Clinical Trial Results:
A phase II/III, randomized, cross-over, open-label trial to demonstrate superiority of prophylaxis over on-demand therapy in previously treated subjects with severe hemophilia A treated with plasma protein-free recombinant FVIII formulated with sucrose (BAY 81-8973)
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Summary
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EudraCT number |
2009-012150-20 |
Trial protocol |
CZ |
Global end of trial date |
05 Dec 2012
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Results information
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Results version number |
v2(current) |
This version publication date |
03 Sep 2016
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First version publication date |
28 Jun 2015
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Other versions |
v1 |
Version creation reason |
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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 |
BAY81-8973/14319
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01233258 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 May 2013
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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 |
05 Dec 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 |
To demonstrate that 2-3 times per week prophylaxis therapy with BAY81-8973 is superior to on-demand therapy with BAY81-8973 in subjects with severe Hemophilia A. The hypothesis was that prophylaxis will result in fewer bleeds than on-demand treatment.
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representatives. Participating subjects and/or their legally authorized representatives signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Jan 2011
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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 |
Japan: 9
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Country: Number of subjects enrolled |
Mexico: 9
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Country: Number of subjects enrolled |
Romania: 18
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Country: Number of subjects enrolled |
China: 31
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Country: Number of subjects enrolled |
Serbia: 5
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Country: Number of subjects enrolled |
Russian Federation: 7
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Country: Number of subjects enrolled |
Turkey: 5
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Country: Number of subjects enrolled |
Taiwan: 3
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Country: Number of subjects enrolled |
United States: 2
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Country: Number of subjects enrolled |
South Africa: 6
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Country: Number of subjects enrolled |
Czech Republic: 2
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Worldwide total number of subjects |
97
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EEA total number of subjects |
20
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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) |
11
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Adults (18-64 years) |
86
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were recruited from specialized hemophilia treatment centers. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 83 subjects were randomized, but 3 of these terminated the study before their first injection of study drug. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
First Intervention (6 Months)
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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On Demand, BAY81-8973 Potency First EP Then ADJ | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by Chromogenic Substrate Assay per European Pharmacopoeia (CS/EP) for 6 months, followed by crossover to study drug assayed by Chromogenic Substrate Assay/label adjusted to one-stage assay (CS/ADJ) for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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Investigational medicinal product code |
BAY81-8973
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Other name |
rFVIII
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received BAY81-8973 as an intravenous (IV) injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.
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Arm title
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On Demand, BAY81-8973 Potency First ADJ Then EP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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Investigational medicinal product code |
BAY81-8973
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Other name |
rFVIII
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received BAY81-8973 as an IV injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.
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Arm title
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Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 international units per kilogram (IU/kg) twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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Investigational medicinal product code |
BAY81-8973
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Other name |
rFVIII
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
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Arm title
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Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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Investigational medicinal product code |
BAY81-8973
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Other name |
rFVIII
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.
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Arm title
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High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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Investigational medicinal product code |
BAY81-8973
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Other name |
rFVIII
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
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Arm title
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High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
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Other name |
rFVIII
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.
