Download PDF

Clinical Trial Results:
A Randomised, Open-label Study to Evaluate the Pharmacokinetics and Safety of Recombinant Factor VIII Fc Fusion Protein (Recombinant Coagulation Factor VIII Fc Fusion Protein [rFVIIIFc]; BIIB031) Manufactured at 15K Scale and at Different Vial Strengths in Previously Treated Subjects With Severe Hemophilia A

Summary
EudraCT number	2014-003895-21
Trial protocol	Outside EU/EEA
Global end of trial date	03 Apr 2017

Results information
Results version number	v1(current)
This version publication date	20 May 2021
First version publication date	20 May 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

997HA309

ISRCTN number

US NCT number

NCT02502149

WHO universal trial number (UTN)

Sponsor organisation name

Biogen MA Inc.

Sponsor organisation address

250 Binney Street, Cambridge, MA, United States, 02142

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

17 May 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Apr 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to compare the pharmacokinetics (PK) of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) manufactured at the current scale of 2000 litres (L) (2K [2000 litres bioreactor scale]) to the PK of rFVIIIFc manufactured at the 15,000 L (15K [15000 litres bioreactor scale]) scale in previously treated subjects with severe hemophilia A.

Protection of trial subjects

The study was conducted by investigators experienced in the treatment of adolescent and adult subjects. The parent(s) or guardian(s) as well as the subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in age-appropriate language was provided and explained to the subject. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. All subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in accordance with the trial subjects’ written informed consent and applicable personal data protection laws.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Aug 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 7

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

New Zealand: 12

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

The study was conducted at 11 active centres in 3 countries. 24 subjects were enrolled between 31 August 2015 and 4 August 2016. Washout period (between PK1 and PK2) started at the time of the PK1 dosing (PK1 assessment); at this stage 1 subject of 15K 6000 International Unit (IU)/vial cohort discontinued before entering PK2 assessment period.

Screening details

Subjects were randomised on Day 1 of PK 1 via the Interactive Voice/Web Response System in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc in the subsequent PK2 and PK3 assessments.

Period 1 title

Pharmacokinetic 1 (PK1) Assessment

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

2K rFVIIIFc (1000 IU/Vial Strength) (PK1)

Arm description

All subjects received rFVIIIFc (1000 IU/vial strength), 50 IU per kilogram (IU/kg), manufactured in 2K for PK1 assessment.

Arm type

Experimental

Investigational medicinal product name

Recombinant coagulation factor VIII Fc fusion protein

Investigational medicinal product code

Other name

rFVIIIFc; BIIB031

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

On Day 1, a single intravenous (IV) injection of 2K rFVIIIFc, 50 IU/kg of 1000 IU/vial.

Number of subjects in period 1	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
Started	24
Completed	24

Period 2 title

Washout Period (between PK1 and PK2)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

2K rFVIIIFc (1000 IU/Vial Strength) (PK1)

Arm description

All subjects received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K for PK1.

Arm type

Experimental

Investigational medicinal product name

Recombinant coagulation factor VIII Fc fusion protein

Investigational medicinal product code

Other name

rFVIIIFc; BIIB031

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

On Day 1, a single IV injection of 2K rFVIIIFc, 50 IU/kg of 1000 IU/vial.

Number of subjects in period 2	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)
Started	24
Completed	23
Not completed	1
Discontinued prematurely	1

Period 3 title

Treatment Period - PK2 Assessment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

15K rFVIIIFc (1000 IU/Vial Strength) (PK2)

Arm description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent pharmacokinetic 2 (PK2) assessment and pharmacokinetic 3 (PK3) assessment. For this treatment arm, subjects that received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2 after a minimum of 120 hours (hr) of washout prior to the PK2. Following PK2 assessment, subjects received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase of 13 weeks.

Arm type

Experimental

Investigational medicinal product name

Recombinant coagulation factor VIII Fc fusion protein

Investigational medicinal product code

Other name

rFVIIIFc; BIIB031

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Within 2 to 6 weeks after PK1 assessment, a single IV injection of 15K rFVIIIFc (1000 IU/vial strength), 50 IU/kg.

15K rFVIIIFc (6000 IU/Vial Strength) (PK2)

Arm description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. For this treatment arm, subjects that received rFVIIIFc (6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2 after a minimum of 120 hr of washout prior to the PK2. Following PK2 assessment, subjects received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase of 13 weeks.

Arm type

Experimental

Investigational medicinal product name

Recombinant coagulation factor VIII Fc fusion protein

Investigational medicinal product code

Other name

rFVIIIFc; BIIB031

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Within 2 to 6 weeks after PK1 assessment, a single IV injection of 15K rFVIIIFc (6000 IU/vial strength), 50 IU/kg.

Number of subjects in period 3	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Started	11	12
Completed	11	12

Period 4 title

Treatment Period - PK3 Assessment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

15K rFVIIIFc (1000 IU/Vial Strength) (PK3)

Arm description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. For this treatment arm, subjects that received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.

Arm type

Experimental

Investigational medicinal product name

Recombinant coagulation factor VIII Fc fusion protein

Investigational medicinal product code

Other name

rFVIIIFc; BIIB031

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

After 13 weeks of PK2 assessment, a single IV injection of 15K rFVIIIFc (1000 IU/vial strength), 50 IU/kg.

15K rFVIIIFc (6000 IU/Vial Strength) (PK3)

Arm description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. For this treatment arm, subjects that received rFVIIIFc (6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.

Arm type

Experimental

Investigational medicinal product name

Recombinant coagulation factor VIII Fc fusion protein

Investigational medicinal product code

Other name

rFVIIIFc; BIIB031

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

After 13 weeks of PK2 assessment, a single IV injection of 15K rFVIIIFc (6000 IU/vial strength), 50 IU/kg.

Number of subjects in period 4	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Started	11	12
Completed	11	12

Baseline characteristics

Top of page

Reporting group title

Pharmacokinetic 1 (PK1) Assessment

Reporting group description

All subjects received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K for PK1.

Reporting group values	Pharmacokinetic 1 (PK1) Assessment	Total
Number of subjects	24	24
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	30.8 ( 12.78 )	-
Gender categorical
Units: Subjects
Female	0	0
Male	24	24
Ethnicity
Units: Subjects
Hispanic or Latino	1	1
Not Hispanic or Latino	6	6
Not reported	17	17

End points

Top of page

Reporting group title

2K rFVIIIFc (1000 IU/Vial Strength) (PK1)

Reporting group description

All subjects received rFVIIIFc (1000 IU/vial strength), 50 IU per kilogram (IU/kg), manufactured in 2K for PK1 assessment.

Reporting group title

2K rFVIIIFc (1000 IU/Vial Strength) (PK1)

Reporting group description

All subjects received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K for PK1.

Reporting group title

15K rFVIIIFc (1000 IU/Vial Strength) (PK2)

Reporting group description

Reporting group title

15K rFVIIIFc (6000 IU/Vial Strength) (PK2)

Reporting group description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. For this treatment arm, subjects that received rFVIIIFc (6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2 after a minimum of 120 hr of washout prior to the PK2. Following PK2 assessment, subjects received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase of 13 weeks.

Reporting group title

15K rFVIIIFc (1000 IU/Vial Strength) (PK3)

Reporting group description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. For this treatment arm, subjects that received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.

Reporting group title

15K rFVIIIFc (6000 IU/Vial Strength) (PK3)

Reporting group description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. For this treatment arm, subjects that received rFVIIIFc (6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.

Subject analysis set title

15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomised to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2. Following PK2, subjects received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, subjects were re-evaluated at PK3 at the same vial strength as in PK2. A minimum of 120 hr of washout was observed prior to the PK2. Following the PK3, subjects resumed rFVIIIFc in the Treatment Period until they complete a total of at least 26 weeks of treatment.

Subject analysis set title

15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who were randomised to receive 15K rFVIIIFc 1000 or 6000 IU/vial for PK2 assessment were re-evaluated after 13 weeks on treatment for PK3 assessment at same vial strength.

Subject analysis set title

2K/15K rFVIIIFc (1000/6000 IU/Vial Strength)- All Subjects

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K for PK1. At PK1, subjects were randomised to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2. Following PK2 assessments, subjects received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, subjects were re-evaluated at PK3 at the same vial strength as in PK2. A minimum of 120 hr of washout was observed prior to the PK2 assessment. Following the PK3 assessment, subjects were resumed to treatment in the treatment period until they complete a total of at least 26 weeks of treatment.

Subject analysis set title

15K rFVIIIFc (1000 and 6000 IU/Vial Strength) (PK2 and PK3)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received 2K rFVIIIFc 1000 IU/vial (50 IU/kg) for PK1 were randomised to receive rFVIIIFc (1000 or 6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2. Following PK2, subjects received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase. After 13 weeks of treatment with 15K rFVIIIFc, subjects were re-evaluated at PK3 at the same vial strength as in PK2. A minimum of 120 hr of washout was observed prior to the PK2 assessment. Following the PK3, subjects were resumed to treatment in the Treatment Period until they complete a total of at least 26 weeks of treatment.

Primary: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) as Measured by One-stage Activated Partial Thromboplastin Time (aPTT) Clotting Assay for PK1 Assessment and PK2 Assessment

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) as Measured by One-stage Activated Partial Thromboplastin Time (aPTT) Clotting Assay for PK1 Assessment and PK2 Assessment

End point description

AUC0-inf is area under the concentration-time curve from time zero to infinity. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PK Analysis Set (PKAS) included all subjects who have evaluable PK profiles.

End point type

Primary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: IUhour per decilitre (IUhr/dL)
geometric mean (confidence interval 90%)	2255.6 (1886.2 to 2697.4)	2425.8 (2084.2 to 2823.4)

PK1 versus PK2

Statistical analysis description

The adjusted geometric mean ratio is calculated as 15K (PK2)/2K (PK1).

Comparison groups

2K rFVIIIFc (1000 IU/Vial Strength) (PK1) v 15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Adjusted Geometric Mean Ratio

Point estimate

1.08

Confidence interval

level

90%

sides

2-sided

lower limit

0.93

upper limit

1.24

Primary: Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Top of page

End point title

Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

End point description

IR is defined as the increase in the circulating FVIII activity in international unit per decilitre (IU/dL) per unit dose administered in international unit per kilogram (IU/kg) (IU/dL per IU/kg). Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Primary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: IU/dL per IU/kg
geometric mean (confidence interval 90%)	2.684 (2.364 to 3.049)	2.700 (2.458 to 2.964)

PK1 versus PK2

Statistical analysis description

The adjusted geometric mean ratio is calculated as 15K (PK2)/2K (PK1).

Comparison groups

2K rFVIIIFc (1000 IU/Vial Strength) (PK1) v 15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Adjusted Geometric Mean Ratio

Point estimate

1.01

Confidence interval

level

90%

sides

2-sided

lower limit

0.87

upper limit

1.16

Secondary: Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Top of page

End point title

Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

End point description

Cmax is defined as maximum activity of rFVIIIFc. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: IU/dL
geometric mean (confidence interval 95%)	133.20 (123.00 to 144.24)	134.67 (121.46 to 149.32)

No statistical analyses for this end point

Secondary: Half-life (t1/2) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Top of page

End point title

Half-life (t1/2) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

End point description

t1/2 is time required for the concentration of the drug to reach half of its original value. Results were summarised overall for 15K 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: hours
geometric mean (confidence interval 95%)	14.229 (12.458 to 16.252)	14.771 (12.910 to 16.900)

No statistical analyses for this end point

Secondary: Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Top of page

End point title

Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

End point description

CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after IV dose was estimated by dividing the total administered dose by AUC(0-infinity). Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: millilitreper hourper kilogram(mL/hr/kg)
geometric mean (confidence interval 95%)	2.1847 (1.8943 to 2.5198)	2.0420 (1.7421 to 2.3935)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Top of page

End point title

Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

End point description

Vss is defined as theoretical volume in which total amount of drug would need to be uniformly distributed to produce desired blood concentration of a drug. Vss is first moment curve extrapolated to infinity and AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 apparent Vss which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is dose of study drug, AUMC(0-infinity) is area under first moment curve extrapolated to infinity and AUC(0-infinity) is area under plasma concentration-time curve from time zero to infinite time. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: millilitre per kilogram (mL/kg)
geometric mean (confidence interval 95%)	43.80 (40.70 to 47.14)	43.01 (39.69 to 46.61)

No statistical analyses for this end point

Secondary: Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Top of page

End point title

Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

End point description

The 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)/ 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 summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: hours
geometric mean (confidence interval 95%)	20.048 (17.561 to 22.887)	21.063 (18.501 to 23.980)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

End point description

AUC0-inf is area under the concentration-time curve from time zero to infinity. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	21
Units: IU*hr/dL
geometric mean (confidence interval 95%)	2448.6 (2089.0 to 2870.1)	2697.8 (2295.1 to 3171.0)

No statistical analyses for this end point

Secondary: Incremental Recovery as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Top of page

End point title

Incremental Recovery as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

End point description

IR 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 summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	23
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)	2.693 (2.429 to 2.986)	2.804 (2.588 to 3.038)

No statistical analyses for this end point

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Top of page

End point title

Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

End point description

Cmax is defined as maximum activity of rFVIIIFc. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	23
Units: IU/dL
geometric mean (confidence interval 95%)	134.67 (121.46 to 149.32)	140.38 (129.62 to 152.04)

No statistical analyses for this end point

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Top of page

End point title

Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

End point description

t1/2 is time required for the concentration of the drug to reach half of its original value. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	21
Units: hours
geometric mean (confidence interval 95%)	14.771 (12.910 to 16.900)	15.493 (13.625 to 17.617)

No statistical analyses for this end point

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Top of page

End point title

Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

End point description

CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after IV dose was estimated by dividing the total administered dose by AUC(0-infinity). Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	21
Units: mL/hr/kg
geometric mean (confidence interval 95%)	2.0420 (1.7421 to 2.3935)	1.8556 (1.5786 to 2.1813)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Top of page

End point title

Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

End point description

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. 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 summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	21
Units: mL/kg
geometric mean (confidence interval 95%)	43.01 (39.69 to 46.61)	40.19 (37.44 to 43.14)

No statistical analyses for this end point

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Top of page

End point title

Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

End point description

MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC (0-infinity)/ 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 summarised overall for 15K rFVIIIFc 1000 IU/Vial and 6000 IU/Vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	21
Units: hours
geometric mean (confidence interval 95%)	21.063 (18.501 to 23.980)	21.657 (18.877 to 24.847)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

AUC0-inf is area under the concentration-time curve from time zero to infinity. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: IU*hr/dL
geometric mean (confidence interval 95%)	2356.8 (1950.4 to 2847.9)	2535.8 (1915.6 to 3356.8)

No statistical analyses for this end point

Secondary: Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

IR 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). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)	2.614 (2.186 to 3.126)	2.768 (2.408 to 3.181)

No statistical analyses for this end point

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

Cmax is defined as maximum activity of rFVIIIFc. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: IU/dL
geometric mean (confidence interval 95%)	130.73 (109.33 to 156.31)	138.40 (120.42 to 159.06)

No statistical analyses for this end point

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

t1/2 is time required for the concentration of the drug to reach half of its original value. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: hours
geometric mean (confidence interval 95%)	14.118 (11.469 to 17.379)	15.395 (12.555 to 18.879)

No statistical analyses for this end point

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic CL after IV dose was estimated by dividing the total administered dose by AUC(0-infinity). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: mL/hr/kg
geometric mean (confidence interval 95%)	2.1215 (1.7557 to 2.5635)	1.9718 (1.4895 to 2.6101)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

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. 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. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: mL/kg
geometric mean (confidence interval 95%)	42.61 (37.28 to 48.71)	43.38 (38.66 to 48.67)

No statistical analyses for this end point

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

The MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC (0-infinity)/ 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. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: hours
geometric mean (confidence interval 95%)	20.087 (16.333 to 24.704)	22.000 (18.193 to 26.603)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

AUC0-inf is area under the concentration-time curve from time zero to infinity. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	9	12
Units: IU*hr/dL
geometric mean (confidence interval 95%)	2634.5 (2079.8 to 3337.1)	2746.3 (2130.5 to 3539.9)

No statistical analyses for this end point

Secondary: Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

IR 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). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	11	12
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)	2.623 (2.343 to 2.936)	2.982 (2.650 to 3.355)

No statistical analyses for this end point

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

Cmax is defined as maximum activity of rFVIIIFc. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	11	12
Units: IU/dL
geometric mean (confidence interval 95%)	131.15 (117.18 to 146.80)	149.41 (132.99 to 167.86)

No statistical analyses for this end point

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

t1/2 is time required for the concentration of the drug to reach half of its original value. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	9	12
Units: hours
geometric mean (confidence interval 95%)	15.599 (12.925 to 18.826)	15.414 (12.593 to 18.868)

No statistical analyses for this end point

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after IV 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]). The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	9	12
Units: mL/hr/kg
geometric mean (confidence interval 95%)	1.8979 (1.4983 to 2.4041)	1.8246 (1.4151 to 2.3524)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

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. 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. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	9	12
Units: mL/kg
geometric mean (confidence interval 95%)	42.12 (36.95 to 48.02)	38.80 (35.47 to 42.43)

No statistical analyses for this end point

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	9	12
Units: hours
geometric mean (confidence interval 95%)	22.193 (17.923 to 27.480)	21.264 (17.247 to 26.216)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

End point description

AUC0-inf is area under the concentration-time curve from time zero to infinity. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: IU*hr/dL
geometric mean (confidence interval 95%)	2386.4 (2124.1 to 2681.0)	2777.6 (2453.0 to 3145.2)

No statistical analyses for this end point

Secondary: Incremental Recovery as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Top of page

End point title

Incremental Recovery as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

End point description

IR 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 summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)	2.807 (2.412 to 3.267)	3.253 (2.910 to 3.636)

No statistical analyses for this end point

Secondary: Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Top of page

End point title

Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

End point description

Cmax is defined as maximum activity of rFVIIIFc. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: IU/dL
geometric mean (confidence interval 95%)	140.36 (120.61 to 163.34)	162.73 (145.61 to 181.86)

No statistical analyses for this end point

Secondary: Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Top of page

End point title

Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

End point description

t1/2 is time required for the concentration of the drug to reach half of its original value. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: hours
geometric mean (confidence interval 95%)	17.312 (15.840 to 18.921)	18.146 (15.980 to 20.605)

No statistical analyses for this end point

Secondary: Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Top of page

End point title

Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: mL/hr/kg
geometric mean (confidence interval 95%)	2.0952 (1.8649 to 2.3539)	1.8001 (1.5897 to 2.0383)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Top of page

End point title

Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

End point description

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. 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 summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: mL/kg
geometric mean (confidence interval 95%)	46.87 (41.48 to 52.96)	42.02 (37.96 to 46.51)

