| 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 | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053753 |
| E.1.2 | Term | Hemophilia A without inhibitors |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060612 |
| E.1.2 | Term | Hemophilia A |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060613 |
| E.1.2 | Term | Hemophilia A (Factor VIII) |
|
| 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 non-inferiority of prophylactic treatment with (as of Amd 1) BAY 81 8973 (dose determined by [as of Amd 1] CS/EP versus dose determined by [as of Amd 1] CS/ADJ) as measured by bleeding rate (after combining results of this study with results from Protocol 14319). |
|
| E.2.2 | Secondary objectives of the trial |
• To compare in vivo recovery at the start & end of 6 month periods based on potency (CS/EP versus CS/ADJ) during prophylactic treatment.
• Evaluate potential for inhibitory antibody formation during prophylactic treatment
• To evaluate the potential for antibody formation to HSP-70 and/or hamster proteins during prophylactic treatment with BAY 81-8973 (after combining results of this study with results from Protocol 14319 [as of Amd 1]).
• To evaluate surgical outcomes in ≥ 15 anticipated surgeries in ≥ 15 subjects (as of Amd 6) across both studies (Protocol 12954 & 14319) (as of Amd 1) during prophylactic treatment with BAY 81-8973. Among the surgeries, at least 8 must be classified as major surgeries (as of Amd 6), & both minor & major surgeries (defined in Section 4.1) will be represented (as of Amd 1).
• To assess the control of bleeding with BAY 81-8973
• To assess quality of life (QoL) & pharmaco-economic parameters
• To assess safety & tolerability of BAY 81-8973.
|
|
| 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 6): Documented historical evidence from a recognized (certified) clinical laboratory (acceptable to GCL) demonstrating < 1% FVIII:C as determined by one-stage clotting assay, or 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 on-demand or any type of prophylaxis treatment regimen with any FVIII product.
• No current evidence of inhibitor antibody as measured by the Nijmegen modified Bethesda assay [<0.3 Bethesda units (BU/mL)] (as of Amd 5) 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. Second negative, confirmatory sample testing 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 5) prior to the collection of samples for inhibitor testing.
• No history of FVIII inhibitor formation, defined as inhibitor antibody < 0.6 BU/mL, by the Nijmegen modified Bethesda assay. However, patients with a maximum historical titer of 1.0 BU (as of Amd 5) 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 significant portal vein hypertension in the judgment of the Investigator. (as of Amd 5)
• 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 5)
• 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 protein.
• Any subject who cannot forego at least 3 days without receiving FVIII for washout purposes.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • 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 14319). |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | No |
| 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). |
|
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
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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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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