Trial Outcomes & Findings for Pharmacokinetics of rFVIIIFc at Two Vial Strengths (NCT NCT02083965)
NCT ID: NCT02083965
Last Updated: 2020-12-19
Results Overview
Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
COMPLETED
PHASE1
19 participants
Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
2020-12-19
Participant Flow
Participant milestones
| Measure |
rFVIIIFc 1000 / 3000
Following a minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 1000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of pharmacokinetic (PK) assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at strength of 3000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
rFVIIIFc 3000 / 1000
Following the minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 3000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
|---|---|---|
|
PK Period 1
STARTED
|
10
|
9
|
|
PK Period 1
COMPLETED
|
10
|
9
|
|
PK Period 1
NOT COMPLETED
|
0
|
0
|
|
Washout Period
STARTED
|
10
|
9
|
|
Washout Period
COMPLETED
|
10
|
9
|
|
Washout Period
NOT COMPLETED
|
0
|
0
|
|
PK Period 2
STARTED
|
10
|
9
|
|
PK Period 2
COMPLETED
|
10
|
9
|
|
PK Period 2
NOT COMPLETED
|
0
|
0
|
|
Treatment Period
STARTED
|
10
|
8
|
|
Treatment Period
COMPLETED
|
9
|
8
|
|
Treatment Period
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
rFVIIIFc 1000 / 3000
Following a minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 1000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of pharmacokinetic (PK) assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at strength of 3000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
rFVIIIFc 3000 / 1000
Following the minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 3000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
|---|---|---|
|
Treatment Period
Other
|
1
|
0
|
Baseline Characteristics
Pharmacokinetics of rFVIIIFc at Two Vial Strengths
Baseline characteristics by cohort
| Measure |
rFVIIIFc 1000 / 3000
n=10 Participants
Following the minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 1000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
rFVIIIFc 3000 / 1000
n=9 Participants
Following the minimum 4-day washout, participants received a single injection 50 IU/kg at strength of 3000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments.
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
Total
n=19 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
23 years
STANDARD_DEVIATION 12.45 • n=5 Participants
|
30.9 years
STANDARD_DEVIATION 19.76 • n=7 Participants
|
26.7 years
STANDARD_DEVIATION 16.35 • n=5 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
10 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
19 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay
|
2888.9 IU*h/dL
Interval 2440.0 to 3420.5
|
2646.3 IU*h/dL
Interval 2149.8 to 3257.5
|
PRIMARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay
|
2.33 IU/dL
Interval 2.182 to 2.487
|
2.412 IU/dL
Interval 2.169 to 2.682
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Maximum measured concentration of rFVIIIFc.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay
|
122.2 IU/dL
Interval 113.77 to 131.25
|
129.08 IU/dL
Interval 114.62 to 145.37
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Time required for the concentration of the drug to reach half of its original value.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Half-life (t½) as Measured by aPTT Clotting Assay
|
18.28 hours
Interval 16.1 to 20.75
|
17.49 hours
Interval 15.22 to 20.1
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Clearance (CL) as Measured by the aPTT Clotting Assay
|
1.807 mL/h/kg
Interval 1.534 to 2.128
|
2.016 mL/h/kg
Interval 1.642 to 2.476
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay
|
47.00 mL/kg
Interval 43.87 to 50.35
|
48.65 mL/kg
Interval 44.83 to 52.79
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay
|
26.01 hours
Interval 22.49 to 30.08
|
24.13 hours
Interval 20.46 to 28.46
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Time at which maximum activity (Cmax) is observed.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Time of Cmax (Tmax) as Measured by aPTT Clotting Assay
|
0.66 hours
Interval 0.55 to 0.79
|
0.58 hours
Interval 0.51 to 0.67
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Area under the plasma concentration time-curve from zero to the last measured concentration.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay
|
2792.5 IU*h/dL
Interval 2378.5 to 3278.6
|
2562.2 IU*h/dL
Interval 2100.8 to 3125.0
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
First order rate constant associated with the terminal portion of the curve (lambda z) .
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay
|
0.03792 1/h
Interval 0.0334 to 0.04304
|
0.03963 1/h
Interval 0.03449 to 0.04554
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Percentage of AUCinf extrapolated from the last data point to infinity.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay
|
2.561 percentage of AUCinf
Interval 1.703 to 3.852
|
2.279 percentage of AUCinf
Interval 1.505 to 3.45
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Dose normalized area under the FVIII activity-time curve.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay
|
55.35 IU*h/dL per IU/kg
Interval 47.0 to 65.18
|
49.6 IU*h/dL per IU/kg
Interval 40.4 to 60.9
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT
|
47.65 mL/kg
Interval 43.73 to 51.93
|
50.87 mL/kg
Interval 45.56 to 56.8
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay
|
2649.0 IU*h/dL
Interval 2230.2 to 3146.5
|
2628.0 IU*h/dL
Interval 2206.2 to 3130.5
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay
|
2.535 IU/dL per IU/kg
Interval 2.245 to 2.862
|
2.287 IU/dL per IU/kg
Interval 2.01 to 2.601
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Maximum measured concentration of rFVIIIFc.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Cmax as Measured by Two-Stage Chromogenic Clotting Assay
|
132.61 IU/dL
Interval 116.85 to 150.5
|
122.29 IU/dL
Interval 106.8 to 140.03
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Time required for the concentration of the drug to reach half of its original value.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
t½ as Measured by Two-Stage Chromogenic Clotting Assay
|
18.58 hours
Interval 16.35 to 21.12
|
19.10 hours
Interval 16.44 to 22.19
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
CL as Measured by Two-Stage Chromogenic Clotting Assay
|
1.962 mL/h/kg
Interval 1.665 to 2.311
|
2.006 mL/h/kg
Interval 1.72 to 2.339
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Vss as Measured by Two-Stage Chromogenic Clotting Assay
|
47.41 mL/kg
Interval 43.01 to 52.26
|
51.27 mL/kg
Interval 44.65 to 58.88
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
MRT as Measured by Two-Stage Chromogenic Clotting Assay
|
24.17 hours
Interval 21.16 to 27.6
|
25.56 hours
Interval 22.15 to 29.5
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Time at which maximum activity (Cmax) is observed.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=17 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=18 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Tmax as Measured by Two-Stage Chromogenic Clotting Assay
|
0.61 hours
Interval 0.51 to 0.71
|
0.61 hours
Interval 0.52 to 0.72
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Area under the plasma concentration time-curve from zero to the last measured concentration.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
AUClast as Measured by Two-Stage Chromogenic Clotting Assay
|
2555.4 IU*h/dL
Interval 2166.7 to 3013.9
|
2520.5 IU*h/dL
Interval 2124.4 to 2990.5
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
First order rate constant associated with the terminal portion of the curve (lambda z).
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay
|
0.03730 1/h
Interval 0.03282 to 0.04239
|
0.03629 1/h
Interval 0.03124 to 0.04216
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Percentage of AUCinf extrapolated from the last data point to infinity.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
AUCext as Measured by Two-Stage Chromogenic Clotting Assay
|
2.923 percentage of AUCinf
Interval 2.106 to 4.057
|
2.965 percentage of AUCinf
Interval 1.89 to 4.65
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
Dose normalized area under the FVIII activity-time curve.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
DNAUC as Measured by Two-Stage Chromogenic Clotting Assay
|
50.97 IU*h/dL per IU/kg
Interval 43.27 to 60.05
|
49.85 IU*h/dL per IU/kg
Interval 42.75 to 58.13
|
SECONDARY outcome
Timeframe: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injectionPopulation: The Pharmacokinetic Analysis Set is defined as all eligible participants who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.
The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=15 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
n=16 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Vz as Measured by Two-Stage Chromogenic Clotting Assay
|
52.59 mL/kg
Interval 47.31 to 58.47
|
55.28 mL/kg
Interval 47.12 to 64.84
|
SECONDARY outcome
Timeframe: Predose, Month 3, Month 6/early withdrawal. Additionally: If inhibitor suspected; at 10-15 EDs; 2-4 weeks prior to scheduled surgery; preoperatively on day of surgery; 1-2 weeks post-surgery; at last postoperative visit (last 2 for major surgery only)Population: The Safety Analysis Set included participants who received at least 1 dose of rFVIIIFc.
An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of participants with confirmed inhibitor development was summarized overall.
Outcome measures
| Measure |
rFVIIIFc 1000 IU
n=19 Participants
a single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial
|
rFVIIIFc 3000 IU
a single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial
|
|---|---|---|
|
Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay
|
0 percentage of participants
Interval 0.0 to 17.65
|
—
|
Adverse Events
Total Active
Serious adverse events
| Measure |
Total Active
n=19 participants at risk
Following the minimum 4-day washout, participants received their first injection of rFVIIIFc (on Injection 1 Day 1) rFVIIIFc 50 IU/kg at a strength of either 1000 or 3000 IU/vial. The second injection of rFVIIIFc 50 IU/kg at a strength of either 1000 or 3000 IU/vial was administered, in a crossover fashion, after a minimum of a 5-day washout (on Injection 2 Day 1).
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate participants who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
|---|---|
|
Congenital, familial and genetic disorders
Hydrocele
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Musculoskeletal and connective tissue disorders
Arthropathy
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
Other adverse events
| Measure |
Total Active
n=19 participants at risk
Following the minimum 4-day washout, participants received their first injection of rFVIIIFc (on Injection 1 Day 1) rFVIIIFc 50 IU/kg at a strength of either 1000 or 3000 IU/vial. The second injection of rFVIIIFc 50 IU/kg at a strength of either 1000 or 3000 IU/vial was administered, in a crossover fashion, after a minimum of a 5-day washout (on Injection 2 Day 1).
After completing the PK assessment, all participants began 1 of 3 continued treatment regimens for up to 6 months:
1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator's discretion as needed to prevent or treat bleeding.
2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate participants who were selected based on the opinion of the Investigator.
3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
|
|---|---|
|
Ear and labyrinth disorders
Tympanic membrane perforation
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Gastrointestinal disorders
Abdominal discomfort
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Infections and infestations
Influenza
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Infections and infestations
Nasopharyngitis
|
10.5%
2/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Infections and infestations
Oral herpes
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Infections and infestations
Post procedural cellulitis
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Infections and infestations
Upper respiratory tract infection
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Injury, poisoning and procedural complications
Contusion
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Injury, poisoning and procedural complications
Fall
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Injury, poisoning and procedural complications
Joint injury
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Injury, poisoning and procedural complications
Limb injury
|
10.5%
2/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Metabolism and nutrition disorders
Vitamin d deficiency
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Nervous system disorders
Headache
|
5.3%
1/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
|
Skin and subcutaneous tissue disorders
Acne
|
10.5%
2/19 • From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
|
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