CSLCT-BIO-03-97

CSL Limited

45 Poplar Road, Parkville, Australia, 3052

Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com

Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com

No

No

Yes

Final

05 Jul 2007

No

Yes

18 May 2007

Yes

The primary objectives of this study were to evaluate the efficacy and safety of Biostate® in the treatment of non-surgery bleeds, in the management of surgery procedures and prophylactic therapy in patients with VWD where 1-deamino-8-D-arginine vasopressin/Desmopressin (DDAVP) treatment was deemed by the Investigator to be ineffective, inadequate, or contraindicated.

This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring. The study protocol and all amendments were approved by the Independent Ethics Committee(s)/ Institutional Review Board(s) 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 If a subject is withdrawn from the study or further participation is declined, the subject will continue to have access to medical care and will be treated according to routine medical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.

07 Dec 2004

No

No

Australia: 21

New Zealand: 2

23

0

0

0

0

0

1

0

16

5

1

Overall Study (overall period)

Not applicable

Yes

Human coagulation Factor VIII / von Willebrand Factor

Biostate®, Voncento®

Powder and solvent for solution for injection/infusion

Intravenous use

Biostate was to be administered as a bolus intravenous infusion over a period of approximately 5 minutes, or as tolerated by the subject.

Human coagulation Factor VIII / von Willebrand Factor

Biostate®, Voncento®

Powder and solvent for solution for injection/infusion

Intravenous use

Biostate was to be administered as a bolus intravenous infusion over a period of approximately 5 minutes, or as tolerated by the subject.

Human coagulation Factor VIII / von Willebrand Factor

Biostate®, Voncento®

Powder and solvent for solution for injection/infusion

Intravenous use

Biostate was to be administered as a bolus intravenous infusion over a period of approximately 5 minutes, or as tolerated by the subject.

Human coagulation Factor VIII / von Willebrand Factor

Biostate®, Voncento®

Powder and solvent for solution for injection/infusion

Intravenous use

Biostate was to be administered as a bolus intravenous infusion over a period of approximately 5 minutes, or as tolerated by the subject.

Prophylactic

Minor Surgery

Major Surgery

Non-surgery Bleed

Prophylactic

Minor Surgery

Major Surgery

Non-surgery Bleed

Minor Surgery - Intent to Treat (ITT) Set

The ITT Set was defined by treatment event (not subject). An event was included in the ITT Set if the subject received at least one dose of Biostate (either trial or non-trial product) and had at least one post-dose haemostatic efficacy measurement performed for that event. Fifteen treatment events were included in the Minor Surgery ITT set.

Major Surgery - ITT Set

The ITT Set was defined by treatment event (not subject). An event was included in the ITT Set if the subject received at least one dose of Biostate (either trial or non-trial product) and had at least one post-dose haemostatic efficacy measurement performed for that event. Ten treatment events were included in the Major Surgery set.

Non-surgery Bleed - ITT Set

The ITT Set was defined by treatment event (not subject). An event was included in the ITT Set if the subject received at least one dose of Biostate (either trial or non-trial product) and had at least one post-dose haemostatic efficacy measurement performed for that event. Six treatment events were included in the Non-surgery Bleed ITT set.

Prophylactic - ITT Set

The ITT Set was defined by treatment event (not subject). An event was included in the ITT Set if the subject received at least one dose of Biostate (either trial or non-trial product) and had at least one post-dose haemostatic efficacy measurement performed for that event. Twenty-two treatment events were included in the Prophylactic ITT set.

Minor Surgery - Safety Set

The Safety Set is defined as all subjects who received at least one dose of Biostate (either trial or non-trial Biostate). Nineteen treatment events were included in the Minor Surgery Safety Set.

Major Surgery - Safety Set

The Safety Set is defined as all subjects who received at least one dose of Biostate (either trial or non-trial Biostate). Ten treatment events were included in the Minor Surgery Safety Set.

Non-surgery Bleed - Safety Set

The Safety Set is defined as all subjects who received at least one dose of Biostate (either trial or non-trial Biostate). Nineteen treatment events were included in the Non-surgery Bleed Safety Set.

Prophylactic - Safety Set

The Safety Set is defined as all subjects who received at least one dose of Biostate (either trial or non-trial Biostate). The 4 prophylactic subjects were included as 4 separate “treatment events” for the safety analysis.

All Subjects - Safety Set

The Safety Set is defined as all subjects who received at least one dose of Biostate (either trial or non-trial Biostate).

The efficacy grading scale was as follows: Excellent = cessation of bleeding; Good = slight oozing/partial but adequate control of bleeding/no additional product required; Moderate = moderate bleeding/moderate control of bleeding/additional product required; None = severe uncontrolled bleeding. Subjects (including those on prophylactic therapy) could be assessed in the study for more than one non-surgery bleed or surgery event with the possibility of the treatment phase for an additional event overlapping the follow-up phase of a previous event. Any haemostatic efficacy assessments for events requiring treatment at Day 0 only were performed at the Post-treatment Visit. If a subject did not receive Biostate on his/her last "Day X Visit" and did not have Post-treatment Visit data either, the haemostatic efficacy result for that last day was recorded but not included in this analysis.

Primary

Days 1, 2, 3, 4, 5, 6, Post-treatment Visit (24 hrs after final dose, applicable for all surgery procedures during the 12-month period)

The efficacy grading scale was as follows: Excellent = cessation of bleeding; Good = slight oozing/partial but adequate control of bleeding/no additional product required; Moderate = moderate bleeding/moderate control of bleeding/additional product required; None = severe uncontrolled bleeding. Subjects (including those on prophylactic therapy) could be assessed in the study for more than one non-surgery bleed or surgery event with the possibility of the treatment phase for an additional event overlapping the follow-up phase of a previous event. Any haemostatic efficacy assessments for events requiring treatment at Day 0 only were performed at the Post-treatment Visit. If a subject did not receive Biostate on his/her last "Day X Visit" and did not have Post-treatment Visit data either, the haemostatic efficacy result for that last day was recorded but not included in this analysis.

Primary

Assessed every 3 months up to Month 12

Blood samples were to be taken before administration of Biostate each day including Day 0. Levels for factor VIII:coagulant activity (FVIII:C) = Low < 50%; Normal 50%-200%; High > 200%. Von Willebrand factor:antigen (VWF:Ag) = Low < 40%; Normal 40%-200%; High > 200%. Von Willebrand factor:collagen binding capacity (VWF:CB) = Low < 50%; Normal 50%-400%; High > 400%. Von Willebrand factor:ristocetin co-factor activity (VWF:RCo) = Low < 45%; Normal 45%-200%; High > 200%. Any missing results were likely to be due to blood samples not being collected at the site or patients administering Biostate at home.

Primary

Days 0, 1, 2, 3, Post-treatment Visit (24 hrs after final dose, applicable for all surgery procedures during the 12-month period)

Surgical team's assessment of blood loss during surgery is comparing the blood loss to the expected blood loss in a subject without a bleeding disorder undergoing the same procedure (less, equivalent, or more than expected). 'Missing' = assessment of blood loss not provided by surgical team.

Primary

Day 0 (day of surgery)

The number of units and type of blood transfusions are presented overall (including platelets, packed red blood cells or fresh frozen plasma) and by packed red blood cells.

Primary

Through Month 12

Primary

through Month 12

The number of infusions required until resolution of the event.

Primary

Through Month 12

Primary

Through Month 12

Primary

Through Month 12

A TEAE was defined as an adverse event that began or increased in intensity after the first dose of Biostate. A related TEAE was defined as an event considered by the investigator to be possibly, probably or definitely related Biostate. In addition to adverse events (AEs) collected during the stated time frame, AEs for all subjects undergoing surgery were collected from the first administration of Biostate used to treat/manage any additional nonsurgery bleeds/surgery procedures, up to 30 days after the last administration of Biostate used to treat/manage the event.

Primary

Prophylactic subjects: from Day 0 through Month 12. Elective surgery subjects: Screening Visit through Month 12 + 30 days follow-up. Non-surgery bleeds/emergency surgery subjects: Day 0 through Month 12 + 30 days follow-up.

A subject is considered to have a newly detected FVIII inhibitor if the result was 'not detected' at screening and 'detected' at any time post-screening. Subjects are presented based on their initial treatment event.

Primary

Screening through 30-day Follow-up

A subject is considered to have a newly detected FVIII inhibitor if the result was 'not detected' at screening and 'detected' at any time post-screening. Subjects are presented based on their initial treatment event.

Primary

Screening, Months 3, 6, 9, and 12 (or Completion Visit)

Primary

Through Month 12

Prophylactic subjects: from Day 0 through Month 12. Elective surgery subjects: Screening Visit through Month 12 + 30 days follow-up. Non-surgery bleeds/emergency surgery subjects: Day 0 through Month 12 + 30 days follow-up.

Treatment-emergent AEs only. In addition to AEs collected during the stated time frame, AEs for all subjects undergoing surgery were collected from the first administration of Biostate used to treat/manage any additional nonsurgery bleeds/surgery procedures, up to 30 days after the last administration of Biostate used to treat/manage the event.

9.0

All Subjects - Safety Set