Hemophilia A
Conditions
Brief summary
The primary purpose was to assess the safety and tolerability of a single intravenous (IV) administration of BIVV001 in adult previously treated patients (PTPs) with severe hemophilia A.
Interventions
BIOLOGICALAdvate (Low Dose)
Participants received a single IV low dose of Advate 25 IU/kg.
BIOLOGICALAdvate (High Dose)
Participants received a single IV high dose of Advate 65 IU/kg.
BIOLOGICALBIVV001 (Low Dose)
Participants received single IV low dose of BIVV001 25 IU/kg.
BIOLOGICALBIVV001 (High Dose)
Participants received single IV high dose of BIVV001 65 IU/kg.
Sponsors
Bioverativ, a Sanofi company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Ability of the participant, or his legally authorized representative (e.g., parent or legal guardian) if applicable in accordance with local regulations, to understand the purpose and risks of the study and provide signed and dated informed consent/assent and authorization to use confidential health information in accordance with national and local participant privacy regulations. * Severe hemophilia A, defined as less than (\<) 1 international units per deciliter (IU/dL) (\<1 percent \[%\]) endogenous FVIII at screening as determined by the one-stage clotting assay from the central laboratory. If the initial screening result was greater than or equal to (\>=) 1%, then a repeat endogenous FVIII activity level was performed using the one stage clotting assay from the central laboratory. If the repeated result was \< 1 IU/dL (\<1%), then the participant met this inclusion requirement. * Previous treatment for hemophilia A, defined as at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days. * Platelet count \>=100,000 cells/ microliter (mcL) at screening (test performed by the central laboratory and reviewed prior to the Day 1 Advate dose). * A participant known to be human immunodeficiency virus (HIV) antibody positive, either previously documented or identified from screening assessments, must have the following results prior to Day 1 Advate dose: cluster of differentiation 4 (CD4) lymphocyte count greater than (\>) 200 cells/millimeter (mm)\^3; viral load of \<400 copies/mL.
Exclusion criteria
Medical History: * Any concurrent clinically significant major disease that, in the opinion of the Investigator, made the participant unsuitable for enrollment. * Serious active bacterial or viral infection (other than chronic hepatitis or HIV) present within 30 days of screening. * Other known coagulation disorder(s) in addition to hemophilia A. * History of hypersensitivity or anaphylaxis associated with any FVIII product. * Known or suspected allergy to mice, hamsters, or any ingredient in Advate. * History of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors not excluded the participant. Medications and Procedures: \- Current enrollment or participation within 30 days prior to screening in any other investigational study. Other: * Inability to comply with study requirements as assessed by the Investigator. * Other unspecified reasons that, in the opinion of the Investigator or Sponsor, made the participant unsuitable for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period | Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg | AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the single dose of Advate but before the single dose of BIVV001. Serious AE (SAE) was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period | Up to 28 days after BIVV001 administration | AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the study treatment (BIVV001) and within 28 days after BIVV001 administration. SAE was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. |
| Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period | Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg | Number of Participants with Clinically Significant Abnormalities in Laboratory tests (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported. |
| Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period | Up to 28 days after BIVV001 administration | Number of participants with clinically significant abnormalities (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported. |
| Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay | Up to 28 days after BIVV001 administration | Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (\>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample, collected within 2 to 4 weeks of the first positive sample, with both tests performed by the central laboratory using Nijmegen-modified Bethesda assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | AUCinfinity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | AUCinfinity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | Cmax of Advate and BIVV001 at low dose was assessed and compared based on One-stage activated partial thromboplastin time (aPTT)-based clotting assay. |
| PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | Cmax of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Half-Life for Advate and BIVV001 (High Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours | Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay. |
| PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) | For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay. |
Countries
Japan, United States
Participant flow
Recruitment details
The study was conducted in Japan and United States between 28 August 2017 to 12 November 2018.
Pre-assignment details
A total of 16 participants were enrolled, 7 participants to low dose cohort (LDC) and 9 to high dose cohort (HDC).
Participants by arm
| Arm | Count |
|---|---|
| LDC: Advate 25 IU/kg Then BIVV001 25 IU/kg Participants received a single IV dose of Advate 25 IU/kg on Day 1 of ATP (3 days) followed by a single IV dose of BIVV001 25 IU/kg in BTP (28 days). ATP consisted of a washout of at least 72 hours which was started from the time of Advate dosing. | 7 |
| HDC: Advate 65 IU/kg Then BIVV001 65 IU/kg Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days) followed by a single IV dose of BIVV001 65 IU/kg in BTP (28 days). ATP consisted of a washout of at least 96 hours which was started from the time of Advate dosing. | 9 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| ATP (LDC: 3 Days; HDC: 4 Days) | Sponsor Decision | 1 | 0 |
Baseline characteristics
| Characteristic | HDC: Advate 65 IU/kg Then BIVV001 65 IU/kg | Total | LDC: Advate 25 IU/kg Then BIVV001 25 IU/kg |
|---|---|---|---|
| Age, Continuous | 44.0 years STANDARD_DEVIATION 11.65 | 39.2 years STANDARD_DEVIATION 13.43 | 33.0 years STANDARD_DEVIATION 13.81 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 16 Participants | 7 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 / 7 | 0 / 9 | 0 / 6 | 0 / 9 |
| other Total, other adverse events | 1 / 7 | 1 / 9 | 3 / 6 | 6 / 9 |
| serious Total, serious adverse events | 1 / 7 | 0 / 9 | 1 / 6 | 0 / 9 |
Outcome results
Primary
Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period
Number of Participants with Clinically Significant Abnormalities in Laboratory tests (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
Time frame: Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg
Population: Analysis was performed on safety analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Advate 25 IU/kg | Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period | 0 Participants |
| Advate 65 IU/kg | Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period | 0 Participants |
Primary
Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period
Number of participants with clinically significant abnormalities (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
Time frame: Up to 28 days after BIVV001 administration
Population: Analysis was performed on safety analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Advate 25 IU/kg | Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period | 0 Participants |
| Advate 65 IU/kg | Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period
AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the single dose of Advate but before the single dose of BIVV001. Serious AE (SAE) was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.
Time frame: Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg
Population: Analysis was performed on safety analysis set which included all participants who received at least 1 dose of Advate.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Advate 25 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period | TEAE | 2 Participants |
| Advate 25 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period | TESAE | 1 Participants |
| Advate 65 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period | TEAE | 1 Participants |
| Advate 65 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period | TESAE | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period
AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the study treatment (BIVV001) and within 28 days after BIVV001 administration. SAE was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.
Time frame: Up to 28 days after BIVV001 administration
Population: Analysis was performed on safety analysis set which included all participants who received at least 1 dose of BIVV001.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Advate 25 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period | TEAE | 3 Participants |
| Advate 25 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period | TESAE | 1 Participants |
| Advate 65 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period | TEAE | 6 Participants |
| Advate 65 IU/kg | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period | TESAE | 0 Participants |
Primary
Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay
Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (\>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample, collected within 2 to 4 weeks of the first positive sample, with both tests performed by the central laboratory using Nijmegen-modified Bethesda assay.
Time frame: Up to 28 days after BIVV001 administration
Population: Analysis was performed on safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Advate 25 IU/kg | Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay | 0 percentage of participants |
| Advate 65 IU/kg | Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay | 0 percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison)
Cmax of Advate and BIVV001 at low dose was assessed and compared based on One-stage activated partial thromboplastin time (aPTT)-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on pharmacokinetic analysis set (PKAS) which included participants who had adequate blood sample collections (following Advate or BIVV001 administration), to assess key PK parameters, as determined by the PK scientist.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) | 51.8 International unit/deciliter (IU/dL) |
| Advate 65 IU/kg | Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) | 70.1 International unit/deciliter (IU/dL) |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an analysis of variance (ANOVA) model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and geometric mean ratio (GMR) were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: 0.03295% CI: [1.04, 1.77]ANOVA
Secondary
PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison)
AUCinfinity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) | 638 hour*international unit/deciliter |
| Advate 65 IU/kg | PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) | 4470 hour*international unit/deciliter |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [5.78, 8.48]ANOVA
Secondary
PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison)
AUCinfinity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) | 1960 hour*international unit/deciliter |
| Advate 65 IU/kg | PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) | 12800 hour*international unit/deciliter |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [5.89, 7.27]ANOVA
Secondary
PK: Half-Life for Advate and BIVV001 (High Dose Comparison)
Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Half-Life for Advate and BIVV001 (High Dose Comparison) | 13.15 hours |
| Advate 65 IU/kg | PK: Half-Life for Advate and BIVV001 (High Dose Comparison) | 42.54 hours |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [2.76, 3.79]ANOVA
Secondary
PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison)
Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) | 9.12 hours |
| Advate 65 IU/kg | PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) | 37.61 hours |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [2.94, 5.79]ANOVA
Secondary
PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison)
Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) | 2.11 IU/dL per IU/kg |
| Advate 65 IU/kg | PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) | 2.48 IU/dL per IU/kg |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [1.1, 1.26]ANOVA
Secondary
PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison)
Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) | 2.0 IU/dL per IU/kg |
| Advate 65 IU/kg | PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) | 2.72 IU/dL per IU/kg |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: 0.06395% CI: [0.978, 1.89]ANOVA
Secondary
PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison)
Cmax of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) | 138 IU/dL |
| Advate 65 IU/kg | PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) | 161 IU/dL |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [1.09, 1.25]ANOVA
Secondary
PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison)
The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) | 15.66 hours |
| Advate 65 IU/kg | PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) | 67.66 hours |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [3.96, 4.72]ANOVA
Secondary
PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison)
The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) | 12.54 hours |
| Advate 65 IU/kg | PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) | 56.93 hours |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [3.64, 5.66]ANOVA
Secondary
PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison)
Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison) | 78.48 hours |
| Advate 65 IU/kg | PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison) | 350.34 hours |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [4.16, 4.79]ANOVA
Secondary
PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison)
Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) | 56.97 hours |
| Advate 65 IU/kg | PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) | 260.53 hours |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [4, 5.23]ANOVA
Secondary
PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison)
Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) | 3.31 mL/hr/kg |
| Advate 65 IU/kg | PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) | 0.505 mL/hr/kg |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [0.138, 0.17]ANOVA
Secondary
PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison)
Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) | 3.91 milliliter/hour/kilogram (mL/hr/kg) |
| Advate 65 IU/kg | PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) | 0.558 milliliter/hour/kilogram (mL/hr/kg) |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [0.118, 0.172]ANOVA
Secondary
PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) | 58.3 mL/kg |
| Advate 65 IU/kg | PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) | 35.0 mL/kg |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: <0.00195% CI: [0.525, 0.684]ANOVA
Secondary
PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time frame: For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Population: Analysis was performed on PKAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Advate 25 IU/kg | PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) | 55.9 milliliter/kilogram (mL/kg) |
| Advate 65 IU/kg | PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) | 34.8 milliliter/kilogram (mL/kg) |
Comparison: Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.p-value: 0.00395% CI: [0.492, 0.786]ANOVA