Clinical Trial Results:
An Open-label, Multi-centre Study to Assess the Pharmacokinetics, Efficacy and Safety of Biostate® in Subjects with Von Willebrand Disease
Summary
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EudraCT number |
2008-004922-18 |
Trial protocol |
BG |
Global end of trial date |
16 Feb 2012
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
06 Aug 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CSLCT-BIO-08-54
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
CSL Behring GmbH
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Sponsor organisation address |
Emil-von-Behring-Str 76, Marburg, Germany, 35041
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Public contact |
Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
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Scientific contact |
Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000312-PIP01-08 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Aug 2012
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Feb 2012
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
1. To investigate the initial and repeat pharmacokinetic profile of Biostate in subjects with von Willebrand disease (VWD).
2. To assess the haemostatic efficacy of Biostate in subjects with VWD who require a von Willebrand Factor product to control a non-surgical bleeding (NSB) event.
3. To assess the effectiveness of a prophylaxis regimen as compared to on-demand therapy with Biostate in preventing NSB events.
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Protection of trial subjects |
This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring (CSLB). The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) / Institutional Review Board(s) (IRBs) of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study.
The investigator may cease study treatment and withdraw the subject, or the subject may withdraw himself from participation in the study at any time. If a subject is withdrawn from the study or further participation is declined, the subject will continue to have access to medical care and will be treated according to routine medical practice, but will no longer receive the investigational medicinal product (IMP).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Jun 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 9
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Country: Number of subjects enrolled |
Poland: 4
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Country: Number of subjects enrolled |
Russian Federation: 4
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Country: Number of subjects enrolled |
Brazil: 2
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Country: Number of subjects enrolled |
Ukraine: 3
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Worldwide total number of subjects |
22
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EEA total number of subjects |
13
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
3
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Adults (18-64 years) |
18
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||
Pre-assignment
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Screening details |
This study included a Screening period of up to 28 days. | ||||||||||||||||||||
Period 1
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Period 1 title |
Pharmacokinetic (PK) Component
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Is this the baseline period? |
No | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
Arms
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Arm title
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PK Component | ||||||||||||||||||||
Arm description |
A single bolus intravenous (i.v.) infusion of 80 IU/kg von Willebrand factor: ristocetin cofactor (VWF RCo) on Day 1 (for the initial PK assessment) and on Day 180 (Month 6) for the repeat PK assessment (in type 3 VWD subjects only). | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Human coagulation Factor VIII / von Willebrand Factor
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Investigational medicinal product code |
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Other name |
Biostate®, Voncento®
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
A single bolus i.v.infusion of 80 IU/kg Biostate on Day 1 (for the initial PK assessment) and on Day 180 (repeat PK for Type 3 VWD PK subjects only).
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Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 8 subjects with VWD Type 3 participated in the repeat PK assessment, which occurred after the treatment period of the study had started. These subjects continued in the treatment period until the end of the study along with the other subjects. |
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Period 2
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Period 2 title |
Treatment Period (Efficacy Component)
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Is this the baseline period? |
Yes [2] | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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Arm 1: Prophylaxis Therapy | ||||||||||||||||||||
Arm description |
Subjects who were being treated on a set prophylaxis regimen with a VWF product at the time of study entry, or who were not on a set prophylaxis regimen but in whom prophylaxis treatment was justifiable in the opinion of the investigator, were enrolled into Arm 1 and received Biostate as part of a prophylaxis regimen as determined by the severity of their disease for a period of 12 months. Arm 1 subjects completed the study with a Final Visit at Month 12. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Human coagulation Factor VIII / von Willebrand Factor
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Investigational medicinal product code |
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Other name |
Biostate®, Voncento®
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Frequency and dose was determined by the Investigator based on the subject's clinical condition, previous VWF concentrate requirements, response to therapy, body weight and reason for usage.
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Arm title
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Arm 2: On-Demand Therapy | ||||||||||||||||||||
Arm description |
Subjects who were not on a set prophylaxis regimen with a VWF product at the time of study entry, and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (spontaneous or trauma-induced), were enrolled into Arm 2 and commenced using Biostate as on-demand therapy for the treatment of NSB events. At the Month 12 visit and based on the extent and location of any bleeding events, Arm 2 subjects were assessed for eligibility to be switched to a set prophylaxis regimen with Biostate for an additional 12 months (Arm 3). The total treatment duration for subjects in Arm 2 only was up to 12 months. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Human coagulation Factor VIII / von Willebrand Factor
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Investigational medicinal product code |
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Other name |
Biostate®, Voncento®
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Frequency and dose was determined by the Investigator based on the subject's clinical condition, previous VWF concentrate requirements, response to therapy, body weight and reason for usage.
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Arm title
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Arm 3: Prophylaxis Therapy (Post On-Demand Therapy) | ||||||||||||||||||||
Arm description |
Subjects who completed treatment (on-demand therapy with Biostate) in Arm 2 and who at the Month 12 visit qualified to be switched to a set prophylactic regimen according to the criteria prespecified in the study protocol, entered Arm 3 and started Biostate treatment as prophylaxis therapy for an additional 12 months. The prophylaxis regimen was determined by the extent and location of NSB events during the preceding 12-month on-demand therapy period. The total treatment duration for subjects in Arm 3 was up to 24 months. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Human coagulation Factor VIII / von Willebrand Factor
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Investigational medicinal product code |
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Other name |
Biostate®, Voncento®
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Frequency and dose was determined by the Investigator based on the subject's clinical condition, previous VWF concentrate requirements, response to therapy, body weight and reason for usage.
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Notes [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: The PK component (period 1), which took place prior to the Efficacy component (used as for Baseline values), does not include all subjects enrolled in this study. |
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Baseline characteristics reporting groups
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Reporting group title |
Arm 1: Prophylaxis Therapy
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Reporting group description |
Subjects who were being treated on a set prophylaxis regimen with a VWF product at the time of study entry, or who were not on a set prophylaxis regimen but in whom prophylaxis treatment was justifiable in the opinion of the investigator, were enrolled into Arm 1 and received Biostate as part of a prophylaxis regimen as determined by the severity of their disease for a period of 12 months. Arm 1 subjects completed the study with a Final Visit at Month 12. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 2: On-Demand Therapy
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Reporting group description |
Subjects who were not on a set prophylaxis regimen with a VWF product at the time of study entry, and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (spontaneous or trauma-induced), were enrolled into Arm 2 and commenced using Biostate as on-demand therapy for the treatment of NSB events. At the Month 12 visit and based on the extent and location of any bleeding events, Arm 2 subjects were assessed for eligibility to be switched to a set prophylaxis regimen with Biostate for an additional 12 months (Arm 3). The total treatment duration for subjects in Arm 2 only was up to 12 months. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 3: Prophylaxis Therapy (Post On-Demand Therapy)
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Reporting group description |
Subjects who completed treatment (on-demand therapy with Biostate) in Arm 2 and who at the Month 12 visit qualified to be switched to a set prophylactic regimen according to the criteria prespecified in the study protocol, entered Arm 3 and started Biostate treatment as prophylaxis therapy for an additional 12 months. The prophylaxis regimen was determined by the extent and location of NSB events during the preceding 12-month on-demand therapy period. The total treatment duration for subjects in Arm 3 was up to 24 months. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
PK Component
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Reporting group description |
A single bolus intravenous (i.v.) infusion of 80 IU/kg von Willebrand factor: ristocetin cofactor (VWF RCo) on Day 1 (for the initial PK assessment) and on Day 180 (Month 6) for the repeat PK assessment (in type 3 VWD subjects only). | ||
Reporting group title |
Arm 1: Prophylaxis Therapy
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Reporting group description |