No statistical analyses for this end point

Secondary: Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Top of page

End point title

Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

End point description

The MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC (0-infinity)/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 summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial (PK2). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)
Number of subjects analysed	24	23
Units: hours
geometric mean (confidence interval 95%)	22.370 (19.921 to 25.120)	23.342 (20.472 to 26.615)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

End point description

AUC0-inf is area under the concentration-time curve from time zero to infinity. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3.The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	20
Units: IU*hr/dL
geometric mean (confidence interval 95%)	2777.6 (2453.0 to 3145.2)	2754.9 (2312.2 to 3282.4)

No statistical analyses for this end point

Secondary: Incremental Recovery as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

Top of page

End point title

Incremental Recovery as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	23
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)	3.253 (2.910 to 3.636)	2.956 (2.656 to 3.289)

No statistical analyses for this end point

Secondary: Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

Top of page

End point title

Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	23
Units: IU/dL
geometric mean (confidence interval 95%)	162.73 (145.61 to 181.86)	147.97 (133.02 to 164.60)

No statistical analyses for this end point

Secondary: Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

Top of page

End point title

Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

End point description

t1/2 is the time required for the concentration of the drug to reach half of its original value. Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	20
Units: hours
geometric mean (confidence interval 95%)	18.146 (15.980 to 20.605)	17.289 (15.078 to 19.823)

No statistical analyses for this end point

Secondary: Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

Top of page

End point title

Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

End point description

CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after IV dose was estimated by dividing the total administered dose by AUC(0-infinity). Results were summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	20
Units: mL/hr/kg
geometric mean (confidence interval 95%)	1.8001 (1.5897 to 2.0383)	1.8173 (1.5251 to 2.1654)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured the Two-stage Chromogenic Assay for PK2 and PK3

Top of page

End point title

Volume of Distribution at Steady State of rFVIIIFc as Measured the Two-stage Chromogenic Assay for PK2 and PK3

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	20
Units: mL/kg
geometric mean (confidence interval 95%)	42.02 (37.96 to 46.51)	40.59 (36.01 to 45.75)

No statistical analyses for this end point

Secondary: Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

Top of page

End point title

Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 and PK3

End point description

The MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC (0-infinity)/ 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 summarised overall for 15K rFVIIIFc 1000 IU/vial and 6000 IU/vial for PK2 and PK3. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK2)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength Combined) (PK3)
Number of subjects analysed	23	20
Units: hours
geometric mean (confidence interval 95%)	23.342 (20.472 to 26.615)	22.337 (19.574 to 25.490)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

AUC0-inf is area under the concentration-time curve from time zero to infinity. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: IU*hr/dL
geometric mean (confidence interval 95%)	2599.2 (2257.2 to 2993.1)	2951.9 (2376.1 to 3667.2)

No statistical analyses for this end point

Secondary: Incremental Recovery of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Incremental Recovery of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

IR 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). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)	3.225 (2.643 to 3.936)	3.278 (2.835 to 3.792)

No statistical analyses for this end point

Secondary: Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

Cmax is defined as maximum activity of rFVIIIFc. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: IU/dL
geometric mean (confidence interval 95%)	161.38 (132.29 to 196.88)	163.97 (141.78 to 189.64)

No statistical analyses for this end point

Secondary: Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

t1/2 is time required for the concentration of the drug to reach half of its original value. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: hours
geometric mean (confidence interval 95%)	16.687 (14.593 to 19.080)	19.595 (15.680 to 24.488)

No statistical analyses for this end point

Secondary: Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/vial)

Top of page

End point title

Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/vial)

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: mL/hr/kg
geometric mean (confidence interval 95%)	1.9236 (1.6705 to 2.2152)	1.6938 (1.3634 to 2.1043)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

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. 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. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: mL/kg
geometric mean (confidence interval 95%)	41.15 (34.50 to 49.07)	42.83 (37.33 to 49.15)

No statistical analyses for this end point

Secondary: Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK2)	15K rFVIIIFc (6000 IU/Vial Strength) (PK2)
Number of subjects analysed	11	12
Units: hours
geometric mean (confidence interval 95%)	21.391 (17.713 to 25.833)	25.287 (20.729 to 30.847)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	8	12
Units: IU*hr/dL
geometric mean (confidence interval 95%)	2646.8 (1891.8 to 3703.0)	2829.4 (2235.7 to 3580.8)

No statistical analyses for this end point

Secondary: Incremental Recovery of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Incremental Recovery of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

IR 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). The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	11	12
Units: IU/dL per IU/kg
geometric mean (confidence interval 95%)	2.891 (2.413 to 3.464)	3.016 (2.597 to 3.504)

No statistical analyses for this end point

Secondary: Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

Cmax is defined as maximum activity of rFVIIIFc. The PKAS included all subjects who have evaluable PK profiles.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	11	12
Units: IU/dL
geometric mean (confidence interval 95%)	144.58 (120.66 to 173.25)	151.15 (130.34 to 175.28)

No statistical analyses for this end point

Secondary: Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	8	12
Units: hours
geometric mean (confidence interval 95%)	16.945 (13.793 to 20.818)	17.522 (14.213 to 21.601)

No statistical analyses for this end point

Secondary: Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	8	12
Units: mL/hr/kg
geometric mean (confidence interval 95%)	1.8891 (1.3502 to 2.6429)	1.7709 (1.3989 to 2.2419)

No statistical analyses for this end point

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

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. 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. The PKAS included all subjects who have evaluable PK profiles. Here, ‘number of subjects analysed’ signifies those subjects who were evaluable for this endpoints.

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	8	12
Units: mL/kg
geometric mean (confidence interval 95%)	41.78 (30.70 to 56.87)	39.82 (35.98 to 44.06)

No statistical analyses for this end point

Secondary: Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Top of page

End point title

Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

End point description

End point type

Secondary

End point timeframe

Pre-dose and post dose at: 0.5 hr, 1 hr, 6 hr, 24 hr, 48 hr, 72 hr and 96 hr

End point values	15K rFVIIIFc (1000 IU/Vial Strength) (PK3)	15K rFVIIIFc (6000 IU/Vial Strength) (PK3)
Number of subjects analysed	8	12
Units: hours
geometric mean (confidence interval 95%)	22.119 (17.717 to 27.614)	22.483 (18.532 to 27.277)

No statistical analyses for this end point

Secondary: Development of Inhibitors as Measured by the Nijmegen-modified Bethesda Assay

Top of page

End point title

Development of Inhibitors as Measured by the Nijmegen-modified Bethesda Assay

End point description

Defined as an inhibitor test result greater than or equal to (>=) 0.6 Bethesda units [BU]/mL, confirmed on 2 separate samples drawn approximately 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 subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of subjects with confirmed inhibitor development was summarised overall. The population analysed included all subjects who received at least 1 dose of rFVIIIFc.

End point type

Secondary

End point timeframe

At screening, predose on Day 1, and 13 and 26 weeks after PK2 injection or at Early Termination (Approximately 43 weeks)

End point values	2K/15K rFVIIIFc (1000/6000 IU/Vial Strength)- All Subjects
Number of subjects analysed	24
Units: percentage of subjects
number (confidence interval 95%)	0 (0 to 14.25)

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) at 15K Manufacturing Scale

Top of page

End point title

Number of Subjects With Treatment Emergent Adverse Events (TEAEs) at 15K Manufacturing Scale

End point description

An AE was any untoward medical occurrence in a subject or clinical investigation subject 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 subjects with TEAEs were summarised overall. The population analysed included all subjects who received at least 1 dose of rFVIIIFc at 15k manufacturing scale.

End point type

Secondary

End point timeframe

Approximately 43 weeks

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength) (PK2 and PK3)
Number of subjects analysed	23
Units: subjects
number (not applicable)	10

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent Serious Adverse Events (TESAEs) at 15K Manufacturing Scale

Top of page

End point title

Number of Subjects With Treatment Emergent Serious Adverse Events (TESAEs) at 15K Manufacturing Scale

End point description

An SAE was any untoward medical occurrence that at any dose: resulted in death or in the view of the Investigator, places the subject at immediate risk of death (a life-threatening event); required inpatient hospitalisation or prolongation of existing hospitalisation; resulted in persistent or significant disability/incapacity; or resulted 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 jeopardise the subject or may required intervention to prevent one of the other outcomes listed in the SAE definition. Number of subjects with TESAEs were summarised overall. The population analysed included all subjects who received at least 1 dose of rFVIIIFc at 15k manufacturing scale.

End point type

Secondary

End point timeframe

Approximately 43 weeks

End point values	15K rFVIIIFc (1000 and 6000 IU/Vial Strength) (PK2 and PK3)
Number of subjects analysed	23
Units: subjects
number (not applicable)	0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Approximately 43 weeks

Adverse event reporting additional description

Safety Population included all subjects who received at least 1 dose of rFVIIIFc. AEs are reported based on overall number of subjects treated with 2K rFVIIIFc at 1000 IU/vial strength (PK1 assessment & Intermediate period) and 15K rFVIIIFc at 1000 & 6000 IU/vial strength (PK2 assessment period & Treatment Period [including PK3 assessment period]).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

2K rFVIIIFc (1000 IU/Vial Strength) (PK1)

Reporting group description

All subjects received rFVIIIFc (1000 IU/vial strength), 50 IU/kg, manufactured in 2K for PK1.

Reporting group title

15K rFVIIIFc (1000 and 6000 IU/Vial Strength)

Reporting group description

During the PK1 assessment period, subjects randomised in a 1:1 ratio to receive either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc (a single IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. Subjects received rFVIIIFc (1000/6000 IU/vial strength), 50 IU/kg, manufactured in 15K for PK2/PK3 after a minimum of 120 hr of washout prior to the PK2. Following PK2 assessment, subjects received prophylactic treatment with any of 5 available 15K vial strengths during the treatment phase of 13 weeks.

Serious adverse events	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	2K rFVIIIFc (1000 IU/Vial Strength) (PK1)	15K rFVIIIFc (1000 and 6000 IU/Vial Strength)
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 24 (0.00%)	3 / 23 (13.04%)
Nervous system disorders
Headache
subjects affected / exposed	0 / 24 (0.00%)	3 / 23 (13.04%)
occurrences all number	0	3

More information

Top of page

Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) as Measured by One-stage Activated Partial Thromboplastin Time (aPTT) Clotting Assay for PK1 Assessment and PK2 Assessment

Primary: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) as Measured by One-stage Activated Partial Thromboplastin Time (aPTT) Clotting Assay for PK1 Assessment and PK2 Assessment

Primary: Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Primary: Incremental Recovery (IR) as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Maximum Activity (Cmax) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Half-life (t1/2) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Half-life (t1/2) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Clearance (CL) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Volume of Distribution at Steady State (Vss) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Mean Residence Time (MRT) of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK1 and PK2

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Incremental Recovery as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Incremental Recovery as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 and PK3

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK2 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Incremental Recovery of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Maximum Activity of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Half-life of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Clearance of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Mean Residence Time of rFVIIIFc as Measured by One-stage aPTT Clotting Assay for PK3 at Different Vial Strengths (1000 and 6000 IU/Vial)

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Incremental Recovery as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Incremental Recovery as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Maximum Activity of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Half-life of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Clearance of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Volume of Distribution at Steady State of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Mean Residence Time of rFVIIIFc as Measured by the Two-stage Chromogenic Assay for PK1 and PK2

Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity as Measured by the Two-stage Chromogenic Assay for PK2 and PK3