Clinical Trial Results:
A Phase 3, Prospective, Multicenter Study to Evaluate Efficacy and Safety of Recombinant von Willebrand Factor (rVWF) with or without ADVATE in Elective Surgical Procedures in Subjects With Severe von Willebrand Disease
|
Summary
|
|
EudraCT number |
2014-003575-38 |
Trial protocol |
AT IT CZ GB NL ES DE |
Global end of trial date |
06 Jul 2016
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
19 Jul 2017
|
First version publication date |
19 Jul 2017
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
071101
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02283268 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
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
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
06 Jul 2016
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
06 Jul 2016
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
06 Jul 2016
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To assess the hemostatic efficacy and safety of rVWF with or without ADVATE in subjects (≥18 years) diagnosed with hereditary severe VWD undergoing major or minor elective surgical procedures.
|
||
Protection of trial subjects |
The study was conducted in accordance with the study protocol, the International Conference on Harmonization Guideline for Good Clinical Practice E6 (ICH GCP April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Apr 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United States: 2
|
||
Country: Number of subjects enrolled |
Australia: 2
|
||
Country: Number of subjects enrolled |
Taiwan: 3
|
||
Country: Number of subjects enrolled |
Germany: 1
|
||
Country: Number of subjects enrolled |
Russian Federation: 5
|
||
Country: Number of subjects enrolled |
Spain: 2
|
||
Country: Number of subjects enrolled |
Ukraine: 3
|
||
Country: Number of subjects enrolled |
United Kingdom: 2
|
||
Country: Number of subjects enrolled |
Italy: 3
|
||
Country: Number of subjects enrolled |
Turkey: 1
|
||
Worldwide total number of subjects |
24
|
||
EEA total number of subjects |
8
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
21
|
||
From 65 to 84 years |
3
|
||
85 years and over |
0
|
||
|
|||||||||||
|
Recruitment
|
|||||||||||
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
|
|||||||||||
Screening details |
A total of 24 subjects were enrolled (signed informed consent) and screened. Of these, 15 participants were treated with investigational product. | ||||||||||
|
Pre-assignment period milestones
|
|||||||||||
Number of subjects started |
24 | ||||||||||
Number of subjects completed |
15 | ||||||||||
|
Pre-assignment subject non-completion reasons
|
|||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 1 | ||||||||||
Reason: Number of subjects |
Screen Failure: 8 | ||||||||||
|
Period 1
|
|||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||
Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
|
||||||||||
Blinding used |
Not blinded | ||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Recombinant von Willebrand Factor (rVWF) | ||||||||||
Arm description |
Surgery participants treated with Recombinant von Willebrand Factor (rVWF) | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
rVWF (Recombinant von Willebrand Factor)
|
||||||||||
Investigational medicinal product code |
BAX111
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Powder for solution for injection/infusion
|
||||||||||
Routes of administration |
Intravenous bolus use
|
||||||||||
Dosage and administration details |
The dose will be tailored to raise Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) concentration to 100% of normal for major surgeries and to 50-60% of normal for minor and oral surgeries. PK infusion (major surgeries) with 50±5 IU rVWF:RCo/kg will be given within 42 days prior surgery to guide the preoperative priming dose. Priming dose with rVWF will be administered (12-24 hours prior surgery). If FVIII levels prior to loading dose administration are not at least 30 IU/dL ADVATE will be administered in addition to rVWF in order to raise FVIII:C levels to recommended levels. A rVWF loading dose with or without ADVATE within 1 hour prior to surgery will be administered. The peri- and postoperative substitution regimen will be individualized according to the PK results, intensity and duration of the hemostatic challenge, and the institution’s standard of care.
|
||||||||||
|
|||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 24 subjects were enrolled (signed informed consent) and screened. Of these, 15 subjects were treated with investigational product, 8 subjects were screen failures and 1 subject withdrew consent prior to treatment. |
|||||||||||
|
||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||
Reporting group title |
Recombinant von Willebrand Factor (rVWF)
|
|||||||||||||||||||||||||||||||||
Reporting group description |
Surgery participants treated with Recombinant von Willebrand Factor (rVWF) | |||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Recombinant von Willebrand Factor (rVWF)
|
||
Reporting group description |
Surgery participants treated with Recombinant von Willebrand Factor (rVWF) | ||
Subject analysis set title |
All Subjects Enrolled Set
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who signed informed consent.
|
||
Subject analysis set title |
Full Ananalysis Set
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects included in the Safety Analysis Set with at least one hemostatic assessment.
|
||
Subject analysis set title |
Per Protocol Analysis Set
|
||
Subject analysis set type |
Per protocol | ||
Subject analysis set description |
All subjects with available overall assessment of hemostatic efficacy assessed by the investigator 24 hours after last infusion of study drug or at completion visit who met all study entry criteria and who had no major protocol violations that might impact hemostatic efficacy.
|
||
Subject analysis set title |
Pharmacokinetic Analysis Set
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All subjects who underwent a PK assessment and have at least one post dose concentration without protocol deviations or events with potential to affect PK.
|
||
Subject analysis set title |
Safety Analysis Set
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects included in the All Subjects Enrolled Set that received any amount of investigational product.
|
||
Subject analysis set title |
Minor surgery
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who underwent minor surgery.
|
||
Subject analysis set title |
Major surgery
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who underwent major surgery.
|
||
Subject analysis set title |
Oral surgery
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who underwent oral surgery.
|
||
Subject analysis set title |
Von Willebrand Disease Type 1
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects with von Willebrand Disease Type 1.
|
||
Subject analysis set title |
Von Willebrand Disease Type 2A
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects with von Willebrand Disease Type 2A.
|
||
Subject analysis set title |
Von Willebrand Disease Type 2B
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects with von Willebrand Disease Type 2B.
|
||
Subject analysis set title |
Von Willebrand Disease Type 2M
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects with von Willebrand Disease Type 2M.
|
||
Subject analysis set title |
Von Willebrand Disease Type 3
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects with von Willebrand Disease Type 3.
|
||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Overall hemostatic efficacy as assessed by the investigator (hemophilia physician) [1] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
24 hours after last peri-operative infusion or at completion of Day 14 visit, whichever occurs earlier
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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: Per protocol, only descriptive statistics were collected for this endpoint. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Intraoperative actual versus predicted blood loss as assessed by the operating surgeon | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 0 (at completion of surgery)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [2] - predicted blood loss: 14 [3] - predicted blood loss: 9 [4] - no dispersion possible as n=1, 9999 entered [5] - predicted blood loss=1; no dispersion possible as n=1, 9999 entered [6] - no dispersion possible as n=1, 9999 entered [7] - no dispersion possible as n=1, 9999 entered |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Intraoperative actual blood loss relative to predicted blood loss | ||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 0 (at completion of surgery)
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| Notes [8] - No standard deviation possible as only one participant was analyzed. 9999 was entered. [9] - No standard deviation possible as only one participant was analyzed. 9999 was entered. [10] - No standard deviation possible as only one participant was analyzed. 9999 was entered. [11] - No standard deviation possible as only one participant was analyzed. 9999 was entered. [12] - No standard deviation possible as only one participant was analyzed. 9999 was entered. |
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Intraoperative actual versus predicted blood loss score as assessed by the operating surgeon | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 0 (at completion of surgery)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Intraoperative hemostatic efficacy score as assessed by the operating surgeon | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 0 (at completion of surgery)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE | ||||||||||||||||||||||||||||||||||||||||
End point description |
|||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Daily, from day of surgery through postoperative Day 14
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Occurrence of adverse events | ||||||||||||||||||||||||||||||||||||
End point description |
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated.
The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
From first infusion of investigational product through study completion (ie, 14 days post surgery)
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||
End point title |
Occurrence of thrombotic events | ||||||||||
End point description |
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated.
The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
From first infusion of investigational product through study completion (ie, 14 days post surgery)
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||
End point title |
Occurrence of severe allergic reactions (eg, anaphylaxis) | ||||||||||
End point description |
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated.
The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
From first infusion of investigational product through study completion (ie, 14 days post surgery)
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||
End point title |
Number of subjects who developed inhibitory and total binding antibodies to von Willebrand Factor (VWF) and inhibitory antibodies to Factor VIII (FVIII) | ||||||||||||
End point description |
Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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 days post surgery).
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||
End point title |
Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) or recombinant Furin (rFurin) | ||||||
End point description |
Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
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 days post surgery).
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||||||||
End point title |
Pharmacokinetics: Area under the plasma concentration versus time curve from 0 to 72 hours post-infusion (AUC 0-72 h/dose) | ||||||||||||||||||
End point 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)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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.
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [13] - For FVIII:C n=5 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Pharmacokinetics: Area under the plasma concentration versus time curve from time 0 to infinity (AUC 0-∞ /dose) | ||||||||||||||||||
End point 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)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
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.
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [14] - For FVIII:C n=3 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||
End point title |
Pharmacokinetics: Mean residence time (MRT) | ||||||||||||||||
End point 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)
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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.
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Pharmacokinetics: Clearance (CL) | ||||||||||||||||
End point 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. 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)
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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.
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Pharmacokinetics: Incremental recovery (IR) | ||||||||||||||||
End point 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. 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)
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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.
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Pharmacokinetics: Elimination phase half-life (T1/2) | ||||||||||||||||
End point 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. 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)
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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.
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Pharmacokinetics: Volume of distribution at steady state (Vss) | ||||||||||||||||
End point 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. 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)
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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.
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
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.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Recombinant von Willebrand Factor (rVWF)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Surgery participants treated with Recombinant von Willebrand Factor (rVWF) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
30 Aug 2012 |
The various types of severe VWD that are eligible for the study were clarified to include VWD with a history of requiring substitution therapy containing VWF to control bleeding; Type 1 (VWF:RCoF < 20 IU/dL); Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2N (FVIII:C<10% and historically documented genetics), and Type 2M; or Type 3 (VWF:Ag ≤ 3 IU/dL).
The option to give a priming dose of rVWF 12-24 hours before surgery was deleted to reduce the number of different dose regimens investigated.
The primary efficacy endpoint was updated to include intra- and post-operative actual versus predicted blood loss; and overall assessment of clinical (hemostatic) efficacy at 24 hours after last infusion of IP. Furthermore, it was made mandatory that the surgeon documents predicted values with a source data document to strengthen the quality of the predicted average and maximum blood loss.
Two options for administration of the combination of rVWF and rFVIII were added to ease reconstitution and mixing of study drugs. Option 1: Infusion of premixed drug, Option 2: Sequential infusion
Treatment success was defined as a mean primary efficacy rating score of <2 for a subject’s IP-covered surgery, dental, or invasive procedure (Excellent = 1, Good = 2, Moderate = 3, None = 4). |
||
27 Nov 2013 |
Throughout the protocol, wording on analysis of primary and secondary outcome measures was adjusted to reflect revised primary and secondary objectives.
Primary hemostatic efficacy assessment rating scale was revised to reflect the authority’s feedback (inclusion of objective measure of cessation of bleeding).
Completion visit was changed from 30 days (± 3 days) after the last IP infusion to 14 days (± 2 days) after surgery to standardize treatment duration and evaluation of primary efficacy endpoint.
The priming dose VWF infusion 12-24 hours prior surgery included in the original protocol and deleted in Global Amendment 1 was reintroduced to improve the IP treatment scheme. |
||
19 Mar 2015 |
The sponsor name/entity was changed. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
