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 | 20.0 |
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 100 PUPs suffering from severe haemophilia A (FVIII:C < 1%). |
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E.2.2 | Secondary objectives of the trial |
• 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.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1.Recovery investigation (optional); A recovery investigation is recommended to be performed with the first Human-cl rhFVIII administration, or within the first three months after treatment start with Human-cl rhFVIII, in any case in a non-bleeding patient. A dose of 40 IU FVIII/kg BW will be administered and the in vivo recovery will be calculated from the FVIII levels before infusion and the peak level obtained from the 15 min and 1 hour post-infusion samples. Recovery investigations are recommended to be repeated approximately every 6 months. 2.RNA Expression. RNA expression analysis will optionally be performed in order to provide an understanding of the transcript activity of the genes involved in immune responses that may be responsible for FVIII inhibitor formation in patients receiving exogenous FVIII. RNA expression analysis will also be optionally performed on patients undergoing ITI to provide information on the transcript activity of genes involved in immune tolerance. The analysis will be carried out using a customised PAXgene protocol in which RNA samples will be obtained by using commercially available PAXgene RNA blood collection tubes and customised microfuge tubes. This customised approach has previously been used in both a paediatric and animal study where samples volumes are limited. 3.Immunogenotyping (Partly Optional); Immunogenotyping will be performed in order to investigate genetic factors that might influence development of FVIII inhibitors. It will include analysis of FVIII gene mutations, HLA-typing, immune response gene profiling and FVIII ethnic haplotype analysis. FVIII mutation analysis is a required assessment, whereas HLA-typing, immune response gene profiling and FVIII ethnic haplotype are optional. Blood samples required for this analysis can be obtained at any time during study, but it is recommended that they be obtained at the same time as the samples for scheduled study visits. 4.In vitro immunogenicity of FVIII products (optional). Immunogenicity of Human-cl rhFVIII will be assessed by culturing peripheral blood monocyte cells (PBMC) from the patients (including a positive control) with Human-cl rhFVIII. The nature of T cell response will be assessed by analysing cytokine expression (measured in a multiplex format) and T cell proliferation. Cytokines analysed will include IL-2, TNFα, IFNγ, IL-5, IL-6, IL-10, and IL-17 (TGFβ may also included in an ELISA format). 5.Epitope mapping in case of inhibitor development;
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E.3 | Principal inclusion criteria |
In order to qualify for study enrolment, the following criteria must be fulfilled before study entry: 1. Male patients 2. Severe haemophilia A (FVIII:C < 1%) 3. No previous treatment with FVIII concentrates or other blood products containing FVIII 4. Voluntarily given, fully informed written and signed consent given before any study related procedures are conducted (obtained from the patient’s parent(s)/legal guardian(s)) |
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E.4 | Principal exclusion criteria |
Patients will not be included if any of the following exclusion criteria are met: 1. Diagnosis of a coagulation disorder other than haemophilia A 2. Severe liver or kidney disease (ALT or AST levels >5 times of upper limit of normal (ULN), creatinine >120 μmol/L) 3. Concomitant treatment with any systemic immunosuppressive drug 4. Participation in another interventional clinical study currently or during the past 4 weeks |
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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 FVIIIdeficient 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 being “negative”. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• At baseline (Screening Visit) • Every 3-4 EDs until ED 20 • Every 10-12 EDs or every 3 months ± 2 weeks (whichever comes first) after ED 20 until 100 EDs are reached • Any time in the case of suspicion of an 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: • Overall efficacy assessment (taking into account the intra- and post-operative assessment) after the end of surgical prophylactic treatment phase, performed by the surgeon and by 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 In the prevention and the treatment of bleeds, the frequency of break-through bleeds in case of prophylactic treatment, the efficacy in surgical prophylaxis of Human-cl rhFVIII will be thoroughly assessed. In the course of the follow-up visits (i.e. every 3-4 EDs until ED 20, then every 10-12 EDs until ED 100), scheduled to be performed after the Screening Visit, FVIII inhibitor levels will be assessed. These visits may be combined with the additional regular 3 monthly (± 2 weeks) follow-up visits. 2) Safety AEs and changes in concomitant medication, overall safety and tolerability will be checked and documented at each follow-up 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 | No |
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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 |
Brazil |
Canada |
Colombia |
France |
Georgia |
Germany |
India |
Moldova, Republic of |
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 | 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 | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |