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Recombinant Von Willebrand Factor in Subjects With Severe Von Willebrand Disease Undergoing Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02283268
Recruitment Status : Completed
First Posted : November 5, 2014
Results First Posted : August 31, 2017
Last Update Posted : May 14, 2019
Sponsor:
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Von Willebrand Disease
Intervention Biological: Recombinant von Willebrand Factor (rVWF)
Enrollment 24
Recruitment Details Enrollment was conducted at 14 study sites in 10 countries (USA, Australia, Taiwan, Germany, Russia, Spain, Ukraine, United Kingdom, Italy, Turkey).
Pre-assignment Details A total of 24 participants were enrolled (signed informed consent) and screened. Of these, 15 participants were treated with investigational product.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Period Title: Overall Study
Started 15
Completed 14
Not Completed 1
Reason Not Completed
Withdrawal by Subject             1
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Baseline Participants 15
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 15 participants
40.0
(20.0 to 70.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants
Female
8
  53.3%
Male
7
  46.7%
1.Primary Outcome
Title Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)
Hide Description

Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none.

Excellent: Intra-, and postoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject.

Good: Intra-, and postoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject.

Moderate: Intra-, and postoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate.

None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.
Time Frame 24 hours after last peri-operative infusion or at completion of Day 14 (± 2 days) visit, whichever occurs earlier
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants with major, minor and oral surgery and number of participant with Von Willebrand Type 1, 2A, 2B, 2M and 3 do sum up to the overall number of participants analyzed. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF) Minor Surgery Major Surgery Oral Surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
All participants who underwent minor surgery.
All participants who underwent major surgery.
All participants who underwent oral surgery.
All participants with von Willebrand Disease Type 1.
All participants with von Willebrand Disease Type 2A.
All participants with von Willebrand Disease Type 2B.
All participants with von Willebrand Disease Type 2M.
All participants with von Willebrand Disease Type 3.
Overall Number of Participants Analyzed 15 4 10 1 3 2 1 1 8
Measure Type: Count of Participants
Unit of Measure: Participants
Excellent
11
  73.3%
4
 100.0%
7
  70.0%
0
   0.0%
2
  66.7%
1
  50.0%
1
 100.0%
0
   0.0%
7
  87.5%
Good
4
  26.7%
0
   0.0%
3
  30.0%
1
 100.0%
1
  33.3%
1
  50.0%
0
   0.0%
1
 100.0%
1
  12.5%
Moderate
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
None
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2.Secondary Outcome
Title Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon
Hide Description

The predicted blood loss will be estimated preoperatively by the operating surgeon based on a hemostatically normal individual of the same sex, age, stature and co-morbidities as the participant.

The actual blood loss will be assessed consisting of the estimated blood loss, including into swabs, towels and suction during the procedure, per the anesthesiologist's record.
Time Frame Day 0 (at completion of surgery)
Hide Outcome Measure Data
Hide Analysis Population Description
For predicted blood loss the number of participants analyzed is 14 as for one participant (included in the major surgery reporting group) the predicted blood loss was not collected. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF) Minor Surgery Major Surgery Oral Surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
All participants who underwent minor surgery.
All participants who underwent major surgery.
All participants who underwent oral surgery.
All participants with von Willebrand Disease Type 1.
All participants with von Willebrand Disease Type 2A.
All participants with von Willebrand Disease Type 2B.
All participants with von Willebrand Disease Type 2M.
All participants with von Willebrand Disease Type 3.
Overall Number of Participants Analyzed 15 4 10 1 3 2 1 1 8
Mean (Standard Deviation)
Unit of Measure: mL
Actual blood loss Number Analyzed 15 participants 4 participants 10 participants 1 participants 3 participants 2 participants 1 participants 1 participants 8 participants
94.3  (177.88) 0.0  (0.00) 127.0  (209.27) 145.0 [1]   (NA) 115.0  (103.32) 42.5  (53.03) 50.0 [1]   (NA) 50.0 [1]   (NA) 110.6  (240.87)
Predicted blood loss Number Analyzed 14 participants 4 participants 9 participants 1 participants 3 participants 1 participants 1 participants 1 participants 8 participants
106.1  (161.82) 2.5  (5.00) 152.8  (186.33) 100.0 [1]   (NA) 100.0  (100.00) 10.0 [1]   (NA) 50.0 [1]   (NA) 50.0 [1]   (NA) 134.4  (206.46)
[1]
No standard deviation possible as only one participant was analyzed.
3.Secondary Outcome
Title Intraoperative Actual Blood Loss Relative to Predicted Blood Loss
Hide Description Actual blood loss relative to predicted blood loss will be calculated as [Actual Blood loss (mL)] divided by [Predicted Blood Loss (mL) multiplied by 100.
Time Frame Day 0 (at completion of surgery)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is 11, as for 3 participants the actual and the predicted blood loss was zero and for 1 participant the predicted blood loss was not collected. Therefore 'actual blood loss relative to predicted blood loss' could not be calculated. The full analysis data set was used for the analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF) Minor Surgery Major Surgery Oral Surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
All participants who underwent minor surgery.
All participants who underwent major surgery.
All participants who underwent oral surgery.
All participants with von Willebrand Disease Type 1.
All participants with von Willebrand Disease Type 2A.
All participants with von Willebrand Disease Type 2B.
All participants with von Willebrand Disease Type 2M.
All participants with von Willebrand Disease Type 3.
Overall Number of Participants Analyzed 11 1 9 1 2 1 1 1 6
Mean (Standard Deviation)
Unit of Measure: Percent
69.6  (44.77) 0.0 [1]   (NA) 68.9  (34.48) 145.0 [1]   (NA) 122.5  (31.82) 50.0 [1]   (NA) 100.0 [1]   (NA) 100.0 [1]   (NA) 45.0  (38.92)
[1]
No standard deviation possible as only one participant was analyzed.
4.Secondary Outcome
Title Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon
Hide Description

Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none.

Excellent: Intraoperative blood loss was less than or equal to the maximum blood loss expected for the type of procedure performed in a hemostatically normal subject (≤ 100%).

Good: Intraoperative blood loss was up to 50% more than the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (101-150%) Moderate: Intraoperative blood loss was more than 50% of the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (>150%).

None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of clotting factor replacement regimen.
Time Frame Day 0 (at completion of surgery)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants with major, minor and oral surgery and number of participant with Von Willebrand Type 1, 2A, 2B, 2M and 3 do sum up to the overall number of participants analyzed. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF) Minor Surgery Major Surgery Oral Surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
All participants who underwent minor surgery.
All participants who underwent major surgery.
All participants who underwent oral surgery.
All participants with von Willebrand Disease Type 1.
All participants with von Willebrand Disease Type 2A.
All participants with von Willebrand Disease Type 2B.
All participants with von Willebrand Disease Type 2M.
All participants with von Willebrand Disease Type 3.
Overall Number of Participants Analyzed 15 4 10 1 3 2 1 1 8
Measure Type: Count of Participants
Unit of Measure: Participants
Excellent
13
  86.7%
4
 100.0%
8
  80.0%
1
 100.0%
3
 100.0%
1
  50.0%
1
 100.0%
1
 100.0%
7
  87.5%
Good
2
  13.3%
0
   0.0%
2
  20.0%
0
   0.0%
0
   0.0%
1
  50.0%
0
   0.0%
0
   0.0%
1
  12.5%
Moderate
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
None
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
5.Secondary Outcome
Title Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon
Hide Description

Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none.

Excellent: Intraoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject.

Good: Intraoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject.

Moderate: Intraoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate.