Subjects who were being treated on a set prophylaxis regimen with a VWF product at the time of study entry, or who were not on a set prophylaxis regimen but in whom prophylaxis treatment was justifiable in the opinion of the investigator, were enrolled into Arm 1 and received Biostate as part of a prophylaxis regimen as determined by the severity of their disease for a period of 12 months. Arm 1 subjects completed the study with a Final Visit at Month 12. | ||
Reporting group title |
Arm 2: On-Demand Therapy
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Reporting group description |
Subjects who were not on a set prophylaxis regimen with a VWF product at the time of study entry, and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (spontaneous or trauma-induced), were enrolled into Arm 2 and commenced using Biostate as on-demand therapy for the treatment of NSB events. At the Month 12 visit and based on the extent and location of any bleeding events, Arm 2 subjects were assessed for eligibility to be switched to a set prophylaxis regimen with Biostate for an additional 12 months (Arm 3). The total treatment duration for subjects in Arm 2 only was up to 12 months. | ||
Reporting group title |
Arm 3: Prophylaxis Therapy (Post On-Demand Therapy)
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Reporting group description |
Subjects who completed treatment (on-demand therapy with Biostate) in Arm 2 and who at the Month 12 visit qualified to be switched to a set prophylactic regimen according to the criteria prespecified in the study protocol, entered Arm 3 and started Biostate treatment as prophylaxis therapy for an additional 12 months. The prophylaxis regimen was determined by the extent and location of NSB events during the preceding 12-month on-demand therapy period. The total treatment duration for subjects in Arm 3 was up to 24 months. |
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End point title |
Initial PK Assessment: Incremental Recovery (IR) [1] | ||||||||||||||
End point description |
Baseline-adjusted IR of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor:collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [2] - PK population (subjects who participated in the PK component) with evaluable data. |
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No statistical analyses for this end point |
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End point title |
Initial PK Assessment: Half-life (t1/2) [3] | ||||||||||||||
End point description |
Baseline-adjusted t1/2 of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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Notes [3] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [4] - PK population (subjects who participated in the PK component); n=subjects w/evaluable data specified |
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No statistical analyses for this end point |
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End point title |
Initial PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to 72 hours (AUC[0-72]) [5] | ||||||||||||||
End point description |
Baseline-adjusted AUC(0-72) of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor: antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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Notes [5] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [6] - PK population (subjects who participated in the PK component); n=subjects w/evaluable data specified |
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No statistical analyses for this end point |
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End point title |
Initial PK Assessment: Mean Residence Time (MRT) [7] | ||||||||||||||
End point description |
Baseline-adjusted MRT of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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Notes [7] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [8] - PK population (subjects who participated in the PK component); n=subjects w/evaluable data specified |
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No statistical analyses for this end point |
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End point title |
Initial PK Assessment: Maximum Plasma Concentration (Cmax) [9] | ||||||||||||||
End point description |
Baseline-adjusted Cmax of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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Notes [9] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [10] - PK population (subjects who participated in the PK component) with evaluable data. |
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No statistical analyses for this end point |
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End point title |
Initial PK Assessment: Time the Maximum Concentration Occurs (Tmax) [11] | ||||||||||||||
End point description |
Baseline-adjusted Tmax of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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Notes [11] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [12] - PK population (subjects who participated in the PK component) with evaluable data. |
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No statistical analyses for this end point |
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End point title |
Initial PK Assessment: Minimum Plasma Concentration (Cmin) [13] | ||||||||||||||
End point description |
Baseline-adjusted Cmin of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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Notes [13] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [14] - PK population (subjects who participated in the PK component) with evaluable data. |
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No statistical analyses for this end point |
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End point title |
Initial PK Assessment: Total Clearance (CL) [15] | ||||||||||||||
End point description |
Baseline-adjusted total clearance of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
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End point type |
Primary
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End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
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Notes [15] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
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Notes [16] - PK population (subjects who participated in the PK component); n=subjects w/evaluable data specified |
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No statistical analyses for this end point |
|
|||||||||||||||
End point title |
Initial PK Assessment: Volume of Distribution at Steady State (Vss) [17] | ||||||||||||||
End point description |
Baseline-adjusted Vss of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||
End point type |
Primary
|
||||||||||||||
End point timeframe |
Day 1: preinfusion; Days 1-4: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||
Notes [17] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||
|
|||||||||||||||
Notes [18] - PK population (subjects who participated in the PK component); n=subjects w/evaluable data specified |
|||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Incremental Recovery (IR) [19] | ||||||||||||||||||||
End point description |
Baseline-adjusted IR of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [19] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [20] - Repeat PK population (Type 3 VWD subjects who participated in the PK component) with evaluable data. |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Half-life (t1/2) [21] | ||||||||||||||||||||
End point description |
Baseline-adjusted t1/2 of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor:collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [21] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [22] - Repeat PK population (Type 3 VWD subjects in the PK component);n=subjects w/evaluable data specified |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to 72 hours (AUC[0-72]) [23] | ||||||||||||||||||||
End point description |
Baseline-adjusted AUC(0-72) of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor: antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [23] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [24] - Repeat PK population (Type 3 VWD subjects in the PK component);n=subjects w/evaluable data specified |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Mean Residence Time (MRT) [25] | ||||||||||||||||||||
End point description |
Baseline-adjusted MRT of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor: collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [25] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [26] - Repeat PK population (Type 3 VWD subjects in the PK component);n=subjects w/evaluable data specified |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Maximum Plasma Concentration (Cmax) [27] | ||||||||||||||||||||
End point description |
Baseline-adjusted Cmax of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor:collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [27] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [28] - Repeat PK population (Type 3 VWD subjects who participated in the PK component) with evaluable data. |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Time the Maximum Concentration Occurs (Tmax) [29] | ||||||||||||||||||||
End point description |
Baseline-adjusted Tmax of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor:collagen binding (VWF:CB) from the initial and repeat PK assessment. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [29] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [30] - Repeat PK population (Type 3 VWD subjects who participated in the PK component) with evaluable data. |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Minimum Plasma Concentration (Cmin) [31] | ||||||||||||||||||||
End point description |
Baseline-adjusted Cmin of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor:collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [31] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [32] - Repeat PK population (Type 3 VWD subjects who participated in the PK component) with evaluable data. |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Total Clearance (CL) [33] | ||||||||||||||||||||
End point description |
Baseline-adjusted total clearance of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor:collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [33] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [34] - Repeat PK population (Type 3 VWD subjects in the PK component);n=subjects w/evaluable data specified |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Initial and Repeat PK Assessment: Volume of Distribution at Steady State (Vss) [35] | ||||||||||||||||||||
End point description |
Baseline-adjusted Vss of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), and von Willebrand factor:collagen binding (VWF:CB) from the initial and repeat PK assessments. PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Day 1 and Day 180: preinfusion; Days 1-4 and Days 180-183: 15 (±5) min, 1 h (±5 min), 3 h (±5 min), 6 h (±15 min), 8 h (±30 min), 12 h (±30 min), 24 h (±2 h), 30 h (±2 h), 48 h (±2 h), 72 h (±2 h) after the end of infusion.
|
||||||||||||||||||||
Notes [35] - 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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [36] - Repeat PK population (Type 3 VWD subjects in the PK component);n=subjects w/evaluable data specified |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Investigator's 3-monthly Assessment of Haemostatic Efficacy [37] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
For each 3-month interval of the study, haemostatic efficacy was assessed by the Investigator for subjects with a bleeding event. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Subjects who did not have any bleeding events are included in this table. Bleeding events for which no Biostate treatment was needed are not included in this table.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Months 3, 6, 9, 12, 15, 18, 21, 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [37] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [38] - Efficacy population; n=subjects with available investigator's assessment in given month interval. [39] - Efficacy population; n=subjects with available investigator's assessment in given month interval. [40] - Efficacy population; n=subjects with available investigator's assessment in given month interval. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Investigator’s Assessment of Haemostatic Efficacy per Non-surgical Bleeding (NSB) Event [41] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinical assessments of haemostatic efficacy for all non-surgical bleeding events were done by the investigator in conjunction with the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: Excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Bleeding events with missing Investigator’s assessment for efficacy, or events for which no Biostate treatment was needed, were not considered for this table. Major bleeding event=one that involves any bleeding into a joint, muscle, or mucosal bleeds of the gastro-intestinal tract (excluding nasal or oral bleeding). All other bleeding events were classified as minor unless the Investigator assessment noted otherwise.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to Month 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [41] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [42] - Efficacy population; n=NSB events treated with Biostate and with a haemostatic efficacy assessment. [43] - Efficacy population; n=NSB events treated with Biostate and with a haemostatic efficacy assessment. [44] - Efficacy population; n=NSB events treated with Biostate and with a haemostatic efficacy assessment. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Subject’s Assessment of Haemostatic Efficacy per Day of Non-surgical Bleeding (NSB) Event [45] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Assessments of haemostatic efficacy were done by the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Bleeding events with missing subject's assessment for efficacy or events for which no Biostate treatment was needed are not included in this table.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to Month 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [45] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [46] - Efficacy population; n=total number of days due to bleeds with available subject's assessment. [47] - Efficacy population; n=total number of days due to bleeds with available subject's assessment. [48] - Efficacy population; n=total number of days due to bleeds with available subject's assessment. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Number of Subjects Requiring Blood Product Transfusions [49] | ||||||||||||||||||||
End point description |
Blood products include any infusions of whole blood, packed red blood cells, and platelets.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
Up to 24 Months
|
||||||||||||||||||||
Notes [49] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Notes [50] - Efficacy population [51] - Efficacy population [52] - Efficacy population |
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Blood Product Transfusions: Total Amount Received [53] | ||||||||||||||||||||||||
End point description |
The type of blood product, and the number of units required by a subject during the study period was recorded. This includes any infusions of whole blood, packed red blood cells, and platelets.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Up to Month 24
|
||||||||||||||||||||||||
Notes [53] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [54] - Efficacy population; n=subjects receiving the respective blood product at least once. [55] - Efficacy population; n=subjects receiving the respective blood product at least once. [56] - Efficacy population; n=subjects receiving the respective blood product at least once. |
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Usage of Biostate: Average Dose by Study Month [57] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
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End point timeframe |
Month 1 through Month 24
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Notes [57] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
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Notes [58] - Efficacy population; n=subjects with an infusion during given time period. [59] - Efficacy population; n=subjects with an infusion during given time period. [60] - Efficacy population; n=subjects with an infusion during given time period. |
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No statistical analyses for this end point |
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End point title |
Assessment of Blood Loss During Surgeries By Type of Surgery [61] | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
In the case of any surgical procedures, the surgical team was to provide an assessment at the time of the procedure of the extent of blood loss for each specific surgical procedure performed on a subject. The blood loss was compared to the expected blood loss from a subject without a bleeding disorder undergoing the same procedure. The following grading scale was used: less than expected loss, equivalent to expected loss, more than expected loss.
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End point type |
Primary
|
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End point timeframe |
Up to Month 24
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Notes [61] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
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Notes [62] - Efficacy population; n=number of surgeries of given type. [63] - Efficacy population; n=number of surgeries of given type. [64] - Efficacy population; n=number of surgeries of given type. |
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No statistical analyses for this end point |
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End point title |
Number of Non-Surgical Bleeding (NSB) Events Per Subject [65] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
|
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End point timeframe |
Up to Month 24
|
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Notes [65] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
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Notes [66] - Efficacy population; N=subjects with respective events / n=total number of bleeding events. [67] - Efficacy population; N=subjects with respective events / n=total number of bleeding events. [68] - Efficacy population; N=subjects with respective events / n=total number of bleeding events. |
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No statistical analyses for this end point |
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End point title |
Usage of Biostate: Number of Infusions by Study Month [69] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
|
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End point timeframe |
Month 1 through Month 24
|
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Notes [69] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. |
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Notes [70] - Efficacy population; n=subjects receiving an infusion at given time point. 0=not applicable. [71] - Efficacy population; n=subjects receiving an infusion at given time point. 0=not applicable. [72] - Efficacy population; n=subjects receiving an infusion at given time point. 0=not applicable. |
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No statistical analyses for this end point |
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End point title |
Subject's Monthly Self-rating of Biostate Efficacy: Arms 1 and 3 [73] [74] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Assessments of haemostatic efficacy were done by the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding.
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End point type |
Primary
|
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End point timeframe |
Month 1 through Month 24
|
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Notes [73] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed. [74] - 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: This analysis was planned for Arms 1 and 3, per protocol. |
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Notes [75] - Efficacy population [76] - Efficacy population |
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No statistical analyses for this end point |
|
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End point title |
Overview of Treatment Emergent Adverse Events (TEAEs) | ||||||||||||||||||||||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence that does not necessarily have a causal relationship to the study product. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is another medically important condition. The intensity/severity of AEs was categorized as mild, moderate, or severe. The relationship of the AE to the study product was categorized as not related, unlikely, possibly, probably or definitely. AEs occurring after the first dose of study medication were considered treatment-emergent.
|
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End point type |
Secondary
|
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End point timeframe |
From 1st study drug dose on Day 1 (PK component), or after 1st study drug dose (Efficacy only component), until Final Visit or 7 days after last dose of study drug, whichever occurs last. AEs related to a study procedure recorded from informed consent.
|
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|
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Notes [77] - Safety population [78] - Safety population [79] - Safety population |
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No statistical analyses for this end point |
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End point title |
VWF and Factor VIII Inhibitors | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of subjects with VWF and Factor VIII inhibitors at given time points.
|
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End point type |
Secondary
|
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End point timeframe |
Screening, Months 3, 6, 9, 12, 15, 18, 21, 24
|
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Notes [80] - Safety population; n=subjects with an available test result for given visit. [81] - Safety population; n=subjects with an available test result for given visit. [82] - Safety population; n=subjects with an available test result for given visit. |
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No statistical analyses for this end point |
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End point title |
Investigator's Assessment of Haemostatic Efficacy During Surgeries at Discharge | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinical assessments of haemostatic efficacy were done by the investigator in conjunction with the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Surgeries with missing investigator's assessment for efficacy are not included. Major surgery included surgery involving a risk to the life of the subject; minor surgery included surgery involving little risk to the life of the subject.
|
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End point type |
Secondary
|
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End point timeframe |
Up to Month 24
|
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Notes [83] - Efficacy population; n=number of surgeries of given type with available investigator's assessment. [84] - Efficacy population; n=number of surgeries of given type with available investigator's assessment. [85] - Efficacy population; n=number of surgeries of given type with available investigator's assessment. |
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No statistical analyses for this end point |
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End point title |
Investigator's Assessment of Haemostatic Efficacy During Surgeries per In-house Day | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinical assessments of haemostatic efficacy were done by the investigator in conjunction with the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale
was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment;
moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Surgeries with missing investigator's assessment for efficacy are not included.
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End point type |
Secondary
|
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End point timeframe |
Up to Month 24
|
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Notes [86] - Efficacy population; n=in-house days due to surgeries with available investigator's assessment. [87] - Efficacy population; n=in-house days due to surgeries with available investigator's assessment. [88] - Efficacy population; n=in-house days due to surgeries with available investigator's assessment. |
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No statistical analyses for this end point |
|
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End point title |
Investigator's Post-Surgery Assessment of Haemostatic Efficacy at Home | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate= moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Surgeries with missing investigator's assessment for efficacy are not included.
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End point type |
Secondary
|
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End point timeframe |
Up to Month 24
|
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Notes [89] - Efficacy population; n=surgeries of the given type with available post-surgery assessment. [90] - Efficacy population; n=surgeries of the given type with available post-surgery assessment. [91] - Efficacy population; n=surgeries of the given type with available post-surgery assessment. |
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No statistical analyses for this end point |
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End point title |
Subject's Daily Post-Surgery Assessment of Haemostatic Efficacy at Home | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Assessments of haemostatic efficacy were done by the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis
achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Surgeries with missing subject's assessment for efficacy are not included.
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End point type |
Secondary
|
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End point timeframe |
Up to Month 24
|
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Notes [92] - Efficacy population; n=total post-surgery days at home with available subject's assessment. [93] - Efficacy population; n=total post-surgery days at home with available subject's assessment. [94] - Efficacy population; n=total post-surgery days at home with available subject's assessment. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects Requiring Surgery-Related Blood Product Transfusions | ||||||||||||
End point description |
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End point type |
Secondary
|
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End point timeframe |
Up to Month 24
|
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|
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Notes [95] - Efficacy population [96] - Efficacy population [97] - Efficacy population |
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No statistical analyses for this end point |
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Adverse events information
|
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Timeframe for reporting adverse events |
From first administration of the IMP until Final Visit or until 7 days (for AEs) or 30 days (for SAEs) after the last IMP administration (up to 24 months). Events considered related to a study procedure were recorded from the point of informed consent.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
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Reporting groups
|
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Reporting group title |
Arm 1: Prophylaxis Therapy
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Reporting group description |
Subjects who were being treated on a set prophylaxis regimen with a VWF product at the time of study entry, or who were not on a set prophylaxis regimen but in whom prophylaxis treatment was justifiable in the opinion of the investigator, were enrolled into Arm 1 and received Biostate as part of a prophylaxis regimen as determined by the severity of their disease for a period of 12 months. Arm 1 subjects completed the study with a Final Visit at Month 12. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 2: On-Demand Therapy
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Reporting group description |
Subjects who were not on a set prophylaxis regimen with a VWF product at the time of study entry, and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (spontaneous or trauma-induced), were enrolled into Arm 2 and commenced using Biostate as on-demand therapy for the treatment of NSB events. At the Month 12 visit and based on the extent and location of any bleeding events, Arm 2 subjects were assessed for eligibility to be switched to a set prophylaxis regimen with Biostate for an additional 12 months (Arm 3). The total treatment duration for subjects in Arm 2 only was up to 12 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 3: Prophylaxis Therapy (Post On-Demand Therapy)
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Reporting group description |
Subjects who completed treatment (on-demand therapy with Biostate) in Arm 2 and who at the Month 12 visit qualified to be switched to a set prophylactic regimen according to the criteria prespecified in the study protocol, entered Arm 3 and started Biostate treatment as prophylaxis therapy for an additional 12 months. The prophylaxis regimen was determined by the extent and location of NSB events during the preceding 12-month on-demand therapy period. The total treatment duration for subjects in Arm 3 was up to 24 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Dec 2008 |
• All subjects had their VWD phenotype confirmed at the screening visit. This was performed by a central laboratory to ensure consistency in the phenotyping method used across sites and to ensure
reliability of the phenotype result.
• The duration of the screening period was increased from up to 14 days to up to 21 days to allow sufficient processing time for the phenotype assessment.
• Reduced blood volumes for adolescents were inserted.
• Introduction of a Data Safety Monitoring Board.
• Text inserted to emphasize that, whilst the initial PK component could be performed in Types 1, 2a, and 3 VWD subjects, only the Type 3 PK subjects were to participate in the repeat PK assessment. |
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23 Apr 2009 |
• A reduction in the volume of blood taken for both adults and adolescents (the same volumes required for adults and adolescents).
• Amendment to exclusion criterion number 9.
• Removal of Human Immunodeficiency Virus testing at screening.
• Modification of the requirements for Hepatitis C testing at screening.
• The duration of the screening period was increased from up to 21 days to up to 28 days to allow sufficient processing time for the phenotype assessment.
• Confirmation that a urine pregnancy test rather than a serum pregnancy test was to be performed in females of childbearing potential at screening.
• Bicarbonate testing was deleted from Biochemistry determinations as the testing procedure is contraindicated in bleeding disorders.
• Clarification regarding Hepatitis A and Hepatitis B eligibility testing at screening and pre-dose vaccination requirements.
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15 Dec 2009 |
• Adjustment of inclusion criterion number 3 to allow for the enrolment of subjects in Bulgaria where DDAVP is not available.
• Wash-out period prior to the screening visit.
• Adjustment of safety assessments with regard to suspected inhibitor formation.
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |