Severe Hemophilia A
Conditions
Brief summary
The primary objective of the study is to characterize the pharmacokinetics (PK) of rFVIIIFc administered at vial strengths of 1000 and 3000 IU in subjects with severe hemophilia A. The secondary objective of the study is to evaluate the safety of rFVIIIFc beyond the PK assessment for up to 6 months for a continued treatment period.
Detailed description
This is a randomized, open-label, crossover study during which each participant receives a single injection of rFVIIIFc from 2 different vial concentrations (PK assessment). After the PK assessment, participants are provided with rFVIIIFc for either prophylactic or episodic (on-demand) treatment for up to 6 months.
Interventions
BIOLOGICALrFVIIIFc
Administered as specified in the treatment arm.
Sponsors
Bioverativ Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Have severe hemophilia A * Previously treated subject, defined as having at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products (other than any use of rFVIIIFc- study drug or commercial product) at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days. * No history of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors will not exclude subjects. * No measurable inhibitor activity using the Nijmegen-modified Bethesda assay at Screening. * Platelet count ≥100,000 platelets/μL at screening * CD4 lymphocytes \>200 mm3 if known as HIV antibody positive at screening. * Viral load of \<400 copies/mL if known HIV antibody positive at screening. Key
Exclusion criteria
* Subject is at high risk of bleeding during the 5-day period between the first and second injections for PK analyses, as per Investigator discretion. * Previous treatment with rFVIIIFc as study drug or commercial product. * Other coagulation disorder(s) in addition to hemophilia A. * History of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration. * Currently taking (or likely to require during the study) acetylsalicylic acid (ASA), except for low-dose ASA as prophylaxis (other nonsteroidal anti-inflammatory drugs are permitted). * Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to Day 1. Exceptions to this include: ribavirin for treatment of hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days at a dose of ≤1 mg/kg within 12 weeks prior to Day 1) and/or inhaled steroids. NOTE: Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). |
| Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Half-life (t½) as Measured by aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Time required for the concentration of the drug to reach half of its original value. |
| Clearance (CL) as Measured by the aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time. |
| Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The apparent volume of distribution at steady state. (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 blood concentration of a drug.) |
| Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The average time at which the number of absorbed molecules reside in the body, after single-dose administration. |
| Time of Cmax (Tmax) as Measured by aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Time at which maximum activity (Cmax) is observed. |
| Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Area under the plasma concentration time-curve from zero to the last measured concentration. |
| Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | First order rate constant associated with the terminal portion of the curve (lambda z) . |
| Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Percentage of AUCinf extrapolated from the last data point to infinity. |
| Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Dose normalized area under the FVIII activity-time curve. |
| Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | 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. |
| AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). |
| Cmax as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Maximum measured concentration of rFVIIIFc. |
| t½ as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Time required for the concentration of the drug to reach half of its original value. |
| CL as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time. |
| Vss as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The apparent volume of distribution at steady state. (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 blood concentration of a drug.) |
| MRT as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The average time at which the number of absorbed molecules reside in the body, after single-dose administration. |
| Tmax as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Time at which maximum activity (Cmax) is observed. |
| AUClast as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Area under the plasma concentration time-curve from zero to the last measured concentration. |
| Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | First order rate constant associated with the terminal portion of the curve (lambda z). |
| AUCext as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Percentage of AUCinf extrapolated from the last data point to infinity. |
| DNAUC as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Dose normalized area under the FVIII activity-time curve. |
| Vz as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | 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. |
| Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay | Predose, Month 3, Month 6/early withdrawal. Additionally: If inhibitor suspected; at 10-15 EDs; 2-4 weeks prior to scheduled surgery; preoperatively on day of surgery; 1-2 weeks post-surgery; at last postoperative visit (last 2 for major surgery only) | An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of participants with confirmed inhibitor development was summarized overall. |
| IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data. |
| Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay | Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection | Maximum measured concentration of rFVIIIFc. |
Countries
Australia, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| rFVIIIFc 1000 / 3000 Following the minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 1000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode. | 10 |
| rFVIIIFc 3000 / 1000 Following the minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 3000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode. | 9 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Other | 1 | 0 |
Baseline characteristics
| Characteristic | rFVIIIFc 1000 / 3000 | rFVIIIFc 3000 / 1000 | Total |
|---|---|---|---|
| Age, Continuous | 23 years STANDARD_DEVIATION 12.45 | 30.9 years STANDARD_DEVIATION 19.76 | 26.7 years STANDARD_DEVIATION 16.35 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 19 |
| serious Total, serious adverse events | 2 / 19 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay
Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay | 2888.9 IU*h/dL |
| rFVIIIFc 3000 IU | Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay | 2646.3 IU*h/dL |
Primary
Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay
The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay | 2.33 IU/dL |
| rFVIIIFc 3000 IU | Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay | 2.412 IU/dL |
Secondary
Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay
Area under the plasma concentration time-curve from zero to the last measured concentration.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay | 2792.5 IU*h/dL |
| rFVIIIFc 3000 IU | Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay | 2562.2 IU*h/dL |
Secondary
AUCext as Measured by Two-Stage Chromogenic Clotting Assay
Percentage of AUCinf extrapolated from the last data point to infinity.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | AUCext as Measured by Two-Stage Chromogenic Clotting Assay | 2.923 percentage of AUCinf |
| rFVIIIFc 3000 IU | AUCext as Measured by Two-Stage Chromogenic Clotting Assay | 2.965 percentage of AUCinf |
Secondary
AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay
Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay | 2649.0 IU*h/dL |
| rFVIIIFc 3000 IU | AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay | 2628.0 IU*h/dL |
Secondary
AUClast as Measured by Two-Stage Chromogenic Clotting Assay
Area under the plasma concentration time-curve from zero to the last measured concentration.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | AUClast as Measured by Two-Stage Chromogenic Clotting Assay | 2555.4 IU*h/dL |
| rFVIIIFc 3000 IU | AUClast as Measured by Two-Stage Chromogenic Clotting Assay | 2520.5 IU*h/dL |
Secondary
CL as Measured by Two-Stage Chromogenic Clotting Assay
The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | CL as Measured by Two-Stage Chromogenic Clotting Assay | 1.962 mL/h/kg |
| rFVIIIFc 3000 IU | CL as Measured by Two-Stage Chromogenic Clotting Assay | 2.006 mL/h/kg |
Secondary
Clearance (CL) as Measured by the aPTT Clotting Assay
The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Clearance (CL) as Measured by the aPTT Clotting Assay | 1.807 mL/h/kg |
| rFVIIIFc 3000 IU | Clearance (CL) as Measured by the aPTT Clotting Assay | 2.016 mL/h/kg |
Secondary
Cmax as Measured by Two-Stage Chromogenic Clotting Assay
Maximum measured concentration of rFVIIIFc.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Cmax as Measured by Two-Stage Chromogenic Clotting Assay | 132.61 IU/dL |
| rFVIIIFc 3000 IU | Cmax as Measured by Two-Stage Chromogenic Clotting Assay | 122.29 IU/dL |
Secondary
Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay
An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of participants with confirmed inhibitor development was summarized overall.
Time frame: Predose, Month 3, Month 6/early withdrawal. Additionally: If inhibitor suspected; at 10-15 EDs; 2-4 weeks prior to scheduled surgery; preoperatively on day of surgery; 1-2 weeks post-surgery; at last postoperative visit (last 2 for major surgery only)
Population: The Safety Analysis Set included participants who received at least 1 dose of rFVIIIFc.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rFVIIIFc 1000 IU | Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay | 0 percentage of participants |
Secondary
DNAUC as Measured by Two-Stage Chromogenic Clotting Assay
Dose normalized area under the FVIII activity-time curve.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | DNAUC as Measured by Two-Stage Chromogenic Clotting Assay | 50.97 IU*h/dL per IU/kg |
| rFVIIIFc 3000 IU | DNAUC as Measured by Two-Stage Chromogenic Clotting Assay | 49.85 IU*h/dL per IU/kg |
Secondary
Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay
Dose normalized area under the FVIII activity-time curve.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay | 55.35 IU*h/dL per IU/kg |
| rFVIIIFc 3000 IU | Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay | 49.6 IU*h/dL per IU/kg |
Secondary
Half-life (t½) as Measured by aPTT Clotting Assay
Time required for the concentration of the drug to reach half of its original value.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Half-life (t½) as Measured by aPTT Clotting Assay | 18.28 hours |
| rFVIIIFc 3000 IU | Half-life (t½) as Measured by aPTT Clotting Assay | 17.49 hours |
Secondary
IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay
The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay | 2.535 IU/dL per IU/kg |
| rFVIIIFc 3000 IU | IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay | 2.287 IU/dL per IU/kg |
Secondary
Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay
First order rate constant associated with the terminal portion of the curve (lambda z).
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay | 0.03730 1/h |
| rFVIIIFc 3000 IU | Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay | 0.03629 1/h |
Secondary
Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay
Maximum measured concentration of rFVIIIFc.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay | 122.2 IU/dL |
| rFVIIIFc 3000 IU | Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay | 129.08 IU/dL |
Secondary
Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay
The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay | 26.01 hours |
| rFVIIIFc 3000 IU | Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay | 24.13 hours |
Secondary
MRT as Measured by Two-Stage Chromogenic Clotting Assay
The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | MRT as Measured by Two-Stage Chromogenic Clotting Assay | 24.17 hours |
| rFVIIIFc 3000 IU | MRT as Measured by Two-Stage Chromogenic Clotting Assay | 25.56 hours |
Secondary
Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay
Percentage of AUCinf extrapolated from the last data point to infinity.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay | 2.561 percentage of AUCinf |
| rFVIIIFc 3000 IU | Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay | 2.279 percentage of AUCinf |
Secondary
t½ as Measured by Two-Stage Chromogenic Clotting Assay
Time required for the concentration of the drug to reach half of its original value.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | t½ as Measured by Two-Stage Chromogenic Clotting Assay | 18.58 hours |
| rFVIIIFc 3000 IU | t½ as Measured by Two-Stage Chromogenic Clotting Assay | 19.10 hours |
Secondary
Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay
First order rate constant associated with the terminal portion of the curve (lambda z) .
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay | 0.03792 1/h |
| rFVIIIFc 3000 IU | Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay | 0.03963 1/h |
Secondary
Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT
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.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT | 47.65 mL/kg |
| rFVIIIFc 3000 IU | Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT | 50.87 mL/kg |
Secondary
Time of Cmax (Tmax) as Measured by aPTT Clotting Assay
Time at which maximum activity (Cmax) is observed.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Time of Cmax (Tmax) as Measured by aPTT Clotting Assay | 0.66 hours |
| rFVIIIFc 3000 IU | Time of Cmax (Tmax) as Measured by aPTT Clotting Assay | 0.58 hours |
Secondary
Tmax as Measured by Two-Stage Chromogenic Clotting Assay
Time at which maximum activity (Cmax) is observed.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Tmax as Measured by Two-Stage Chromogenic Clotting Assay | 0.61 hours |
| rFVIIIFc 3000 IU | Tmax as Measured by Two-Stage Chromogenic Clotting Assay | 0.61 hours |
Secondary
Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay
The apparent volume of distribution at steady state. (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 blood concentration of a drug.)
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay | 47.00 mL/kg |
| rFVIIIFc 3000 IU | Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay | 48.65 mL/kg |
Secondary
Vss as Measured by Two-Stage Chromogenic Clotting Assay
The apparent volume of distribution at steady state. (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 blood concentration of a drug.)
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Vss as Measured by Two-Stage Chromogenic Clotting Assay | 47.41 mL/kg |
| rFVIIIFc 3000 IU | Vss as Measured by Two-Stage Chromogenic Clotting Assay | 51.27 mL/kg |
Secondary
Vz as Measured by Two-Stage Chromogenic Clotting Assay
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.
Time frame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Population: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| rFVIIIFc 1000 IU | Vz as Measured by Two-Stage Chromogenic Clotting Assay | 52.59 mL/kg |
| rFVIIIFc 3000 IU | Vz as Measured by Two-Stage Chromogenic Clotting Assay | 55.28 mL/kg |