation 17.47 |
Secondary
Number of Infusions Per Bleeding Episode
The mean value of number of infusions for the treatment of one bleed to achieve hemostasis is reported.
Time frame: Part A: up to 6 months; Part B: up to 51 exposure days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Number of Infusions Per Bleeding Episode | 1.78 Infusion | Standard Deviation 2.28 |
| Part A: PTPs <12 Years | Number of Infusions Per Bleeding Episode | 1.45 Infusion | Standard Deviation 1.29 |
| Part B: PUPs <6 Years | Number of Infusions Per Bleeding Episode | 14.00 Infusion | Standard Deviation 0 |
| Part B: MTPs <6 Years | Number of Infusions Per Bleeding Episode | 1.00 Infusion | Standard Deviation 0 |
Secondary
Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) was any untoward medical occurrence in a participant, associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect; another medical important serious event as judged by the investigator. AEs or SAEs were considered to be treatment emergent (TEAEs or TESAEs) if they started after the first KOVALTRY infusion and up to 3 days after the last dose.
Time frame: Part A: up to 6 months; Part B: up to 51 exposure days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 13 Participants |
| Part A: PTPs ≥12 Years | Number of Participants With Treatment-emergent Adverse Events | Any TESAE | 2 Participants |
| Part A: PTPs ≥12 Years | Number of Participants With Treatment-emergent Adverse Events | Any study drug-related TEAE | 1 Participants |
| Part A: PTPs ≥12 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Mild | 10 Participants |
| Part A: PTPs ≥12 Years | Number of Participants With Treatment-emergent Adverse Events | TEAE with outcome death | 0 Participants |
| Part A: PTPs ≥12 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Moderate | 2 Participants |
| Part A: PTPs ≥12 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Severe | 1 Participants |
| Part A: PTPs <12 Years | Number of Participants With Treatment-emergent Adverse Events | Any TESAE | 0 Participants |
| Part A: PTPs <12 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Severe | 0 Participants |
| Part A: PTPs <12 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Moderate | 0 Participants |
| Part A: PTPs <12 Years | Number of Participants With Treatment-emergent Adverse Events | Any study drug-related TEAE | 0 Participants |
| Part A: PTPs <12 Years | Number of Participants With Treatment-emergent Adverse Events | TEAE with outcome death | 0 Participants |
| Part A: PTPs <12 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Mild | 3 Participants |
| Part A: PTPs <12 Years | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 3 Participants |
| Part B: PUPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Severe | 0 Participants |
| Part B: PUPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 1 Participants |
| Part B: PUPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Mild | 1 Participants |
| Part B: PUPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Moderate | 0 Participants |
| Part B: PUPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Any study drug-related TEAE | 0 Participants |
| Part B: PUPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Any TESAE | 0 Participants |
| Part B: PUPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | TEAE with outcome death | 0 Participants |
| Part B: MTPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Moderate | 0 Participants |
| Part B: MTPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | TEAE with outcome death | 0 Participants |
| Part B: MTPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Any TESAE | 0 Participants |
| Part B: MTPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Mild | 1 Participants |
| Part B: MTPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 1 Participants |
| Part B: MTPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Any study drug-related TEAE | 0 Participants |
| Part B: MTPs <6 Years | Number of Participants With Treatment-emergent Adverse Events | Maximum intensity for any TEAE - Severe | 0 Participants |
Secondary
Number of Surgeries Per Physician's Assessment of Adequacy of Hemostasis in Minor Surgery
For participants who underwent minor surgeries during the study, investigators were ask to assess the adequacy of hemostasis during the surgeries as excellent, good, moderate or poor. Number of surgeries per assessment is reported.
Time frame: Part A: up to 6 months; Part B: up to 51 exposure days
Population: Participants with surgery
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Number of Surgeries Per Physician's Assessment of Adequacy of Hemostasis in Minor Surgery | Total minor surgeries | 2 surgery |
| Part A: PTPs ≥12 Years | Number of Surgeries Per Physician's Assessment of Adequacy of Hemostasis in Minor Surgery | Surgeries with EXCELLENT adequacy of hemostasis | 2 surgery |
| Part A: PTPs <12 Years | Number of Surgeries Per Physician's Assessment of Adequacy of Hemostasis in Minor Surgery | Total minor surgeries | 2 surgery |
| Part A: PTPs <12 Years | Number of Surgeries Per Physician's Assessment of Adequacy of Hemostasis in Minor Surgery | Surgeries with EXCELLENT adequacy of hemostasis | 2 surgery |
Other Pre-specified
Number of Bleeds Per Assessment of Response to Treatment of Bleeds
Participants or caregivers were asked to assess the response to treatment of bleeds as excellent, good, moderate or poor. Number of bleeds per assessment is reported.
Time frame: Part A: up to 6 months; Part B: up to 51 exposure days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Total bleeds | 51 Bleeds |
| Part A: PTPs ≥12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds without response assessment to treatment | 7 Bleeds |
| Part A: PTPs ≥12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with EXCELLENT response to treatment | 4 Bleeds |
| Part A: PTPs ≥12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with GOOD response to treatment | 25 Bleeds |
| Part A: PTPs ≥12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with MODERATE response to treatment | 14 Bleeds |
| Part A: PTPs ≥12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with POOR response to treatment | 1 Bleeds |
| Part A: PTPs <12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with POOR response to treatment | 0 Bleeds |
| Part A: PTPs <12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with GOOD response to treatment | 2 Bleeds |
| Part A: PTPs <12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Total bleeds | 11 Bleeds |
| Part A: PTPs <12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with EXCELLENT response to treatment | 5 Bleeds |
| Part A: PTPs <12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds without response assessment to treatment | 1 Bleeds |
| Part A: PTPs <12 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with MODERATE response to treatment | 3 Bleeds |
| Part B: PUPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds without response assessment to treatment | 0 Bleeds |
| Part B: PUPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with EXCELLENT response to treatment | 0 Bleeds |
| Part B: PUPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with GOOD response to treatment | 0 Bleeds |
| Part B: PUPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with POOR response to treatment | 0 Bleeds |
| Part B: PUPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with MODERATE response to treatment | 1 Bleeds |
| Part B: PUPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Total bleeds | 1 Bleeds |
| Part B: MTPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with MODERATE response to treatment | 0 Bleeds |
| Part B: MTPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with POOR response to treatment | 0 Bleeds |
| Part B: MTPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds without response assessment to treatment | 0 Bleeds |
| Part B: MTPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with GOOD response to treatment | 1 Bleeds |
| Part B: MTPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Total bleeds | 1 Bleeds |
| Part B: MTPs <6 Years | Number of Bleeds Per Assessment of Response to Treatment of Bleeds | Bleeds with EXCELLENT response to treatment | 0 Bleeds |
Other Pre-specified
Number of Participants Without Bleeding Episode
Number of participants who did not experience any bleed during the prophylaxis treatment period or within 48 hours of previous prophylaxis infusion is reported.
Time frame: During prophylaxis treatment in Part A: up to 6 months; Part B: up to 51 exposure days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: PTPs ≥12 Years | Number of Participants Without Bleeding Episode | During prophylaxis treatment | 13 Participants |
| Part A: PTPs ≥12 Years | Number of Participants Without Bleeding Episode | Within 48 hours | 16 Participants |
| Part A: PTPs <12 Years | Number of Participants Without Bleeding Episode | Within 48 hours | 8 Participants |
| Part A: PTPs <12 Years | Number of Participants Without Bleeding Episode | During prophylaxis treatment | 7 Participants |
| Part B: PUPs <6 Years | Number of Participants Without Bleeding Episode | During prophylaxis treatment | 1 Participants |
| Part B: PUPs <6 Years | Number of Participants Without Bleeding Episode | Within 48 hours | 2 Participants |
| Part B: MTPs <6 Years | Number of Participants Without Bleeding Episode | During prophylaxis treatment | 0 Participants |
| Part B: MTPs <6 Years | Number of Participants Without Bleeding Episode | Within 48 hours | 1 Participants |