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Period 2
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Period 2 title |
Second Intervention (6 months)
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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On Demand, BAY81-8973 Potency First EP Then ADJ | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by CS/EP for 6 months, followed by cross-over to study drug assayed by CS/ADJ for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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Investigational medicinal product code |
BAY81-8973
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Other name |
rFVIII
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Pharmaceutical forms |
Injection
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received BAY81-8973 as an intravenous (IV) injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arm title
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On Demand, BAY81-8973 Potency First ADJ Then EP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received BAY81-8973 as an IV injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arm title
|
Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arm title
|
Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arm title
|
High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Arm title
|
High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Period 3
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 3 title |
Baseline period
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Is this the baseline period? |
Yes [1] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Arm title
|
rFVIII (BAY81-8973) on Demand | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received BAY81-8973 as an IV injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Arm title
|
rFVIII (BAY81-8973) Prophylaxis Low-dose | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Arm title
|
rFVIII (BAY81-8973) Prophylaxis High-dose | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant factor VIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
BAY81-8973
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
rFVIII
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: All randomized subjects were included in the intervention periods but the baseline characteristics were recorded only for treated subjects as planned. Hence, a baseline period consisting of only treated subjects was created after the intervention periods. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Not all enrolled subjects were treated with study drugs. As baseline included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
rFVIII (BAY81-8973) on Demand
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
rFVIII (BAY81-8973) Prophylaxis Low-dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
rFVIII (BAY81-8973) Prophylaxis High-dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
On Demand, BAY81-8973 Potency First EP Then ADJ
|
||
Reporting group description |
Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by Chromogenic Substrate Assay per European Pharmacopoeia (CS/EP) for 6 months, followed by crossover to study drug assayed by Chromogenic Substrate Assay/label adjusted to one-stage assay (CS/ADJ) for 6 months. | ||
Reporting group title |
On Demand, BAY81-8973 Potency First ADJ Then EP
|
||
Reporting group description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months. | ||
Reporting group title |
Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
|
||
Reporting group description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 international units per kilogram (IU/kg) twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||
Reporting group title |
Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
|
||
Reporting group description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months. | ||
Reporting group title |
High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
|
||
Reporting group description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||
Reporting group title |
High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
|
||
Reporting group description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months. | ||
Reporting group title |
On Demand, BAY81-8973 Potency First EP Then ADJ
|
||
Reporting group description |
Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by CS/EP for 6 months, followed by cross-over to study drug assayed by CS/ADJ for 6 months. | ||
Reporting group title |
On Demand, BAY81-8973 Potency First ADJ Then EP
|
||
Reporting group description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months. | ||
Reporting group title |
Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
|
||
Reporting group description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||
Reporting group title |
Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
|
||
Reporting group description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months. | ||
Reporting group title |
High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
|
||
Reporting group description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months. | ||
Reporting group title |
High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
|
||
Reporting group description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months. | ||
Reporting group title |
rFVIII (BAY81-8973) on Demand
|
||
Reporting group description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||
Reporting group title |
rFVIII (BAY81-8973) Prophylaxis Low-dose
|
||
Reporting group description |
Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||
Reporting group title |
rFVIII (BAY81-8973) Prophylaxis High-dose
|
||
Reporting group description |
Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period. | ||
Subject analysis set title |
rFVIII (BAY81-8973) Prophylaxis Treatment
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received prophylaxis treatment with rFVIII (BAY81-8973) at low-dose (20, 25 or 30 IU/kg twice per week ) and high-dose (30, 35 or 40 IU/kg 3 times per week ) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization.
|
||
Subject analysis set title |
Safety population
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects randomized into the study who received at least 1 injection of study medication.
|
||
Subject analysis set title |
rFVIII (BAY81-8973) on Demand Assayed by CS/EP
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months.
|
||
Subject analysis set title |
rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months.
|
||
Subject analysis set title |
rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/EP
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received prophylaxis treatment with rFVIII (BAY81-8973) at low-dose (20, 25 or 30 IU/kg twice per week) and high-dose (30, 35 or 40 IU/kg 3 times per week) assayed by CS/EP for 6 months.
|
||
Subject analysis set title |
ITT population
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All subjects in the safety population who have injection / bleeding data from the electronic patient diary (EPD) and/or case report form (CRF).
|
||
Subject analysis set title |
rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/ADJ
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received prophylaxis treatment with rFVIII (BAY81-8973) at low-dose (20, 25 or 30 IU/kg twice per week) and high-dose (30, 35 or 40 IU/kg 3 times per week) assayed by CS/ADJ for 6 months.
|
||
|
|||||||||||||
End point title |
Annualized Number of All Bleeds [1] | ||||||||||||
End point description |
The annualized number of bleeds experienced by subjects.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design)
|
||||||||||||
| Notes [1] - 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: Low and high dose prophylaxis arms of the baseline period and both potencies combined as planned for the statistical analysis to achieve intended sample size. Hence, the end point is reporting statistics for a combined arm (created as a subject analysis set) instead of the individual arms in the baseline period. |
|||||||||||||
|
|||||||||||||
| Notes [2] - ITT population [3] - ITT population |
|||||||||||||
Statistical analysis title |
On Demand versus Prophylaxis Treatment | ||||||||||||
Statistical analysis description |
Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation: Assumption 5 bleeds per year on prophylactic treatment, 15 on on-demand treatment; combined standard deviation of 11; 3:1 randomization; 2-sided alpha 5% and 90% power.
|
||||||||||||
Comparison groups |
rFVIII (BAY81-8973) on Demand v rFVIII (BAY81-8973) Prophylaxis Treatment
|
||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0001 | ||||||||||||
Method |
ANOVA | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Annualized Number of All Bleeds During CS/EP Period | ||||||||||||
End point description |
The annualized number of bleeds experienced by subjects while they were taking rFVIII (BAY81-8973) assayed by CS/EP
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to 6 months (6 months on CS/EP potency assignment)
|
||||||||||||
|
|||||||||||||
| Notes [4] - ITT population [5] - ITT population |
|||||||||||||
Statistical analysis title |
On Demand versus Prophylaxis Treatment | ||||||||||||
Statistical analysis description |
Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation not done for this comparison as not primary comparison.
|
||||||||||||
Comparison groups |
rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/EP v rFVIII (BAY81-8973) on Demand Assayed by CS/EP
|
||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0001 | ||||||||||||
Method |
ANOVA | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Annualized Number of All Bleeds During CS/ADJ Period | ||||||||||||
End point description |
The annualized number of bleeds experienced by subjects while they were taking rFVIII (BAY81-8973) assayed by CS/ADJ.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to 6 months (6 months on CS/ADJ potency assignment)
|
||||||||||||
|
|||||||||||||
| Notes [6] - ITT population [7] - ITT population |
|||||||||||||
Statistical analysis title |
On Demand versus Prophylaxis Treatment | ||||||||||||
Statistical analysis description |
Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation not done for this comparison as not primary comparison.
|
||||||||||||
Comparison groups |
rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/ADJ v rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ
|
||||||||||||
Number of subjects included in analysis |
79
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [8] | ||||||||||||
P-value |
= 0.0001 | ||||||||||||
Method |
ANOVA | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [8] - comment |
|||||||||||||
|
|||||||||||||
End point title |
Percentage of Bleeds Per Subject Controlled With ≤ 2 Injections in Subjects Treated on Demand With rFVIII (BAY81-8973) | ||||||||||||
End point description |
The percentage of bleeds per subject on on-demand treatment that stopped after two or fewer injections
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design)
|
||||||||||||
|
|||||||||||||
| Notes [9] - ITT population [10] - ITT population |
|||||||||||||
Statistical analysis title |
CS/EP versus CS/ADJ | ||||||||||||
Statistical analysis description |
Null hypothesis: the proportion of bleeds controlled by no more than 2 infusions in the CS/EP group +10% is less than the proportion of bleeds controlled by no more than 2 infusions in the CS/ADJ group. Alternative hypothesis: the proportion of bleeds controlled by no more than 2 infusions in the CS/EP group + 10% is greater than or equal to the proportion of bleeds controlled by no more than 2 infusions in the CS/ADJ group. Confidence interval calculated with exact Hodges-Lehmann estimates.
|
||||||||||||
Comparison groups |
rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ v rFVIII (BAY81-8973) on Demand Assayed by CS/EP
|
||||||||||||
Number of subjects included in analysis |
41
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
non-inferiority [11] | ||||||||||||
P-value |
= 0.0001 [12] | ||||||||||||
Method |
Exact Permutation Test for paired sample | ||||||||||||
Parameter type |
Median difference (net) | ||||||||||||
Point estimate |
0
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
1-sided
|
||||||||||||
lower limit |
-0.049 | ||||||||||||
upper limit |
- | ||||||||||||
| Notes [11] - Non-inferiority margin 10% [12] - No multiplicity adjustment as this was not primary endpoint |
|||||||||||||
|
|||||||||||||||||
End point title |
Number of Bleeds During Treatment | ||||||||||||||||
End point description |
The number of bleeds experienced by each subject
|
||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||
End point timeframe |
12 months
|
||||||||||||||||
|
|||||||||||||||||
| Notes [13] - ITT population [14] - ITT population [15] - ITT population |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Inhibitory Antibody Formation | ||||||||||||||||||||||||||||||||
End point description |
A test to ensure that subjects have not developed antibodies that will interfere with the action of rFVIII (BAY81-8973)
|
||||||||||||||||||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||||||||||||||||||
End point timeframe |
3, 6, 9 and 12 months after baseline
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| Notes [16] - Safety population. [17] - Safety population. [18] - Safety population. |
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
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Timeframe for reporting adverse events |
Treatment-emergent adverse event data reported here were collected from start of first treatment up to 12.5 months (end of observation period) but no later than 3 days after last study medication intake
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
rFVIII (BAY81-8973) treatment
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Reporting group description |
Subjects received on-demand or prophylaxis treatment with recombinant factor VIII(rFVIII, BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to Randomization. | ||||||||||||||||||||||||||||||||||||||||||
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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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23 Mar 2010 |
1. Clarifications regarding the surgery indication, such as definitions of the surgery types, safety data required prior to surgery, and evaluation times of the surgery
outcome data during the study, were given as requested by the regulatory agencies
2. The regulatory agencies recommended studying two different dosing regimens to arrive at the optimal dose of BAY81-8973. Consistent with this recommendation, the study design was revised from prophylaxis (20-40 IU/kg BAY81-8973 administered 2-3 times/week) versus on-demand treatment to prophylaxis using 2 different dosing regimens (BAY81-8973 high-dose [30-40 IU 3 times/week] or low-dose [20-30 IU 2 times/week]) versus on-demand treatment
3. Addition of a secondary objective of demonstration of non-inferiority of BAY81-8973 dose determined by CS/EP versus BAY81-8973 dose determined by CS/ADJ
as measured by the proportion of bleeds controlled by 1 or 2 infusions (among all bleeds) in subjects treated on-demand |
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10 Jun 2010 |
1. The definition of severe hemophilia A in the inclusion criteria was clarified and expanded to allow subjects with previous medical history documentation of < 1%
FVIII:C, determined by one-stage clotting assay, included in the trial without further testing/confirmation of severe hemophilia A, if the screening result turned
out to be equal to or higher than 1%. The rationale for the change was to allow subjects with previously documented severe hemophilia A enrolled into the trial
without the delay of having another one-stage clotting assay performed, since severity is not known to change during the course of the disease. The documented
historical evidence of severe hemophilia A could be either from a previous Bayer hemophilia clinical trial, or from a previously performed one-stage clotting assay
from a certified laboratory
2. The number of surgeries was increased from ≥10 to ≥15, and the classification of surgery types was clarified to enable a more thorough evaluation of the safety
and efficacy of BAY 81-8973 in the surgical setting. The amendment further specified that ≥8 surgeries were major surgical procedures
3. To further ensure subject safety, the requirement was added that BAY 81-8973 was not to be supplied for use in the surgical setting until its hemostatic activity
had been assessed in at least 20 bleeding events
4. To be consistent with the sister protocol (Study 12954; EudraCT Number: 2009-012149-43), the following exclusion criterion was added: “Any subject who
cannot forego at least 3 days without receiving FVIII for washout purposes.”
5. The dosage range for prophylaxis treatment was clarified as occurring in 5 IU/kg increments over the range of 20-40 IU/kg 2-3 times per week (ie, low dose:
20, 25, or 30 IU/kg, administered 2 times per week; high dose 30, 35, or 40 IU/kg administered 3 times per week) |
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15 Mar 2011 |
1. For safety reasons, subjects with known hypersensitivity to mouse protein were excluded from participation in the study
2. Primary and secondary study objectives were revised and rearranged to include objectives for results of this study alone, and addendum objectives were added for
the pooled results of this study and Study 12954 |
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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 | |||
