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Clinical Trial Results:
A Phase 3 clinical study to determine the pharmacokinetics, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes in subjects diagnosed with von Willebrand disease

Summary
EudraCT number	2010-024108-84
Trial protocol	GB DE SE AT NL BE BG IT ES
Global end of trial date	15 Feb 2014

Results information
Results version number	v2(current)
This version publication date	12 Mar 2016
First version publication date	07 Aug 2015
Other versions	v1
Version creation reason	New data added to full data set Statistics added in justifications for endpoints 1-3 as unable to add statistics to these endpoints in EudraCT due to EudraCT limitation of not currently accepting statistics for one analysis group. Adverse Events updated. Minor changes to descriptive text.

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

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Trial information

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Sponsor protocol code

071001

ISRCTN number

US NCT number

NCT01410227

WHO universal trial number (UTN)

Sponsor organisation name

Baxalta Innovations GmbH

Sponsor organisation address

Industriestrasse 67, Vienna, Austria, 1221

Public contact

Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com

Scientific contact

Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com

Sponsor organisation name

Baxalta US Inc.

Sponsor organisation address

One Baxter Way, Westlake Village, United States, CA 91362

Public contact

Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com

Scientific contact

Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.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?

Analysis stage

Final

Date of interim/final analysis

15 Feb 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Feb 2014

Was the trial ended prematurely?

Main objective of the trial

The objectives of this study were: To compare the pharmacokinetic (PK) parameters of recombinant von Willebrand Factor (rVWF) alone or concomitantly with recombinant Factor VIII (rFVIII) [rVWF:rFVIII] in subjects with type 3 von Willebrand Disease (VWD); To examine the PK parameters of rVWF in subjects with severe VWD; To evaluate the hemostatic efficacy, safety, and tolerability of rVWF:rFVIII and rVWF alone in subjects with VWD receiving the investigational product for the treatment of bleeding episodes (BEs); To evaluate tolerability and safety of rVWF including the development of inhibitory and total binding anti-VWF antibodies and clinically significant changes in laboratory parameters following study product administration; To assess changes in Health-Related Quality of Life (HRQoL)

Protection of trial subjects

This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Jan 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Bulgaria: 2

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

India: 1

Country: Number of subjects enrolled

Italy: 3

Country: Number of subjects enrolled

Japan: 3

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

Australia: 2

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

United States: 8

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

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Recruitment details

Subjects were enrolled (signed informed consent) from 30 sites in 15 countries.

Screening details

49 subjects provided informed consent and were screened for study, of which 37 were exposed to study product. Reasons for discontinuation are provided in Pre-assignment period.

Number of subjects started

49 ^[1]

Number of subjects completed

Reason: Number of subjects

Consent withdrawn by subject: 3

Reason: Number of subjects

Physician decision: 1

Reason: Number of subjects

Screen failure: 6

Reason: Number of subjects

High doses of rFVIII for oral procedure: 1

Reason: Number of subjects

Arm for which subject eligible was closed: 1

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The worldwide number of subjects enrolled are for subjects treated with study product (N=37) as per definition in EudraCT (Enrolled=Treated) and the number of subjects who started pre-assignment are all subjects enrolled i.e. signed informed consent (N=49).

Period 1 title

Overall Trial (Part A and B Combined) (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Blinding implementation details

Part Randomized: Subjects in Arms 1 and 2 were randomized at ratio of 1:1 to receive either recombinant von Willebrand Factor:recombinant Factor VIII (rVWF:rFVIII) or rVWF:saline (placebo) for pharmacokinetic (PK) analysis. After a washout period, subjects crossed over to receive the alternative treatment to the initial infusion for a further PK analysis. Subject/investigator were blinded and the study product was reconstituted by an unblinded third party (preferably by the hospital pharmacist)

Are arms mutually exclusive

PK50+Treatment

Arm description

In Part A, (pharmacokinetic [PK] assessment followed by on-demand treatment for bleeding episodes [BEs] for 6 months) subjects were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) [rVWF] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline. Subjects then crossed over to the alternate infusion after washout (PK). For on-demand treatment, subjects received study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual subject's PK data at discretion of investigator). In part, B subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months.

Arm type

Experimental

Investigational medicinal product name

rVWF:rFVIII

Investigational medicinal product code

BAX111 with ADVATE

Other name

vonicog alfa with ADVATE

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

PK50 only

Arm description

In Part A, (pharmacokinetic [PK] assessment followed by on-demand treatment for bleeding episodes [BEs] for 6 months) subjects were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) [rVWF] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline. Subjects then crossed over to the alternate infusion after washout (PK). For on-demand treatment, subjects received study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual subject's PK data at discretion of investigator). Subjects then exited the study or could opt to sign informed consent to move to Arm 1 receive treatment for bleeding episodes with study product.

Arm type

Experimental

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

rVWF:rFVIII

Investigational medicinal product code

BAX111 with ADVATE

Other name

vonicog alfa with ADVATE

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PK80+Treatment

Arm description

In Part A, subjects underwent pharmacokinetic (PK) assessment for 2 infusions of recombinant von Willebrand Factor (rVWF). Subjects initially underwent an initial PK assessment of an infusion of 80 IU/kg recombinant von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF]. After the first PK assessment subjects received on demand treatment for bleeding episodes (BEs) with study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rWVF with or without rFVIII, based on FVIII levels. If FVIII levels not available, the individual subject's PK data was used to determine rFVIII dose at discretion of investigator. Subjects received on demand treatment for 6 months after the first study product infusion. After 6 months subjects underwent a second PK assessment of an infusion of 80 IU/kg rVWF. In part B, subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months.

Arm type

Experimental

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

rVWF:rFVIII

Investigational medicinal product code

BAX111 with ADVATE

Other name

vonicog alfa with ADVATE

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Treatment

Arm description

In Part A, subjects received on demand treatment for bleeding episodes (BEs) with study product (recombinant von Willebrand Factor [rVWF] administered together with recombinant Factor VIII [rFVIII] (rVWF:rFVIII) or rVWF alone), where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels. If not available, the individual subject's PK data was used to determine rFVIII dose at discretion of investigator. Subjects received on demand treatment for 6 months after the first study product infusion. In part, B subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months. No pharmacokinetic (PK) assessments were conducted in this arm.

Arm type

Experimental

Investigational medicinal product name

rVWF:rFVIII

Investigational medicinal product code

BAX111 with ADVATE

Other name

vonicog alfa with ADVATE

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Safety Analysis Set

Arm description

The Safety Analysis Set comprises of subjects who were treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) at least once during the study.

Arm type

Experimental

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

rVWF:rFVIII

Investigational medicinal product code

BAX111 with ADVATE

Other name

vonicog alfa with ADVATE

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Full Analysis Set

Arm description

The Full Analysis Set comprised of subjects treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) for whom at least one efficacy rating scale was available.

Arm type

Experimental

Investigational medicinal product name

rVWF:rFVIII

Investigational medicinal product code

BAX111 with ADVATE

Other name

vonicog alfa with ADVATE

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PK50 Arms

Arm description

The PK50 arm comprised of subjects who underwent PK analysis of study product (50 IU/kg recombinant von Willebrand Factor (rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline [rVWF]) i.e. a total subjects from Arm 1 [PK50+Treatment] and Arm 2 [PK50 only]. Subjects in this arm have received at least one PK infusion and have provided data suitable for PK analysis. Only PK data included in this arm.

Arm type

Experimental

Investigational medicinal product name

rVWF:rFVIII

Investigational medicinal product code

BAX111 with ADVATE

Other name

vonicog alfa with ADVATE

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PK80 Arm

Arm description

The PK80 arm comprised of subjects who underwent PK analysis of study product (80 IU/kg recombinant von Willebrand Factor [rVWF]) i.e. subjects from Arm 3 [PK80+Treatment]. Subjects in this arm have received at least one PK infusion and have provided data suitable for PK analysis. Only PK data included in this arm.

Arm type

Experimental

Investigational medicinal product name

rVWF

Investigational medicinal product code

BAX111

Other name

vonicog alfa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1	PK50+Treatment	PK50 only	PK80+Treatment	Treatment	Safety Analysis Set	Full Analysis Set	PK50 Arms	PK80 Arm
Started	8	8	15	6	37	22	16	15
Completed	4	8	13	5	30	20	16	13
Not completed	4	0	2	1	7	2	0	2
Consent withdrawn by subject	3	-	1	-	4	2	-	1
Adverse event, non-fatal	1	-	-	-	1	-	-	-
Pregnancy	-	-	-	1	1	-	-	-
met exclusion criteria after starting study	-	-	1	-	1	-	-	1

Baseline characteristics

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Reporting group title

Overall Trial (Part A and B Combined)

Reporting group description

Overall Trial (Part A and B Combined)

Reporting group values	Overall Trial (Part A and B Combined)	Total
Number of subjects	37
Age categorical
Units: Subjects
Age continuous
Units: years
median (full range (min-max))	37 (18 to 64)	-
Gender categorical
Units:
Female	20	20
Male	17	17

End points

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Reporting group title

PK50+Treatment

Reporting group description

Reporting group title

PK50 only

Reporting group description

In Part A, (pharmacokinetic [PK] assessment followed by on-demand treatment for bleeding episodes [BEs] for 6 months) subjects were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) [rVWF] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline. Subjects then crossed over to the alternate infusion after washout (PK). For on-demand treatment, subjects received study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual subject's PK data at discretion of investigator). Subjects then exited the study or could opt to sign informed consent to move to Arm 1 receive treatment for bleeding episodes with study product.

Reporting group title

PK80+Treatment

Reporting group description

Reporting group title

Treatment

Reporting group description

Reporting group title

Safety Analysis Set

Reporting group description

Reporting group title

Full Analysis Set

Reporting group description

Reporting group title

PK50 Arms

Reporting group description

Reporting group title

PK80 Arm

Reporting group description

Primary: Percentage of subjects with treatment success for treated bleeding episodes

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End point title

Percentage of subjects with treatment success for treated bleeding episodes ^[1] ^[2]

End point description

Treatment success was defined as the extent of control of bleeding episodes (BEs) using a mean efficacy rating score of <2.5 for a subject’s BEs treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) during the study period. Scores used: Excellent = 1 - actual infusions ≤ estimated number of infusions required to treat BE; no additional VWF required (all BEs); Good = 2 - >1-2 infusions (minor/moderate BEs) or <1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); Moderate = 3 ≥ 3 infusions (minor/moderate BEs) or ≥ 1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); None = 4 - severe uncontrolled bleeding or intensity of bleeding not changed; additional VWF required. Included subjects with available primary efficacy rating (prospective-excluding gastrointestinal bleeds) in the Full Analysis Set

End point type

Primary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Currently unable to enter statistics for one analysis group (Full Analysis Set). The null hypothesis H0: p ≤ 0.65 was tested against alternative hypothesis HA: p > 0.65 by two-sided Clopper Pearson 90% CI. Results: Success rate: 100% (90% CI: 84.7-100%).
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Refer to [1]

End point values	Full Analysis Set
Number of subjects analysed	18
Units: Percent of subjects
number (confidence interval 90%)	100 (84.7 to 100)

No statistical analyses for this end point

Secondary: Percentage of treated bleeding episodes treated with an efficacy rating of "excellent" or "good"

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End point title

Percentage of treated bleeding episodes treated with an efficacy rating of "excellent" or "good" ^[3]

End point description

Efficacy ratings "excellent" or "good" for the control of bleeding episodes (BEs) with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are defined as follows: Excellent - actual infusions ≤ estimated number of infusions required to treat BE; no additional von Willebrand Factor (VWF) required (all BEs); Good - >1-2 infusions (minor/moderate BEs) or <1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs). The data set included prospectively estimated BEs [N=130] treated with study product with an available efficacy rating from subjects in the Full Analysis Set.

End point type

Secondary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Currently unable to enter statistics for one analysis group (Full Analysis Set). The null hypothesis H0: p ≤ 0.65 was tested against alternative hypothesis HA: p > 0.65 by two-sided Clopper Pearson 90% CI. Results: Success rate: 100% (90% CI: 97.7-100%).

End point values	Full Analysis Set
Number of subjects analysed	22
Units: Percent of bleeding episodes
number (confidence interval 90%)	100 (97.7 to 100)

No statistical analyses for this end point

Secondary: Percentage of treated bleeding episodes with an efficacy rating of "excellent" or "good", excluding gastrointestinal bleeds

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End point title

Percentage of treated bleeding episodes with an efficacy rating of "excellent" or "good", excluding gastrointestinal bleeds ^[4]

End point description

Efficacy ratings of "excellent" or "good" for the control of bleeding episodes (BEs) with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are defined as follows: Excellent - actual infusions ≤ estimated number of infusions required to treat BE; no additional von Willebrand Factor (VWF) required (all BEs); Good - >1-2 infusions (minor/moderate BEs) or <1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs). The data set included prospectively estimated BEs [N=126] excluding gastrointestinal (GI) bleeds treated with study product with an available efficacy rating from subjects in the Full Analysis Set.

End point type

Secondary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Currently unable to enter statistics for one analysis group (Full Analysis Set). The null hypothesis H0: p ≤ 0.65 was tested against alternative hypothesis HA: p > 0.65 by two-sided Clopper Pearson 90% CI. Results: Success rate: 100% (90% CI: 84.7-100%).

End point values	Full Analysis Set
Number of subjects analysed	22
Units: Percent of bleeding episodes
geometric mean (confidence interval 90%)	100 (97.7 to 100)

No statistical analyses for this end point

Secondary: Number of infusions of rVWF:rFVIII and/or rVWF per bleeding episode

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End point title

Number of infusions of rVWF:rFVIII and/or rVWF per bleeding episode ^[5]

End point description

The actual number of infusions of recombinant von Willebrand factor:recombinant factor VIII (rVWF:rFVIII) and/or rVWF required to treat a bleeding episode (BE). BEs were to be initially treated with an infusion of rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels, if available. In cases, where no FVIII levels were available, the individual subject’s PK data was used to determine the rFVIII dose. The data set included prospectively estimated BEs [N=192] treated with study product with an available efficacy rating from subjects in the Full Analysis Set.

End point type

Secondary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Full Analysis Set
Number of subjects analysed	22
Units: Number of infusions
median (confidence interval 90%)	1 (1 to 1)

No statistical analyses for this end point

Secondary: Number of units of rVWF:rFVIII and/or rVWF per bleeding episode

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End point title

Number of units of rVWF:rFVIII and/or rVWF per bleeding episode ^[6]

End point description

The number of units is provided as the actual dose [IU/kg] of recombinant von Willebrand factor:recombinant factor VIII (rVWF:rFVIII) and/or rVWF required to treat a bleeding episode (BE). BEs were to be initially treated with an infusion of rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels, if available. In cases, where no FVIII levels were available, the individual subject’s PK data was used to determine the rFVIII dose. The data set included BEs [N=174] treated with study product of known lot number with an available efficacy rating from subjects in the Full Analysis Set.

End point type

Secondary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Full Analysis Set
Number of subjects analysed	22
Units: IU/kg
median (confidence interval 90%)	48.2 (43.9 to 50.2)

No statistical analyses for this end point

Secondary: Percentage of subjects who develop inhibitory antibodies to FVIII

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End point title

Percentage of subjects who develop inhibitory antibodies to FVIII ^[7]

End point description

Development of neutralizing antibodies (inhibitors) to factor VIII (FVIII) was assessed by the Nijmegen modification of the Bethesda assay. Positive FVIII inhibitor tests were defined as ≥ 0.4 Bethesda units/mL (BU/mL) by the Nijmegen-modified Bethesda assay that is confirmed by a second test performed on an independent sample obtained 2-4 weeks following the first test. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Percent of subjects
number (not applicable)
Before 1st treatment with study product [N=37]	0
During 1st treatment until study end [N=27]	0
At final study visit [N=24]	0

No statistical analyses for this end point

Secondary: Percentage of subjects who develop inhibitory antibodies to VWF

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End point title

Percentage of subjects who develop inhibitory antibodies to VWF ^[8]

End point description

Neutralizing antibodies (inhibitors) to Von Willebrand Factor Ristocetin cofactor (VWF:RCo), VWF collagen binding (VWF:CB) and VWF Factor VIII binding (VWF:FVIIIB) activities were measured using Nijmegen modification of the Bethesda assay. One Bethesda Unit (BU) is thereby defined as the amount of inhibitor that decreased the measured activity in the assays to 50% of that of the negative control samples. The assays were validated using human plasma samples from two type 3 VWD patients with low (1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from non-human primates immunized with human rVWF (>100 BU/mL). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Arms in the baseline period are not mutually exclusive - refer to Arm Descriptions in Period 1 (baseline period). Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Percent of subjects
number (not applicable)
Before 1st treatment with study product [N=37]	0
During 1st treatment until study end [N=27]	0
At final study visit [N=24]	0

No statistical analyses for this end point

Secondary: Percentage of subjects who develop binding antibodies to VWF

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End point title

Percentage of subjects who develop binding antibodies to VWF ^[9]

End point description

The presence of total binding anti-VWF antibodies was determined by an enzyme-linked immunosorbent assay (ELISA) employing polyclonal anti-human immunoglobulin (Ig) antibodies (IgG, IgM and IgA). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Percent of subjects
number (not applicable)
Before 1st treatment with study product [N=37]	0
During 1st treatment until study end [N=28]	0
At final study visit [N=24]	0

No statistical analyses for this end point

Secondary: Percentage of subjects who develop binding antibodies to CHO

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End point title

Percentage of subjects who develop binding antibodies to CHO ^[10]

End point description

The presence of total binding anti-CHO antibodies was determined by measuring total immunoglobulin (Ig) antibodies (IgG, IgA, IgM) against Chinese Hamster Ovary (CHO) protein using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Percent of subjects
number (not applicable)
Before 1st treatment with study product [N=37]	0
During 1st treatment until study end [N=28]	0
At final study visit [N=24]	0

No statistical analyses for this end point

Secondary: Percentage of subjects who develop binding antibodies to rFurin

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End point title

Percentage of subjects who develop binding antibodies to rFurin ^[11]

End point description

The presence of total binding anti-rFurin antibodies was determined by measuring total immunoglobulin (Ig) antibodies (IgG, IgA, IgM) against rFurin protein using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Percent of subjects
number (not applicable)
Before 1st treatment with study product [N=37]	0
During 1st treatment until study end [N=28]	0
At final study visit [N=24]	0

No statistical analyses for this end point

Secondary: Percentage of subjects who develop binding antibodies to mouse immunoglobulin

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End point title

Percentage of subjects who develop binding antibodies to mouse immunoglobulin ^[12]

End point description

The presence of total binding anti-Murine immunoglobulin (IgG) antibodies was determined using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	36
Units: Percent of subjects
number (not applicable)
Before 1st treatment with study product [N=36]	2.8
During 1st treatment until study end [N=28]	0
At final study visit [N=24]	0

No statistical analyses for this end point

Secondary: Percentage of subjects who had an occurrence of thrombotic events

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End point title

Percentage of subjects who had an occurrence of thrombotic events ^[13]

End point description

End point type

Secondary

End point timeframe

After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Percent of subjects
number (not applicable)	0

No statistical analyses for this end point

Secondary: Number of adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

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End point title

Number of adverse events related to study product including clinically significant changes in laboratory parameters and vital signs ^[14]

End point description

Adverse Events (AEs) related to study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS) Category title includes number of AEs [N] for the category.

End point type

Secondary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Number of AEs
SAE-GEN-Chest discomfort [N=1]	1
SAE-INV-Heart rate increased [N=1]	1
nsAE-CARD-Tachycardia [N=1]	1
nsAE-GEN-Infusion site paraesthesia [N=1]	1
nsAE-INV-ECG T wave inversion [N=1]	1
nsAE-NERV-Dysgeusia [N=1]	1
nsAE-SKN-Pruritus generalized [N=1]	1
nsAE-VAS-Hot flush [N=1]	1

No statistical analyses for this end point

Secondary: Number of subjects with adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

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End point title

Number of subjects with adverse events related to study product including clinically significant changes in laboratory parameters and vital signs ^[15]

End point description

Number of subjects with Adverse Events (AEs) related to study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS)

End point type

Secondary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Number of subjects
SAE-GEN-Chest discomfort	1
SAE-INV-Heart rate increased	1
nsAE-CARD-Tachycardia	1
nsAE-GEN-Infusion site paraesthesia	1
nsAE-INV-ECG T wave inversion	1
nsAE-NERV-Dysgeusia	1
nsAE-SKN-Pruritus generalized	1
nsAE-VAS-Hot flush	1

No statistical analyses for this end point

Secondary: Number of adverse events by infusion related to study product including clinically significant changes in laboratory parameters and vital signs

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End point title

Number of adverse events by infusion related to study product including clinically significant changes in laboratory parameters and vital signs ^[16]

End point description

Adverse Events (AEs) by infusion related to study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS). A total of 318 infusions were given. Category title includes number of AEs by infusion [N] for the category.

End point type

Secondary

End point timeframe

for 12 months after first infusion of rVWF:rFVIII or rVWF

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	Safety Analysis Set
Number of subjects analysed	37
Units: Number of AEs
SAE-GEN-Chest discomfort [N=1]	1
SAE-INV-Heart rate increased [N=1]	1
nsAE-CARD-Tachycardia [N=1]	1
nsAE-GEN-Infusion site paraesthesia [N=1]	1
nsAE-INV-ECG T wave inversion [N=1]	1
nsAE-NERV-Dysgeusia [N=1]	1
nsAE-SKN-Pruritus generalized [N=1]	1
nSAE-VAS-Hot flush [N=1]	1

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo ^[17]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	32.4 (27.5 to 40.1)
rVWF [N=14]	32.7 (29 to 47.8)

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo ^[18]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	31.6 (27.3 to 37.3)
rVWF [N=14]	31.3 (28.4 to 43.7)

No statistical analyses for this end point

Secondary: PK50 - Mean Residence Time of VWF:RCo

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End point title

PK50 - Mean Residence Time of VWF:RCo ^[19]

End point description

Mean Residence Time (MRT) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: Hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	25.2 (20 to 30.1)
rVWF [N=14]	26.7 (22.7 to 36)

No statistical analyses for this end point

Secondary: PK50 - Clearance of VWF:RCo

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End point title

PK50 - Clearance of VWF:RCo ^[20]

End point description

Clearance (CL) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2) Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg/hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.031 (0.025 to 0.041)
rVWF [N=14]	0.031 (0.021 to 0.035)

No statistical analyses for this end point

Secondary: PK50 - Incremental Recovery of VWF:RCo

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End point title

PK50 - Incremental Recovery of VWF:RCo ^[21]

End point description

Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	1.8 (1.6 to 2.4)
rVWF [N=14]	1.8 (1.5 to 2.2)

No statistical analyses for this end point

Secondary: PK50 - Elimination Phase Half-Life of VWF:Co

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End point title

PK50 - Elimination Phase Half-Life of VWF:Co ^[22]

End point description

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2).. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	16.6 (14.7 to 20.4)
rVWF [N=14]	19.4 (15.5 to 31.3)

No statistical analyses for this end point

Secondary: PK50 - Volume of Distribution at Steady State of VWF:RCo

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End point title

PK50 - Volume of Distribution at Steady State of VWF:RCo ^[23]

End point description

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.7 (0.66 to 0.93)
rVWF [N=14]	0.83 (0.7 to 0.97)

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag ^[24]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	67.8 (55.1 to 81.7)
rVWF [N=14]	67.1 (55.6 to 80.5)

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag ^[25]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	62.1 (52.8 to 74.9)
rVWF [N=14]	62.2 (54.7 to 74.5)

No statistical analyses for this end point

Secondary: PK50 - Mean Residence Time of VWF:Ag

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End point title

PK50 - Mean Residence Time of VWF:Ag ^[26]

End point description

Mean Residence Time (MRT) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	32.1 (29.8 to 41.1)
rVWF [N=14]	34.3 (30.4 to 41.4)

No statistical analyses for this end point

Secondary: PK50 - Clearance of VWF:Ag

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End point title

PK50 - Clearance of VWF:Ag ^[27]

End point description

Clearance (CL) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg/hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.015 (0.013 to 0.018)
rVWF [N=14]	0.015 (0.013 to 0.018)

No statistical analyses for this end point

Secondary: PK50 - Incremental Recovery of VWF:Ag

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End point title

PK50 - Incremental Recovery of VWF:Ag ^[28]

End point description

Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	2.3 (2 to 2.5)
rVWF [N=14]	2.2 (1.9 to 2.5)

No statistical analyses for this end point

Secondary: PK50 - Elimination Phase Half-Life of VWF:Ag

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End point title

PK50 - Elimination Phase Half-Life of VWF:Ag ^[29]

End point description

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	21.8 (19.5 to 27.2)
rVWF [N=14]	25.2 (21.9 to 30.3)

No statistical analyses for this end point

Secondary: PK50 - Volume of Distribution at Steady State of VWF:Ag

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End point title

PK50 - Volume of Distribution at Steady State of VWF:Ag ^[30]

End point description

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.5 (0.45 to 0.56)
rVWF [N=14]	0.49 (0.45 to 0.58)

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB ^[31]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	80.1 (68.4 to 95)
rVWF [N=14]	81.3 (71.2 to 99.8)

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB ^[32]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	78.7 (66.5 to 90.5)
rVWF [N=14]	75.1 (69.2 to 97)

No statistical analyses for this end point

Secondary: PK50 - Mean Residence Time of VWF:CB

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End point title

PK50 - Mean Residence Time of VWF:CB ^[33]

End point description

Mean Residence Time (MRT) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	27.5 (22.7 to 32.1)
rVWF [N=14]	26.1 (25.1 to 33.2)

No statistical analyses for this end point

Secondary: PK50 - Clearance of VWF:CB

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End point title

PK50 - Clearance of VWF:CB ^[34]

End point description

Clearance (CL) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg/hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.012 (0.011 to 0.015)
rVWF [N=14]	0.012 (0.011 to 0.015)

No statistical analyses for this end point

Secondary: PK50 - Incremental Recovery of VWF:CB

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End point title

PK50 - Incremental Recovery of VWF:CB ^[35]

End point description

Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	3.4 (3 to 3.7)
rVWF [N=14]	3.2 (2.8 to 3.7)

No statistical analyses for this end point

Secondary: PK50 - Elimination Phase Half-Life of VWF:CB

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End point title

PK50 - Elimination Phase Half-Life of VWF:CB ^[36]

End point description

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	19.3 (14.9 to 23.4)
rVWF [N=14]	18.3 (17.4 to 24.8)

No statistical analyses for this end point

Secondary: PK50 - Volume of Distribution at Steady State of VWF:CB

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End point title

PK50 - Volume of Distribution at Steady State of VWF:CB ^[37]

End point description

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.35 (0.31 to 0.4)
rVWF [N=14]	0.36 (0.28 to 0.42)

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C ^[38]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	145.4 (118.8 to 189.5)
rVWF [N=14]	113 (93 to 167.4)

No statistical analyses for this end point

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C

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End point title

PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C ^[39]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	127.8 (112.3 to 145.1)
rVWF [N=14]	101.8 (74.4 to 124.4)

No statistical analyses for this end point

Secondary: PK50 - Mean Residence Time of FVIII:C

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End point title

PK50 - Mean Residence Time of FVIII:C ^[40]

End point description

Mean Residence Time (MRT) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	44 (38 to 75)
rVWF [N=0]	0 (0 to 0)

No statistical analyses for this end point

Secondary: PK50 - Clearance of FVIII:C

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End point title

PK50 - Clearance of FVIII:C ^[41]

End point description

Clearance (CL) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg/hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.007 (0.006 to 0.009)
rVWF [N=0]	0 (0 to 0)

No statistical analyses for this end point

Secondary: PK50 - Incremental Recovery of FVIII:C

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End point title

PK50 - Incremental Recovery of FVIII:C ^[42]

End point description

Incremental Recovery (IR) at the maximum plasma concentration of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: (U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
rVWF:rFVIII [N=16]	2.3 (1.9 to 2.7)
rVWF [N=0]	0 (0 to 0)

No statistical analyses for this end point

Secondary: PK50 - Elimination Phase Half-Life of FVIII:C

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End point title

PK50 - Elimination Phase Half-Life of FVIII:C ^[43]

End point description

Elimination Phase Half-Life (T1/2) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: hours
median (confidence interval 95%)
rVWF:rFVIII [N=16]	24.8 (20.1 to 50.5)
rVWF [N=0]	0 (0 to 0)

No statistical analyses for this end point

Secondary: PK50 - Volume of Distribution at Steady State of FVIII:C

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End point title

PK50 - Volume of Distribution at Steady State of FVIII:C ^[44]

End point description

Volume of Distribution at Steady State (Vss) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK50 Arms
Number of subjects analysed	16
Units: dL/kg
median (confidence interval 95%)
rVWF:rFVIII [N=16]	0.32 (0.29 to 0.44)
rVWF [N=0]	0 (0 to 0)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo ^[45]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	36.9 (29.2 to 41.7)
PK2 of rVWF [N=13]	38.9 (28.1 to 43.3)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo ^[46]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	35.6 (28.9 to 41.2)
PK2 of rVWF [N=13]	37.9 (25.9 to 41.8)

No statistical analyses for this end point

Secondary: PK80 - Mean Residence Time of VWF:RCo

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End point title

PK80 - Mean Residence Time of VWF:RCo ^[47]

End point description

Mean Residence Time (MRT) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	26.4 (20.9 to 31.1)
PK2 of rVWF [N=13]	26.4 (23.7 to 32.8)

No statistical analyses for this end point

Secondary: PK80 - Clearance of VWF:RCo

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End point title

PK80 - Clearance of VWF:RCo ^[48]

End point description

Clearance (CL) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: dL/kg/hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	0.027 (0.024 to 0.034)
PK2 of rVWF [N=13]	0.026 (0.023 to 0.036)

No statistical analyses for this end point

Secondary: PK80 - Incremental Recovery of VWF:RCo

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End point title

PK80 - Incremental Recovery of VWF:RCo ^[49]

End point description

Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	1.8 (1.7 to 2.2)
PK2 of rVWF [N=13]	1.8 (1.6 to 2)

No statistical analyses for this end point

Secondary: PK80 - Elimination Phase Half-Life of VWF:Co

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End point title

PK80 - Elimination Phase Half-Life of VWF:Co ^[50]

End point description

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	18.4 (16.4 to 22.1)
PK2 of rVWF [N=13]	19.8 (15.2 to 23.6)

No statistical analyses for this end point

Secondary: PK80 - Volume of Distribution at Steady State of VWF:RCo

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End point title

PK80 - Volume of Distribution at Steady State of VWF:RCo ^[51]

End point description

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study PK evaluations at pre-infusion, then at 15, 30 and 60 minutes, and 3, 6, 12, 24, 48, 72 and 96 hours post-infusion. PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: dL/kg
median (confidence interval 95%)
PK1 of rVWF [N=15]	0.78 (0.58 to 0.86)
PK2 of rVWF [N=13]	0.75 (0.58 to 1.01)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag ^[52]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	66.6 (50.4 to 89.4)
PK2 of rVWF [N=13]	86.9 (54.9 to 100.5)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag ^[53]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	61.3 (48.8 to 73.7)
PK2 of rVWF [N=13]	77.4 (53 to 87.6)

No statistical analyses for this end point

Secondary: PK80 - Mean Residence Time of VWF:Ag

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End point title

PK80 - Mean Residence Time of VWF:Ag ^[54]

End point description

Mean Residence Time (MRT) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	38.4 (31.9 to 48.1)
PK2 of rVWF [N=13]	36.9 (30 to 50.8)

No statistical analyses for this end point

Secondary: PK80 - Clearance of VWF:Ag

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End point title

PK80 - Clearance of VWF:Ag ^[55]

End point description

Clearance (CL) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: dL/kg/hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	0.015 (0.011 to 0.02)
PK2 of rVWF [N=13]	0.012 (0.01 to 0.018)

No statistical analyses for this end point

Secondary: PK80 - Incremental Recovery of VWF:Ag

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End point title

PK80 - Incremental Recovery of VWF:Ag ^[56]

End point description

Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (U/dL)/(U VWF: RCo/kg)
median (confidence interval 0%)
PK1 of rVWF [N=15]	2.2 (1.9 to 2.6)
PK2 of rVWF [N=13]	2.4 (2 to 2.9)

No statistical analyses for this end point

Secondary: PK80 - Elimination Phase Half-Life of VWF:Ag

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End point title

PK80 - Elimination Phase Half-Life of VWF:Ag ^[57]

End point description

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	27.5 (22.5 to 34)
PK2 of rVWF [N=13]	24.8 (21.1 to 37.7)

No statistical analyses for this end point

Secondary: PK80 - Volume of Distribution at Steady State of VWF:Ag

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End point title

PK80 - Volume of Distribution at Steady State of VWF:Ag ^[58]

End point description

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: dL/kg
median (confidence interval 95%)
PK1 of rVWF [N=15]	0.55 (0.46 to 0.61)
PK2 of rVWF [N=13]	0.5 (0.41 to 0.57)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB ^[59]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	73.9 (57.3 to 96.2)
PK2 of rVWF [N=13]	90.8 (66 to 105.2)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB ^[60]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	71.9 (57 to 89.8)
PK2 of rVWF [N=13]	88.1 (63.8 to 96.3)

No statistical analyses for this end point

Secondary: PK80 - Mean Residence Time of VWF:CB

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End point title

PK80 - Mean Residence Time of VWF:CB ^[61]

End point description

Mean Residence Time (MRT) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	30.9 (24.3 to 35)
PK2 of rVWF [N=13]	28.7 (25.6 to 37.2)

No statistical analyses for this end point

Secondary: PK80 - Clearance of VWF:CB

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End point title

PK80 - Clearance of VWF:CB ^[62]

End point description

Clearance (CL) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: dL/kg/hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	0.014 (0.01 to 0.017)
PK2 of rVWF [N=13]	0.011 (0.01 to 0.015)

No statistical analyses for this end point

Secondary: PK80 - Incremental Recovery of VWF:CB

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End point title

PK80 - Incremental Recovery of VWF:CB ^[63]

End point description

Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	3.1 (2.8 to 3.6)
PK2 of rVWF [N=13]	3.7 (2.7 to 4)

No statistical analyses for this end point

Secondary: PK80 - Elimination Phase Half-Life of VWF:CB

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End point title

PK80 - Elimination Phase Half-Life of VWF:CB ^[64]

End point description

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: hours
median (confidence interval 95%)
PK1 of rVWF [N=15]	18.8 (16.6 to 24.9)
PK2 of rVWF [N=13]	20.9 (17.8 to 23.5)

No statistical analyses for this end point

Secondary: PK80 - Volume of Distribution at Steady State of VWF:CB

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End point title

PK80 - Volume of Distribution at Steady State of VWF:CB ^[65]

End point description

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: dL/kg
median (confidence interval 95%)
PK1 of rVWF [N=15]	0.39 (0.34 to 0.46)
PK2 of rVWF [N=13]	0.36 (0.33 to 0.4)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C ^[66]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity of Factor VIII activity (FVIII:C) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	96.8 (64 to 126.5)
PK2 of rVWF [N=13]	94.8 (60.4 to 106.5)

No statistical analyses for this end point

Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C

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End point title

PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C ^[67]

End point description

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of Factor VIII activity (FVIII:C) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.

End point type

Secondary

End point timeframe

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	15
Units: (hours*U/dL)/(U VWF: RCo/kg)
median (confidence interval 95%)
PK1 of rVWF [N=15]	81.7 (54.7 to 104.3)
PK2 of rVWF [N=13]	71.8 (49.6 to 89.2)

No statistical analyses for this end point

Secondary: PK80- Ratio of intra-subject PK of VWF:RCo, VWF:Ag and VWF:CB at baseline and after 6 months

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End point title

PK80- Ratio of intra-subject PK of VWF:RCo, VWF:Ag and VWF:CB at baseline and after 6 months ^[68]

End point description

Area under the plasma concentration curve (AUC) from time 0 to infinity per dose (AUC0-∞/dose) for von Willebrand Factor Ristocetin cofactor (VWF:RCo), von Willebrand Factor Antigen (VWF:Ag) and von Willebrand Factor Collagen Binding (VWF:CB). Each parameter was compared between the two PK assessments after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. 13 subjects had data available for this endpoint i.e. data for PK1 and PK2.

End point type

Secondary

End point timeframe

Notes
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol, only descriptive statistics were collected for this endpoint.

End point values	PK80 Arm
Number of subjects analysed	13
Units: ratio of AUC0-∞/dose
geometric mean (confidence interval 90%)
AUC0-∞/dose - VWF:RCo	0.9587 (0.8466 to 1.0857)
AUC0-∞/dose - VWF:Ag	1.0914 (1.0132 to 1.1757)
AUC0-∞/dose - VWF:CB	1.0666 (1.0004 to 1.1372)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

for 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Safety Analysis Set

Reporting group description

The Safety Analysis Set comprises of subjects who were treated with study product at least once during the study.

Serious adverse events	Safety Analysis Set
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 37 (18.92%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Mesenteric haematoma
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Reproductive system and breast disorders
Uterine polyp
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Heart rate increased
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

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

Non-serious adverse events	Safety Analysis Set
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 37 (27.03%)
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 37 (5.41%)
occurrences all number	2
Laceration
subjects affected / exposed	2 / 37 (5.41%)
occurrences all number	4
Nervous system disorders
Headache
subjects affected / exposed	4 / 37 (10.81%)
occurrences all number	12
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	3 / 37 (8.11%)
occurrences all number	4
Anaemia
subjects affected / exposed	2 / 37 (5.41%)
occurrences all number	2
General disorders and administration site conditions
Infusion site paraesthesia
subjects affected / exposed	2 / 37 (5.41%)
occurrences all number	2
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 37 (5.41%)
occurrences all number	3
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 37 (5.41%)
occurrences all number	2
Vomiting
subjects affected / exposed	3 / 37 (8.11%)
occurrences all number	4
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 37 (8.11%)
occurrences all number	16
Back pain
subjects affected / exposed	2 / 37 (5.41%)
occurrences all number	3
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	3 / 37 (8.11%)
occurrences all number	5

More information

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Were there any global substantial amendments to the protocol? Yes

15 Nov 2011

Exclusion criteria updated to ensure specific cohort of patients plus hypersensitivity of study product components. New study arm added (PK80 analysis). Update for safety stopping rules.

10 Aug 2012

Clarification on procedure for enabling home treatment of bleeding episodes. Inclusion criteria updated to better reflect real life clinical practice for this cohort of patients. Option to use premixed or sequential infusion of study product (when administered together with recombinant Factor VIII).

26 Jul 2013

Final report to be done after completion of study Parts A and B.

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

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Clinical trials

Clinical Trial Results: A Phase 3 clinical study to determine the pharmacokinetics, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes in subjects diagnosed with von Willebrand disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects with treatment success for treated bleeding episodes

Primary: Percentage of subjects with treatment success for treated bleeding episodes

Secondary: Percentage of treated bleeding episodes treated with an efficacy rating of "excellent" or "good"

Secondary: Percentage of treated bleeding episodes treated with an efficacy rating of "excellent" or "good"

Secondary: Percentage of treated bleeding episodes with an efficacy rating of "excellent" or "good", excluding gastrointestinal bleeds

Secondary: Percentage of treated bleeding episodes with an efficacy rating of "excellent" or "good", excluding gastrointestinal bleeds

Secondary: Number of infusions of rVWF:rFVIII and/or rVWF per bleeding episode

Secondary: Number of infusions of rVWF:rFVIII and/or rVWF per bleeding episode

Secondary: Number of units of rVWF:rFVIII and/or rVWF per bleeding episode

Secondary: Number of units of rVWF:rFVIII and/or rVWF per bleeding episode

Secondary: Percentage of subjects who develop inhibitory antibodies to FVIII

Secondary: Percentage of subjects who develop inhibitory antibodies to FVIII

Secondary: Percentage of subjects who develop inhibitory antibodies to VWF

Secondary: Percentage of subjects who develop inhibitory antibodies to VWF

Secondary: Percentage of subjects who develop binding antibodies to VWF

Secondary: Percentage of subjects who develop binding antibodies to VWF

Secondary: Percentage of subjects who develop binding antibodies to CHO

Secondary: Percentage of subjects who develop binding antibodies to CHO

Secondary: Percentage of subjects who develop binding antibodies to rFurin

Secondary: Percentage of subjects who develop binding antibodies to rFurin

Secondary: Percentage of subjects who develop binding antibodies to mouse immunoglobulin

Secondary: Percentage of subjects who develop binding antibodies to mouse immunoglobulin

Secondary: Percentage of subjects who had an occurrence of thrombotic events

Secondary: Percentage of subjects who had an occurrence of thrombotic events

Secondary: Number of adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

Secondary: Number of adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

Secondary: Number of subjects with adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

Secondary: Number of subjects with adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

Secondary: Number of adverse events by infusion related to study product including clinically significant changes in laboratory parameters and vital signs

Secondary: Number of adverse events by infusion related to study product including clinically significant changes in laboratory parameters and vital signs

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo

Secondary: PK50 - Mean Residence Time of VWF:RCo

Secondary: PK50 - Mean Residence Time of VWF:RCo

Secondary: PK50 - Clearance of VWF:RCo

Secondary: PK50 - Clearance of VWF:RCo

Secondary: PK50 - Incremental Recovery of VWF:RCo

Secondary: PK50 - Incremental Recovery of VWF:RCo

Secondary: PK50 - Elimination Phase Half-Life of VWF:Co

Secondary: PK50 - Elimination Phase Half-Life of VWF:Co

Secondary: PK50 - Volume of Distribution at Steady State of VWF:RCo

Secondary: PK50 - Volume of Distribution at Steady State of VWF:RCo

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag

Secondary: PK50 - Mean Residence Time of VWF:Ag

Secondary: PK50 - Mean Residence Time of VWF:Ag

Secondary: PK50 - Clearance of VWF:Ag

Secondary: PK50 - Clearance of VWF:Ag

Secondary: PK50 - Incremental Recovery of VWF:Ag

Secondary: PK50 - Incremental Recovery of VWF:Ag

Secondary: PK50 - Elimination Phase Half-Life of VWF:Ag

Secondary: PK50 - Elimination Phase Half-Life of VWF:Ag

Secondary: PK50 - Volume of Distribution at Steady State of VWF:Ag

Secondary: PK50 - Volume of Distribution at Steady State of VWF:Ag

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB

Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB

Secondary: PK50 - Mean Residence Time of VWF:CB

Secondary: PK50 - Mean Residence Time of VWF:CB

Secondary: PK50 - Clearance of VWF:CB

Secondary: PK50 - Clearance of VWF:CB

Secondary: PK50 - Incremental Recovery of VWF:CB

Secondary: PK50 - Incremental Recovery of VWF:CB

Secondary: PK50 - Elimination Phase Half-Life of VWF:CB

Secondary: PK50 - Elimination Phase Half-Life of VWF:CB

Clinical Trial Results:
A Phase 3 clinical study to determine the pharmacokinetics, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes in subjects diagnosed with von Willebrand disease