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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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is an X-linked congenital bleeding disorder causing frequent bleedings and recurrent spontaneous bleeds into the soft tissue and joints, leading to joint damage and severe disability. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000011915 |
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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 |
The primary objective is to demonstrate the safety and efficacy of the treatment with BAY 81-8973 for prophylaxis and treatment of breakthrough bleeds in children with severe hemophilia A. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are
- To assess the safety and efficacy of BAY 81-8973 during surgeries.
- To assess incremental recovery of BAY 81-8973.
- To characterize pharmacokinetics in a subset of children. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part A
1. Male, age ≤ 12 years. Enrollment will begin with subjects 6-12 years before it is opened to all age groups.
2. Severe hemophilia A defined as < 1% factor VIII concentration (FVIII:C) based on documented prior testing or screening laboratory
3. >/= 50 ED with any FVIII concentrate
4. No current evidence of inhibitor antibody measured using the Nijmegen modified Bethesda assay [<0.6 Bethesda units (BU)/mL] within 2-3 weeks of last FVIII administration.
5. No history of FVIII inhibitor formation. Documentation of negative result in medical records required. [Subjects with a maximum historical titer of 1.0 BU on no more than 1 occasion with the classical Bethesda assay but at least 3 successive negative (<0.6 BU) results thereafter are eligible.]
6. Willingness and ability of subjects and/or parents to complete training in the use of the electronic patient diary (EPD) and to document infusions during the study.
7. Written informed consent by parent/legal representative. Assent should be sought from subjects if appropriate
Part B (PUPs)
1. Male, < 6 years
2. Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing or confirmed on screening laboratory
3a. PUPs: no previous exposure to any FVIII product
3b. MTPs: have previously not more than 3 injections with any FVIII
product and who have no current evidence of inhibitor antibody at
screening with confirmation using local laboratory testing at baseline
3c. MTPs: no history of FVIII inhibitor formation
4. PUPs may be included if they will receive their first FVIII dose with BAY 81-8973 for treatment of first bleeds and agree to start prophylaxis as part of their care. MTPs may be included if they agree to start
prophylaxis as part of their care.
5. Willingness and ability of parents to complete training in the use of the electronic patient diary (EPD) and to document all treatment during the study.
6. Written informed consent by parent/legal representative.
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E.4 | Principal exclusion criteria |
Parts A and B
1. Any individual with another bleeding disorder that is different from Hemophilia A (eg, von Willebrand disease, Hemophilia B)
2. Any individual with thrombocytopenia (platelet count < 100,000/mm3)
3. Creatinine > 2x upper limit of normal or AST/ALT > 5x upper limit of normal
4. Any individual without a negative inhibitor at screening (except for PUPs)
5. Any individual who is receiving chemotherapy, immune modulatory drugs (IVIG, cyclosporine, chronic use of oral or i.v. corticosteroids), has received another investigational FVIII product within the last month, or received another experimental drug within the last 3 months.
6. Any individual who requires any pre-medication to tolerate FVIII treatment (eg, antihistamines).
7. Any individual who is unwilling to comply with study visits or other protocol requirements, for example (eg. prophylaxis treatment) or is not suitable for participation in this study for any reason, according to the Investigator’s judgment.
8. Known hypersensitivity to active substance, mouse or hamster protein.
9. Previous participation in this study
Part B only (PUPs):
10. First treatment with BAY 81-8973 for high risk bleeding situations (e.g. surgery, intracranial bleed), or requiring intensive or prolonged treatment.
11. Unable to tolerate volume of blood draws required for study participation.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary variable is the annualized number of total bleeds (sum of spontaneous bleeds and traumatic bleeds) during prophylaxis that occur within 48 h of the last prophylaxis infusion. Both joint and non-joint bleeding will be assessed.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continuous throughout duration of study |
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E.5.2 | Secondary end point(s) |
• Subject/parents’ assessment of the response of treatment of bleeding events which is assessed as excellent, good, moderately well or poorly.
• Annualized number of total bleeds (sum of spontaneous and trauma bleeds) during prophylaxis treatment
• Assessment of adequacy of haemostasis during surgical interventions
• Number of infusions for the treatment of a bleed
• Consumption of FVIII
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continuous throughout duration of study |
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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 | Yes |
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) | No |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 | No |
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 |
Austria |
Bulgaria |
Canada |
Denmark |
Hungary |
Ireland |
Israel |
Italy |
Latvia |
Lithuania |
Mexico |
Norway |
Poland |
Romania |
Russian Federation |
Spain |
Sweden |
United Kingdom |
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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End of the trial is the last visit (follow-up phone call 1-2 weeks after end of treatment) of the last subject undergoing study.
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 6 |