None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.
Time Frame Day 0 (at completion of surgery)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants with major, minor and oral surgery and number of participant with Von Willebrand Type 1, 2A, 2B, 2M and 3 do sum up to the overall number of participants analyzed. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF) Minor Surgery Major Surgery Oral Surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
All participants who underwent minor surgery.
All participants who underwent major surgery.
All participants who underwent oral surgery.
All participants with von Willebrand Disease Type 1.
All participants with von Willebrand Disease Type 2A.
All participants with von Willebrand Disease Type 2B.
All participants with von Willebrand Disease Type 2M.
All participants with von Willebrand Disease Type 3.
Overall Number of Participants Analyzed 15 4 10 1 3 2 1 1 8
Measure Type: Count of Participants
Unit of Measure: Participants
Excellent
13
  86.7%
4
 100.0%
8
  80.0%
1
 100.0%
3
 100.0%
1
  50.0%
1
 100.0%
1
 100.0%
7
  87.5%
Good
2
  13.3%
0
   0.0%
2
  20.0%
0
   0.0%
0
   0.0%
1
  50.0%
0
   0.0%
0
   0.0%
1
  12.5%
Moderate
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
None
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
6.Secondary Outcome
Title Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE
Hide Description [Not Specified]
Time Frame Daily, from day of surgery through postoperative Day 14 (± 2 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed is different for the time points according to individual treatment. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 15
Median (Inter-Quartile Range)
Unit of Measure: IU/kg
intraoperative Number Analyzed 1 participants
18.1
(18.1 to 18.1)
postoperative day 1 Number Analyzed 3 participants
23.5
(16.9 to 47.2)
postoperative day 2 Number Analyzed 11 participants
42.3
(23.2 to 50.6)
postoperative day 3 Number Analyzed 12 participants
28.6
(20.6 to 48.9)
postoperative day 4 Number Analyzed 9 participants
33.9
(23.2 to 44.3)
postoperative day 5 Number Analyzed 7 participants
31.5
(18.8 to 47.2)
postoperative day 6 Number Analyzed 5 participants
23.2
(18.8 to 23.6)
postoperative day 7 Number Analyzed 5 participants
23.8
(23.6 to 50.8)
postoperative day 8 Number Analyzed 7 participants
33.9
(23.6 to 53.6)
postoperative day 9 Number Analyzed 3 participants
23.6
(16.3 to 53.6)
postoperative day 10 Number Analyzed 3 participants
23.6
(16.3 to 34.8)
postoperative day 11 Number Analyzed 3 participants
23.6
(16.3 to 53.6)
postoperative day 12 Number Analyzed 4 participants
29.3
(20.1 to 44.2)
postoperative day 13 Number Analyzed 1 participants
16.3
(16.3 to 16.3)
postoperative day 14 Number Analyzed 2 participants
25.5
(16.3 to 34.8)
postoperative day 15 Number Analyzed 1 participants
16.3
(16.3 to 16.3)
7.Secondary Outcome
Title Occurrence of Adverse Events
Hide Description Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated.
Time Frame From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Adverse Events
Treatment emergent Adverse Events (TEAEs) 12
Severe TEAEs 1
TEAEs related to rVWF 0
TEAEs related to ADVATE 0
TEAEs related to both rVWF and ADVATE 0
Treatment emergent Serious Adverse Events (TESAEs) 2
TESAEs related to rVWF 0
TESAEs related to ADVATE 0
TESAEs related to both rVWF and ADVATE 0
TEAEs leading to discontinuation of rVWF 0
TEAEs leading to discontinuation of ADVATE 0
TEAEs leading to discontinuation of study 0
TEAEs leading to death 0
TEAEs related to study procedure 0
TESAEs related to study procedure 0
8.Secondary Outcome
Title Occurrence of Thrombotic Events
Hide Description Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for thrombotic events.
Time Frame From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Adverse Events
Thrombotic TEAEs 2
Thrombotic TESAEs 1
9.Secondary Outcome
Title Occurrence of Severe Allergic Reactions (eg, Anaphylaxis)
Hide Description Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for severe allergic reactions.
Time Frame From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 15
Measure Type: Number
Unit of Measure: Adverse Events
Severe allergic reaction TEAEs 0
Severe allergic reaction TESAEs 0
10.Secondary Outcome
Title Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII)
Hide Description Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
Time Frame Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery).
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
Development of inhibitory antibodies to VWF
0
   0.0%
Development of total binding antibodies to VWF
1
   6.7%
Development of inhibitory antibodies to FVIII
0
   0.0%
11.Secondary Outcome
Title Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) or Recombinant Furin (rFurin)
Hide Description Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
Time Frame Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery).
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 15
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
12.Secondary Outcome
Title Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion (AUC 0-72 h/Dose)
Hide Description

This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from 0 to 72 hours post-infusion will be computed using the linear trapezoidal rule. For the calculation of AUC(0-72h) the levels at 72 hours will be linearly interpolated/extrapolated from the 2 nearest sampling time points.

PK analysis was performed for the following analytes:

VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
Time Frame PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 11
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours*IU/dL
VWF:RCo Number Analyzed 11 participants
31.91
(37.5%)
VWF:Ag Number Analyzed 11 participants
57.08
(25.6%)
VWF:CB Number Analyzed 11 participants
63.91
(29.4%)
VWF:Ac Number Analyzed 11 participants
54.61
(28.1%)
FVIII:C Number Analyzed 5 participants
67.49
(31.1%)
13.Secondary Outcome
Title Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞ /Dose)
Hide Description

This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from time 0 to infinity and the area under the first moment curve from time 0 to infinity will be calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant.

PK analysis was performed for the following analytes:

VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
Time Frame PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description:
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 11
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours*IU/dL
VWF:RCo Number Analyzed 11 participants
34.43
(43.3%)
VWF:Ag Number Analyzed 11 participants
68.87
(31.5%)
VWF:CB Number Analyzed 11 participants
71.82
(34.1%)
VWF:Ac Number Analyzed 11 participants
61.90
(32.2%)
FVIII:C Number Analyzed 3 participants
75.00
(30.9%)
14.Secondary Outcome
Title Pharmacokinetics: Mean Residence Time (MRT)
Hide Description

This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Mean residence time will be calculated as area under the first moment curve from time 0 to infinity divided by the area under the curve time 0 to infinity minus T/2 where T is the duration of the infusion.

PK analysis was performed for the following analytes:

VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
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The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
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Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 11
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
VWF:RCo
22.69
(41.3%)
VWF:Ag
37.92
(28.4%)
VWF:CB
29.35
(31.1%)
VWF:Ac
29.75
(28.6%)
15.Secondary Outcome
Title Pharmacokinetics: Clearance (CL)
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This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Clearance will be calculated as dose (IU/kg) divided by the area under the curve time 0 to infinity.

PK analysis was performed for the following analytes:

VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
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Hide Analysis Population Description
The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
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Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 11
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: dL/hour/kg
VWF:RCo
0.02904
(43.3%)
VWF:Ag
0.01452
(31.5%)
VWF:CB
0.01392
(34.1%)
VWF:Ac
0.01616
(32.2%)
16.Secondary Outcome
Title Pharmacokinetics: Incremental Recovery (IR)
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This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Incremental recovery will be calculated as (Cmax minus Cpreinfusion) divided by the dose (IU/kg) where kg refers to the body weight at the time of dosing and Cmax is the observed maximum concentration before correction for pre-infusion values.

PK analysis was performed for the following analytes:

VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
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Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 11
Mean (Standard Deviation)
Unit of Measure: IU/dL
VWF:RCo 1.961  (0.45445)
VWF:Ag 1.991  (0.38395)
VWF:CB 2.780  (0.56640)
VWF:Ac 2.635  (0.38050)
17.Secondary Outcome
Title Pharmacokinetics: Elimination Phase Half-life (T1/2)
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This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Terminal or disposition half-life (T1/2) will be calculated as ln2/λz where λz is the terminal elimination rate constant as calculated in WinNonlin NCA using at least three quantifiable concentrations.

PK analysis was performed for the following analytes:

VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
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Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 11
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours
VWF:RCo
16.52
(42.7%)
VWF:Ag
26.88
(26.5%)
VWF:CB
21.07
(33.2%)
VWF:Ac
22.19
(28.5%)
18.Secondary Outcome
Title Pharmacokinetics: Volume of Distribution at Steady State (Vss)
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This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Vss will be calculated as the clearance multiplied with the mean residence time.

PK analysis was performed for the following analytes:

VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure.
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
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Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Overall Number of Participants Analyzed 11
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: dL/kg
VWF:RCo
0.6591
(28.8%)
VWF:Ag
0.5506
(18.4%)
VWF:CB
0.4086
(24.0%)
VWF:Ac
0.4806
(21.5%)
Time Frame Throughout the study period (from the first exposure to investigational product until study completion or discontinuation date). Total study duration: 1 year and 3 months. Per participant: up to 58 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Recombinant Von Willebrand Factor (rVWF)
Hide Arm/Group Description Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
All-Cause Mortality
Recombinant Von Willebrand Factor (rVWF)
Affected / at Risk (%)
Total   0/15 (0.00%)    
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Recombinant Von Willebrand Factor (rVWF)
Affected / at Risk (%) # Events
Total   2/15 (13.33%)    
Infections and infestations   
Diverticulitis * 1  1/15 (6.67%)  1
Vascular disorders   
Deep vein thrombosis * 1  1/15 (6.67%)  1
1
Term from vocabulary, 19.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Recombinant Von Willebrand Factor (rVWF)
Affected / at Risk (%) # Events
Total   6/15 (40.00%)    
Blood and lymphatic system disorders   
Iron deficiency anaemia * 1  1/15 (6.67%)  1
General disorders   
Peripheral swelling * 1  1/15 (6.67%)  1
Infections and infestations   
Nasopharyngitis * 1  1/15 (6.67%)  1
Musculoskeletal and connective tissue disorders   
Joint swelling * 1  1/15 (6.67%)  1
Nervous system disorders   
Dizziness * 1  1/15 (6.67%)  1
Headache * 1  1/15 (6.67%)  1
Reproductive system and breast disorders   
Pelvic pain * 1  1/15 (6.67%)  1
Skin and subcutaneous tissue disorders   
Acne * 1  1/15 (6.67%)  1
Dry skin * 1  1/15 (6.67%)  1
Vascular disorders   
Deep vein thrombosis * 1  1/15 (6.67%)  1
1
Term from vocabulary, 19.0
*
Indicates events were collected by non-systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until completion of the multicenter publication or one year after the conclusion of the study at all sites. Baxalta requires a review of results communication (e.g. for confidential information) >= 30 days prior to submission. Baxalta may request an additional delay of <= 6 months (e.g. for intellectual property protection).
Results Point of Contact
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Name/Title: Study Director
Organization: Shire
Phone: +1 866 842 5335
EMail: ClinicalTransparency@shire.com
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Responsible Party: Shire ( Baxalta now part of Shire )
ClinicalTrials.gov Identifier: NCT02283268    
Other Study ID Numbers: 071101
2014-003575-38 ( EudraCT Number )
First Submitted: October 27, 2014
First Posted: November 5, 2014
Results First Submitted: July 3, 2017
Results First Posted: August 31, 2017
Last Update Posted: May 14, 2019