E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Severe blood clotting factor VIII deficiency |
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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 | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
E.1.2 | System Organ Class | 100000004850 |
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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 assess the efficacy of BAY 94-9027 in prevention and treatment of bleeding at different infusion schedules
Part B: Major surgery using BAY 94-9027 • To assess the safety and efficacy of BAY 94-9027 in the prevention of bleeding during major surgical procedures
Optional extension phase: To assess the long term safety of BAY 94-9027 over at least 100 accumulated ED (main study plus extension).
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E.2.2 | Secondary objectives of the trial |
• To evaluate the subject’s assessment of response to treatment • To demonstrate the safety and tolerability of BAY 94-9027 when used in both the on-demand and prophylaxis settings • To assess frequency of inhibitor development • To assess pharmacokinetics and incremental recovery following administration of BAY 94-9027 • To assess treatment satisfaction with BAY 94-9027 and its impact on quality-of-life, work productivity and pain as reported by the subjects |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male; 12 to 65 years of age (or Male 18-65 years of age in countries where enrollment of minors is not permitted) • Subjects with severe hemophilia A (baseline FVIII activity FVIII:C <1%) determined by measurement at the time of screening or from reliable prior documentation (eg, measurement in other clinical trials, result from approved clinical laboratory) • Previously treated with FVIII concentrate(s) (plasma derived or recombinant) for a minimum of 150 ED • Immunocompetent. If HIV positive, CD4+ lymphocyte count >200/mm3
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E.4 | Principal exclusion criteria |
• Current evidence of inhibitor to FVIII with a titer ≥ 0.6 BU/mL, measured by the Nijmegen modified Bethesda assay at the time of screening (central laboratory) (BU: Bethesda unit) • History of inhibitor to FVIII with a titer ≥ 0.6 BU, or clinical history suggestive of inhibitor requiring modification of treatment. Subjects with a maximum historical titer of 1.0 BU on a single measurement but with at least 3 subsequent successive negative results (< 0.6 BU) thereafter are eligible • Any other inherited or acquired bleeding disorder in addition to Hemophilia A • Platelet count < 100,000/mm3 • Creatinine > 2x upper limit of normal • AST or ALT > 5x upper limit of normal (AST: aspartate aminotransferase; ALT: alanine aminotransferase) • The subject is currently participating in another investigational drug study, or has participated in a clinical study involving an investigational drug within 30 days of study entry. Subjects who are currently participating in an investigational study in which they are treated with a currently marketed FVIII concentrate are not excluded. Subjects currently treated with BAY 81-8973, and who have received at least 100 ED with the investigational product, may continue treatment with the product up to the start of Visit 1. • Any subject who is receiving chemotherapy, immune modulatory drugs other than anti-retroviral chemotherapy, or chronic use of oral or intravenous (IV) corticosteroids within the last 3 months. Brief courses of prednisone/methyprednisolone (< 14 days) for treatment of disorders such as synovitis, asthma, etc are allowed at the discretion of the treating physician. • Known hypersensitivity to the drug substance or any of its components (e.g. mouse or hamster protein).
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy
Prophylaxis & Treatment of bleeds: • Annualized number of bleeds
Pharmacokinetics: • Pharmacokinetic data and incremental recovery of FVIII activity
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Prophylaxis & Treatment of bleeds: • End of Treatment Visit (after 36 weeks of treatment, main study)
Pharmacokinetics: • Baseline Visit = PK 1 Visit • End of Treatment Visit = PK 2 Visit
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E.5.2 | Secondary end point(s) |
Efficacy Prophylaxis & Treatment of bleeds: • Description of bleeding according to location and frequency of total bleeds (spontaneous and trauma), joint bleeds, trauma, spontaneous bleeds and all bleeds
Treatment of bleeds: • Number of infusions required to control a bleed • Subject or investigator assessment of response to treatment of a bleed, as excellent, good, moderate, poor • When counting bleeds, any infusion for a new spontaneous bleed reported within 72 h of a previous bleed reported for the same site should be considered a follow-up infusion and not a new bleed.
Prophylaxis • Proportion of prophylaxis infusions that were followed by a bleed within 48, 72 and 96 h • Number of patients requiring dose escalation
Pharmacokinetics: • rFVIII usage expressed as number of infusions and IU/kg per year, as well as IU/kg per event (prophylaxis, bleed treatment, and surgery)
Patient reported outcomes: • Patient satisfaction and burden with BAY 94-9027 • Change in overall pain severity and interference due to pain • Change in quality of life ( as assessed by Haemo-QoL/Haemo-QoL-A and HUI) • Change in work productivity and activity impairment
Minor surgery: • Assessment of adequacy of hemostasis during minor surgical interventions including blood loss, transfusion, and/or hemostatic-related surgical complications.
Part B: Major surgery • Change or drop in hemoglobin/hematocrit • Blood loss • Need for additional hemostatic medication, including blood products • Units of blood transfused • Hemostatic-related surgical complications • Surgeon’s assessment of hemostasis as excellent, good, moderate or poor • Investigator’s assessment of response to treatment as excellent, good, moderate or poor • rFVIII usage expressed as number of infusions and IU/kg per year, as well as IU/kg per event (prophylaxis, bleed treatment, and surgery) • Specific diagnostic evaluations (eg. Imaging to follow size of a hematoma)
Safety • Vital signs (pulse, blood pressure, respiratory rate, temperature) • Physical examination • 12-lead ECG • Health assessment • Standard laboratory assessment (CBC, chemistry, routine urinalysis, serum and urine samples for assessment of renal safety [renal biomarkers]) • Development of antibodies to BAY 94-9027, PEG and/or FVIII • Quantitative PEG measurement |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Prophylaxis & Treatment of bleeds: • End of Treatment Visit (after 36 weeks of treatment main study)
Pharmacokinetics: • Baseline Visit = PK 1 Visit • End of Treatment Visit = PK 2 Visit
Part B: Major surgery • Post-operative Visit
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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 | Yes |
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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Renal biomarkers: Serum and urine samples for assessment of renal safety in patients with long term PEG exposure will include e.g. total protein, albumin, cystatin C. |
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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 | No |
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 | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Belgium |
Canada |
Colombia |
Denmark |
France |
Germany |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Poland |
Romania |
Singapore |
Taiwan |
Turkey |
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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Last Patient's Last Visit |
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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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |