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 |
An inherited gender-related coagulation disorder in which affected males do not produce functional coagulation factor VIII (FVIII) in sufficient quantities to achieve satisfactory blood clotting. |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018938 |
E.1.2 | Term | Haemophilia A (Factor VIII) |
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 investigate the immunogenicity of Human-cl rhFVIII in patients who completed GENA-05 in accordance with the study protocol • To assess the efficacy of Human-cl rhFVIII during prophylactic treatment (based on the frequency of spontaneous break-through bleeds) • To assess the efficacy of Human-cl rhFVIII during treatment of bleeds • To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis • To assess the safety and tolerability of Human-cl rhFVIII |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to qualify for study enrolment, the following criteria must be fulfilled before study entry: 1. patients who completed GENA-05 in accordance with the study protocol 2. Voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted (obtained from the patient’s parent/legal guardian) |
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E.4 | Principal exclusion criteria |
Patients will not be included if any of the following exclusion criteria are met: 1. Severe liver or kidney disease (alanine amino transferase (ALT) or aspartate transaminase (AST) levels >5 times of upper limit of normal, creatinine >120 μmol/L); 2. Concomitant treatment with any systemic immunosuppressive drug; 3. Other FVIII concentrate than Human-cl rhFVIII was received between completion visit of GENA-05 and start of GENA-15 (except emergency cases). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Immunogenicity of Human-cl rhFVIII is the primary endpoint. Inhibitor activity will be determined by the modified Bethesda assay (Nijmegen modification), using congenital FVIII-deficient human plasma, spiked with Human-cl rhFVIII. In case of a positive inhibitor result, an inhibitor retesting, using a second separately drawn sample, should be performed. A FVIII inhibitor is defined as “positive”, if the retesting confirms the positive result, otherwise the result is considered as “negative”. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• At Screening Visit, which will most likely be the same sampling time-point as the completion visit of GENA-05 • Once every 6 months in the course of the follow-up visits • At study completion • Any time in the case of a suspicion of inhibitor development. |
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E.5.2 | Secondary end point(s) |
1. Efficacy: a.Efficacy of prophylactic treatment The efficacy of Human-cl rhFVIII in the prophylactic treatment will be investigated by calculating the frequency of spontaneous break-through bleeds under prophylactic treatment. Study drug consumption data (FVIII IU/kg per month, per year) per patient and in total will be evaluated. The dates and times of study drug infusions, the details of dose(s), and the product batch numbers used for the prophylactic treatment will be documented. b. Efficacy of treatment of bleeds The efficacy of Human-cl rhFVIII in the treatment of bleeds will be investigated by using a 4-point ordinal haemostatic efficacy scale. Details of the bleed, the amount of Human-cl rhFVIII needed and the number of injections necessary to stop the bleed will be documented. c. Efficacy of surgical prophylaxis In surgical procedures, the following parameters will be documented: • One overall efficacy assessment (taking into account the intra- and post-operative assessment) after the end of surgical prophylactic treatment phase, agreed upon between the surgeon and the haematologist. • Average and maximum expected estimated blood loss, compared to the actual estimated blood loss • Details on surgical procedure: location, severity, type, expected and actual duration • Pre-, intra-, and post-operative FVIII plasma levels, if appropriate • Details of administered dose(s) of Human-cl rhFVIII given pre-, intra- and/or postoperatively including dates, times and batch numbers • Details on concomitantly administered drugs, including all blood and blood product transfusions, excluding standard anaesthetic drugs • Details on all wound haematomas in terms of capturing, analysing, and reporting these, including any need for surgical evacuation • Outcome of the intervention, described by means of a brief narrative.
2.Safety Safety and tolerability will be assessed by monitoring vital signs, standard laboratory parameters, and by monitoring adverse events (AEs).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1)Efficacy For each patient, the exposure to Human-cl rhFVIII, the efficacy of Human-cl rhFVIII in the prevention and the treatment of bleeds, the frequency of break-through bleeds in case of prophylactic treatment, the efficacy in surgical prophylaxis, and the overall safety and tolerability of Human-cl rhFVIII will be thoroughly assessed. In the course of the follow-up visits scheduled to be performed every 6 months (± 2 weeks) after the Screening Visit, FVIII inhibitor levels will be assessed for each patient. Please refer to section 7.2.2 [Assessments for Secondary Endpoints] on page 30-34 of Protocol
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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 | 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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 12 |
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 |
Brazil |
Canada |
Colombia |
France |
Georgia |
Germany |
India |
Moldova, Republic of |
Morocco |
Poland |
Russian Federation |
Spain |
Ukraine |
United Kingdom |
United States |
Venezuela, Bolivarian Republic of |
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E.8.7 | Trial has a data monitoring committee | No |
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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The patients may stay in the study until the IMP is registered and ready for launch in the individual country of study conduct, but latest after 2 years individual study duration - from screening. The study will be considered completed when the registration of the IMP is achieved. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |