E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe Hemophilia-A (< 1% FVIII:C) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060613 |
E.1.2 | Term | Hemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the superiority of prophylaxis over on demand therapy by a clinically significant decrease in bleeding rate following 12 months of treatment with BAY 81-8973. |
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E.2.2 | Secondary objectives of the trial |
- To demonstrate superiority of prophylaxis versus on-demand treatment with BAY 81-8973 (dose determined by CS/EP) as measured by bleeding rate. - To demonstrate superiority of prophylaxis versus on-demand treatment with BAY 81-8973 (dose determined by CS/ADJ) as measured by bleeding rate. - To demonstrate the non-inferiority of prophylactic treatment with BAY 81 8973 (dose determined by CS/EP versus dose determined by CS/ADJ) as measured by bleeding rate (after combining results of this study with results from Protocol 12954). - To demonstrate the non-inferiority of BAY 81-8973 dose determined by CS/EP versus BAY 81-8973 dose determined by CS/ADJ as measured by the proportion of bleeds controlled by 1 or 2 infusions (among all bleeds) in on-demand patients. (as of Amd 1) - To demonstrate the non-inferiority of prophylactic treatment with BAY 81 8973 (dose determined by CS/EP versus dose determined by CS/ADJ) as measured by in vivo recovery (IVR).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male, aged 12 to 65 years • Severe hemophilia A, defined as < 1% FVIII:C as determined by one-stage clotting assay at the time of screening. If screening result turns out to be equal to or higher than 1%, then severe hemophilia A may be confirmed by one of the following (as of Amd 3): Documented historical evidence from a recognized (certified) clinical laboratory (acceptable to GCL) demonstrating < 1% FVIII:C as determined by one-stage clotting assay Assay results from a previous Bayer hemophilia clinical trial • ≥150 exposure days (ED) in total with any recombinant FVIII or plasma-derived FVIII only. Cryoprecipitate and fresh frozen plasma treatments are not considered in this total. (as of Amd 1) • Currently receiving episodic treatment with FVIII; and no regular prophylaxis for > 6 consecutive months in the previous 5 years • No current evidence of inhibitor antibody as measured by the Nijmegen-modified Bethesda assay [<0.3 Bethesda units (BU/mL)] (as of Amd 1) in 2 consecutive samples and absence of clinical signs or symptoms of decreased response to FVIII administration. (First negative sample can be historical if obtained within 3 months prior to screening with a result of 0.6 BU/mL by a classical Bethesda assay. The testing for a second negative, confirmatory sample must, in all cases, be performed by a central laboratory using the Nijmegen test. If a first recent sample is not available, then testing for 2 negative samples must be performed by the central laboratory at least 1 week apart). Subjects may not receive FVIII within 72 hours (as of Amd 1) prior tothe collection of samples for inhibitor testing. The time period since the last FVIII injection should not be longer than 4 weeks. • No history of FVIII inhibitor formation defined as inhibitor antibody <0.6 BU/mL by the Nijmegen-modified or classical Bethesday assay. However subjects with a maximum historical titer of 1.0 BU with the Classical Bethesda assay on no more than 1 occasion but with at least 3 subsequent (as of Amd 1) successive negative results (<0.6 BU) thereafter are also eligible. • Willingness and ability to complete training in the use of the study electronic patient diary (EPD) by the subject or a surrogate (a caregiver or family member over 18 years of age). (as of Amd 1). • Written informed consent by subject and parent/legal representative, if under age of consent per local regulation.
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E.4 | Principal exclusion criteria |
• Presence of another bleeding disease that is different from hemophilia A (e.g., von Willebrand disease, hemophilia B) • Thrombocytopenia (platelet count < 100 000/mm3) • Abnormal renal function (serum creatinine > 2.0 mg/dL) • Presence of active liver disease verified by medical history or persistent and increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5x the upper limit of normal (ULN) or severe liver disease as evidenced by an INR >4, hypoalbuminemia, and portal vein hypertension. • Received treatment with immunomodulatory agents within the last 3 months prior to study entry or requires treatment during the study. [The following drugs are allowed: interferon-α treatment for hepatitis C virus (HCV), highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV), and or a total of 2 courses of pulse treatment with steroids for a maximum of 7 days at 1 mg/kg or less]. • Absolute CD4 lymphocyte cell count < 250 cells/L (as of Amd 1). • Receiving or has received other experimental drugs within 3 months prior to study entry, with the exception of Bayer Kogenate (Bayer factor VIII study drugs) received in studies within 2 weeks prior to study entry. (as of Amd 1) • Requires any pre-medication to tolerate FVIII injections (e.g., antihistamines) • Unwilling to comply with study visits or other protocol requirements or is not suitable for participation in this study for any reason, according to the Investigator • Known hypersensitivity to hamster and/or mouse protein. • Any subject who cannot forego at least 2-3 days without receiving FVIII for washout purposes. (as of Amd 3)
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E.5 End points |
E.5.1 | Primary end point(s) |
To demonstrate the superiority of prophylaxis over on demand therapy by a clinically significant decrease in bleeding rate following 12 months of treatment with BAY 81-8973. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Comparing different doses of the same study drug: BAY 81-8973 (~18% difference between 2 doses) |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
China |
Colombia |
Czech Republic |
Japan |
Mexico |
Romania |
Russian Federation |
Serbia |
South Africa |
Taiwan |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |