Trial Outcomes & Findings for Pharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale (NCT NCT02502149)
NCT ID: NCT02502149
Last Updated: 2020-12-19
Results Overview
AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
COMPLETED
PHASE3
24 participants
Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr
2020-12-19
Participant Flow
Participant milestones
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
All participants received recombinant factor VIII Fc fusion protein (rFVIIIFc) (1000 IU/vial strength), 50 International Unit per kilogram (IU/kg), manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
|
15K rFVIIIFc (1000 IU/Vial Strength) (PK2)
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with15K rFVIIIFc, participants will be re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants will resume to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for PK2. Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with15K rFVIIIFc, participants will be re-evaluated at PK3 at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants will resume to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
15K rFVIIIFc (1000 IU/Vial Strength) (PK3)
Participants who were randomized to receive 15K rFVIIIFc 1000 IU/vial for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.
|
15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Participants who were randomized to receive 15K rFVIIIFc 6000 IU/vial for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.
|
|---|---|---|---|---|---|
|
PK1 Assessment Period
STARTED
|
24
|
0
|
0
|
0
|
0
|
|
PK1 Assessment Period
COMPLETED
|
24
|
0
|
0
|
0
|
0
|
|
PK1 Assessment Period
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
|
Intermediate
STARTED
|
24
|
0
|
0
|
0
|
0
|
|
Intermediate
COMPLETED
|
23
|
0
|
0
|
0
|
0
|
|
Intermediate
NOT COMPLETED
|
1
|
0
|
0
|
0
|
0
|
|
PK2 Assessment Period
STARTED
|
0
|
11
|
12
|
0
|
0
|
|
PK2 Assessment Period
COMPLETED
|
0
|
11
|
12
|
0
|
0
|
|
PK2 Assessment Period
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
|
Treatment Period
STARTED
|
0
|
0
|
0
|
11
|
12
|
|
Treatment Period
COMPLETED
|
0
|
0
|
0
|
11
|
12
|
|
Treatment Period
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
Reasons for withdrawal
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
All participants received recombinant factor VIII Fc fusion protein (rFVIIIFc) (1000 IU/vial strength), 50 International Unit per kilogram (IU/kg), manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
|
15K rFVIIIFc (1000 IU/Vial Strength) (PK2)
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with15K rFVIIIFc, participants will be re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants will resume to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for PK2. Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with15K rFVIIIFc, participants will be re-evaluated at PK3 at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants will resume to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
15K rFVIIIFc (1000 IU/Vial Strength) (PK3)
Participants who were randomized to receive 15K rFVIIIFc 1000 IU/vial for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.
|
15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Participants who were randomized to receive 15K rFVIIIFc 6000 IU/vial for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.
|
|---|---|---|---|---|---|
|
Intermediate
Discontinued prematurely
|
1
|
0
|
0
|
0
|
0
|
Baseline Characteristics
Pharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale
Baseline characteristics by cohort
| Measure |
2K/15K rFVIIIFc (1000/6000 IU/Vial Strength)- All Participants
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for PK1. At PK1, participants were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for PK2. Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at PK3 at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants will resume to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|
|
Age, Continuous
|
30.8 years
STANDARD_DEVIATION 12.78 • n=5 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
24 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Hispanic or Latino
|
1 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Not Hispanic or Latino
|
6 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Not reported
|
17 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The Pharmacokinetic Analysis Set (PKAS) included all participants who have evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage Activated Partial Thromboplastin Time (aPTT) Clotting Assay for Pharmacokinetic Assessment 1 (PK1) and Pharmacokinetic Assessment 2 (PK2)
|
2255.6 International unit*hour per deciliter
Interval 1886.2 to 2697.4
|
2425.8 International unit*hour per deciliter
Interval 2084.2 to 2823.4
|
PRIMARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS included all participants who have evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
|
2.684 IU/dL per IU/kg
Interval 2.364 to 3.049
|
2.700 IU/dL per IU/kg
Interval 2.458 to 2.964
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
|
133.20 International units per deciliter (IU/dL
Interval 123.0 to 144.24
|
134.67 International units per deciliter (IU/dL
Interval 121.46 to 149.32
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Half-life is time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
|
14.229 Hours (h)
Interval 12.458 to 16.252
|
14.771 Hours (h)
Interval 12.91 to 16.9
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
|
2.1847 milliliter per hour per kilogram(mL/h/kg
Interval 1.8943 to 2.5198
|
2.0420 milliliter per hour per kilogram(mL/h/kg
Interval 1.7421 to 2.3935
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
|
43.80 milliliter per kilogram (mL/kg)
Interval 40.7 to 47.14
|
43.01 milliliter per kilogram (mL/kg)
Interval 39.69 to 46.61
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2
|
20.048 hours (h)
Interval 17.561 to 22.887
|
21.063 hours (h)
Interval 18.501 to 23.98
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=21 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
|
2448.6 IU*h/dL
Interval 2089.0 to 2870.1
|
2697.8 IU*h/dL
Interval 2295.1 to 3171.0
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Incremental Recovery is defined as the increase in the circulating FVIII activity in IU/dL per unit dose administered in IU/kg (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=23 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
|
2.693 IU/dL per IU/kg
Interval 2.429 to 2.986
|
2.804 IU/dL per IU/kg
Interval 2.588 to 3.038
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=23 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
|
134.67 IU/dL
Interval 121.46 to 149.32
|
140.38 IU/dL
Interval 129.62 to 152.04
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=21 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
|
14.771 Hours (h)
Interval 12.91 to 16.9
|
15.493 Hours (h)
Interval 13.625 to 17.617
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=21 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
|
2.0420 mL/h/kg
Interval 1.7421 to 2.3935
|
1.8556 mL/h/kg
Interval 1.5786 to 2.1813
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=21 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
|
43.01 mL/kg
Interval 39.69 to 46.61
|
40.19 mL/kg
Interval 37.44 to 43.14
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=21 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3
|
21.063 hours (h)
Interval 18.501 to 23.98
|
21.657 hours (h)
Interval 18.877 to 24.847
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
AUCinf is area under the concentration-time curve from time zero to infinity.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2356.8 IU*h/dL
Interval 1950.4 to 2847.9
|
2535.8 IU*h/dL
Interval 1915.6 to 3356.8
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2.614 IU/dL per IU/kg
Interval 2.186 to 3.126
|
2.768 IU/dL per IU/kg
Interval 2.408 to 3.181
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Cmax is defined as maximum activity of rFVIIIFc.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
130.73 IU/dL
Interval 109.33 to 156.31
|
138.40 IU/dL
Interval 120.42 to 159.06
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Time required for the concentration of the drug to reach half of its original value.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
14.118 Hours (h)
Interval 11.469 to 17.379
|
15.395 Hours (h)
Interval 12.555 to 18.879
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2.1215 mL/h/kg
Interval 1.7557 to 2.5635
|
1.9718 mL/h/kg
Interval 1.4895 to 2.6101
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
42.61 mL/kg
Interval 37.28 to 48.71
|
43.38 mL/kg
Interval 38.66 to 48.67
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
20.087 hours (h)
Interval 16.333 to 24.704
|
22.000 hours (h)
Interval 18.193 to 26.603
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
AUCinf is area under the concentration-time curve from time zero to infinity.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=9 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2634.5 IU*h/dL
Interval 2079.8 to 3337.1
|
2746.3 IU*h/dL
Interval 2130.5 to 3539.9
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2.623 IU/dL per IU/kg
Interval 2.343 to 2.936
|
2.982 IU/dL per IU/kg
Interval 2.65 to 3.355
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Cmax is defined as maximum activity of rFVIIIFc.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
131.15 IU/dL
Interval 117.18 to 146.8
|
149.41 IU/dL
Interval 132.99 to 167.86
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Time required for the concentration of the drug to reach half of its original value.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=9 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
15.599 Hours (h)
Interval 12.925 to 18.826
|
15.414 Hours (h)
Interval 12.593 to 18.868
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=9 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
1.8979 mL/h/kg
Interval 1.4983 to 2.4041
|
1.8246 mL/h/kg
Interval 1.4151 to 2.3524
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=9 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
42.12 mL/kg
Interval 36.95 to 48.02
|
38.80 mL/kg
Interval 35.47 to 42.43
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=9 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
22.193 hours (h)
Interval 17.923 to 27.48
|
21.264 hours (h)
Interval 17.247 to 26.216
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
|
2386.4 IU*h/dL
Interval 2124.1 to 2681.0
|
2777.6 IU*h/dL
Interval 2453.0 to 3145.2
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Incremental Recovery is defined as the increase in the circulating FVIII activity in IU/dL per unit dose administered in IU/kg (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
|
2.807 IU/dL per IU/kg
Interval 2.412 to 3.267
|
3.253 IU/dL per IU/kg
Interval 2.91 to 3.636
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
|
140.36 IU/dL
Interval 120.61 to 163.34
|
162.73 IU/dL
Interval 145.61 to 181.86
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
|
17.312 Hours (h)
Interval 15.84 to 18.921
|
18.146 Hours (h)
Interval 15.98 to 20.605
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]). Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
|
2.0952 mL/h/kg
Interval 1.8649 to 2.3539
|
1.8001 mL/h/kg
Interval 1.5897 to 2.0383
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
|
46.87 mL/kg
Interval 41.48 to 52.96
|
42.02 mL/kg
Interval 37.96 to 46.51
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. All 24 participants had data available from PK1 and/or PK2 and were included in the analysis model for this outcome. Hence, the data for 24 participants has been reported for PK2.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/Vial (PK2).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=24 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2
|
22.370 hours (h)
Interval 19.921 to 25.12
|
23.342 hours (h)
Interval 20.472 to 26.615
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
AUCinf is area under the concentration-time curve from time zero to infinity. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=20 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
|
2777.6 IU*h/dL
Interval 2453.0 to 3145.2
|
2754.9 IU*h/dL
Interval 2312.2 to 3282.4
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Incremental Recovery is defined as the increase in the circulating FVIII activity in IU/dL per unit dose administered in IU/kg (IU/dL per IU/kg). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=23 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
|
3.253 IU/dL per IU/kg
Interval 2.91 to 3.636
|
2.956 IU/dL per IU/kg
Interval 2.656 to 3.289
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Cmax is defined as maximum activity of rFVIIIFc. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=23 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
|
162.73 IU/dL
Interval 145.61 to 181.86
|
147.97 IU/dL
Interval 133.02 to 164.6
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Time required for the concentration of the drug to reach half of its original value. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=20 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
|
18.146 Hours (h)
Interval 15.98 to 20.605
|
17.289 Hours (h)
Interval 15.078 to 19.823
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]). Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=20 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
|
1.8001 mL/h/kg
Interval 1.5897 to 2.0383
|
1.8173 mL/h/kg
Interval 1.5251 to 2.1654
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=20 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured the Two-stage Chromogenic Assay for PK2 and PK3
|
42.02 mL/kg
Interval 37.96 to 46.51
|
40.59 mL/kg
Interval 36.01 to 45.75
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. Results were summarized overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=20 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3
|
23.342 hours (h)
Interval 20.472 to 26.615
|
22.337 hours (h)
Interval 19.574 to 25.49
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
AUCinf is area under the concentration-time curve from time zero to infinity.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2599.2 IU*h/dL
Interval 2257.2 to 2993.1
|
2951.9 IU*h/dL
Interval 2376.1 to 3667.2
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
3.225 IU/dL per IU/kg
Interval 2.643 to 3.936
|
3.278 IU/dL per IU/kg
Interval 2.835 to 3.792
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Cmax is defined as maximum activity of rFVIIIFc.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
161.38 IU/dL
Interval 132.29 to 196.88
|
163.97 IU/dL
Interval 141.78 to 189.64
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Time required for the concentration of the drug to reach half of its original value.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
16.687 Hours (h)
Interval 14.593 to 19.08
|
19.595 Hours (h)
Interval 15.68 to 24.488
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
1.9236 mL/h/kg
Interval 1.6705 to 2.2152
|
1.6938 mL/h/kg
Interval 1.3634 to 2.1043
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
41.15 mL/kg
Interval 34.5 to 49.07
|
42.83 mL/kg
Interval 37.33 to 49.15
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
21.391 hours (h)
Interval 17.713 to 25.833
|
25.287 hours (h)
Interval 20.729 to 30.847
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hour (hr), 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
AUCinf is area under the concentration-time curve from time zero to infinity.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=8 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2646.8 IU*h/dL
Interval 1891.8 to 3703.0
|
2829.4 IU*h/dL
Interval 2235.7 to 3580.8
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Incremental Recovery is defined as the increase in the circulating FVIII activity in international unit per deciliter (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Incremental Recovery (IR) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
2.891 IU/dL per IU/kg
Interval 2.413 to 3.464
|
3.016 IU/dL per IU/kg
Interval 2.597 to 3.504
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles.
Cmax is defined as maximum activity of rFVIIIFc.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=11 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Maximum Activity (Cmax) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
144.58 IU/dL
Interval 120.66 to 173.25
|
151.15 IU/dL
Interval 130.34 to 175.28
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Time required for the concentration of the drug to reach half of its original value.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=8 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Half-life (t½) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
16.945 Hours (h)
Interval 13.793 to 20.818
|
17.522 Hours (h)
Interval 14.213 to 21.601
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body.The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC\[0-infinity\]).
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=8 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Clearance (CL) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
1.8891 milliliter per hour per kilogram(mL/h/kg
Interval 1.3502 to 2.6429
|
1.7709 milliliter per hour per kilogram(mL/h/kg
Interval 1.3989 to 2.2419
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
Vss 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. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-infinity\])\*(AUMC\[0-infinity\])/AUC\[0-infinity\]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=8 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
41.78 mL/kg
Interval 30.7 to 56.87
|
39.82 mL/kg
Interval 35.98 to 44.06
|
SECONDARY outcome
Timeframe: Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hrPopulation: The PKAS is defined as all participants with evaluable PK profiles. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
The Mean Residence Time (MRT) is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as area under the first moment curve AUMC (0-infinity)/Area Under the Plasma Concentration-Time Curve AUC (0-infinity), where AUMC (0-infinity) is area under the plasma concentration-time first moment curve from time zero to infinite time and AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=8 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
n=12 Participants
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Mean Residence Time (MRT) of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)
|
22.119 hours (h)
Interval 17.717 to 27.614
|
22.483 hours (h)
Interval 18.532 to 27.277
|
SECONDARY outcome
Timeframe: At screening and predose on Day 1, 13 and 26 weeks after PK2 injection or at Early Termination (Approximately 43 weeks)Population: The population analyzed included all participants who received at least 1 dose of rFVIIIFc.
An inhibitor test result greater than or equal to (\>=)0.6 Bethesda units \[BU\]/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. The test was performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the percentage of participants 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.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Development of Inhibitors as Measured by the Nijmegen-modified Bethesda Assay
|
0 percentage of participants
Interval 0.0 to 14.25
|
—
|
SECONDARY outcome
Timeframe: Approximately 43 weeksPopulation: The population analyzed included all participants who received at least 1 dose of rFVIIIFc at 15k manufacturing scale.
An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Number of Participants with TEAEs were summarized overall.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Number of Participants With Treatment Emergent Adverse Events (TEAEs) at 15K Manufacturing Scale
|
10 Participants
|
—
|
SECONDARY outcome
Timeframe: Approximately 43 weeksPopulation: The population analyzed included all participants who received at least 1 dose of rFVIIIFc at 15k manufacturing scale.
An SAE is any untoward medical occurrence that at any dose: results in death or in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or results in a congenital anomaly/birth defect. All major surgeries will be reported as SAEs. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the SAE definition. Number of participants with TESAEs were summarized overall.
Outcome measures
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=23 Participants
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
.
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for pharmacokinetic assessment 2 (PK2). Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at Pharmacokinetic assessment 3 (PK3) at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) at 15K Manufacturing Scale
|
0 Participants
|
—
|
Adverse Events
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
15K rFVIIIFc (1000 and 6000 IU/Vial Strength)
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
n=24 participants at risk
All participants received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K (2000 liter bioreactor scale) for pharmacokinetic assessment 1 (PK1).
|
15K rFVIIIFc (1000 and 6000 IU/Vial Strength)
n=23 participants at risk
Participants who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomized to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K (15000 liter bioreactor scale) for PK2. Following PK2 assessments, participants received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, participants were re-evaluated at PK3 at the same vial strength as in PK2. A minimum of 120 hours of washout was observed prior to the PK2 assessment. Following the PK3 assessment, participants were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.
|
|---|---|---|
|
Nervous system disorders
Headache
|
0.00%
0/24 • Approximately 43 weeks
The Safety Population included all participants who received at least 1 dose of rFVIIIFc. Adverse events are reported based on the overall number of participants treated with 2K rFVIIIFc at 1000 IU/vial strength (PK1 assessment period and Intermediate period) and 15K rFVIIIFc at 1000 and 6000 IU/vial strength (PK2 assessment period and Treatment Period).
|
13.0%
3/23 • Number of events 3 • Approximately 43 weeks
The Safety Population included all participants who received at least 1 dose of rFVIIIFc. Adverse events are reported based on the overall number of participants treated with 2K rFVIIIFc at 1000 IU/vial strength (PK1 assessment period and Intermediate period) and 15K rFVIIIFc at 1000 and 6000 IU/vial strength (PK2 assessment period and Treatment Period).
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
- Publication restrictions are in place
Restriction type: OTHER