E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Inhibitor Development in Previously Untreated Patients (PUPs) or Minimally Blood Component-Treated Patients (MBCTPs) when Exposed to plasma-derived von Willebrand Factor-Containing Factor VIII (VWF/FVIII) Concentrates and to Recombinant Factor VIII (rFVIII) Concentrates: An Independent, International, Multicentre, Prospective, Controlled, Randomised, Open Label, Clinical Trial |
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E.1.1.1 | Medical condition in easily understood language |
Develop. of antibody against FVIII in Patients when Exposed Factor concentrates made from human blood or manufactured in lab using genetically engineered cells that carry a human factor gene |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018937 |
E.1.2 | Term | Haemophilia A |
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 immunogenicity of VWF/FVIII and of rFVIII concentrates by determining the frequency of inhibitor development in PUPs and MBCTs in the first 50 EDs or in the first 3 years from enrolment, whichever comes first |
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E.2.2 | Secondary objectives of the trial |
To evaluate
•the anamnestic response of inhibitor patients
•the frequency of transient inhibitors
•the modality of occurrence of inhibitors (number of EDs, titre at onset, etc)
•clinical factors potentially associated to inhibitor development (age at first treatment, severity of bleeding episodes, surgery, intensity of treatment, modality of treatment, time of treatment in relation to vaccinations, concurrent diseases (in particular viral infections), complications of venous access and/or medications, type of delivery, breast feeding, type of milk formula)
•laboratory factors potentially associated to inhibitor development (severity of FVIII defect, FVIII gene defect, FVIII Ag, HLA phenotype, IL-10.G, TNF alpha, CTLA-4 polymorphisms), analyses of FVIII mRNA expression levels, epitope mapping, FII and •FV gain-of-function thrombophilic mutation
the incidence of all other adverse events related and not related to the products used
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Male subjects
•Any ethnicity
•Age <6 years
•Severe haemophilia A (FVIII:C <1%), as confirmed by the central laboratory
o Patients with FVIII levels >1% will be separately recorded in the screening list
•Previously untreated (0 EDs to any FVIII concentrate or blood products) or minimally treated (<5 EDs) with blood components, namely whole blood, fresh frozen plasma, packed red blood cells, platelets or cryoprecipitate
o Patients not meeting these criteria will be separately recorded in the screening list
•Negative inhibitor measurement at both local and central laboratory at screening
•Ability to comply with study requirements
•Signed informed consent of legal tutors
o Patients who will not accept to enter into the study or to be randomized will be separately recorded
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E.4 | Principal exclusion criteria |
•Plasma FVIII level ≥1%, as assayed at the central laboratory
o Those patients originally diagnosed locally as severe but subsequently found to have FVIII levels > 1% on testing at the central laboratory will be separately recorded in the screening list.
•Previous history of FVIII inhibitor
•Other congenital or acquired bleeding defects
•Concomitant congenital or acquired immunodeficiency
•Concomitant treatment with systemic immunosuppressive drugs
•Concomitant treatment with any investigational drug
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E.5 End points |
E.5.1 | Primary end point(s) |
•To assess the immunogenicity of plasma derived VWF/FVIII and rFVIII concentrates by determining the frequency of inhibitor development in the first 50 EDs or in the first 3 years from enrolment, whichever comes first in PUPs and MBCTs |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after development of the inhibitor, first 50 EDs or 3 years from enrolment |
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E.5.2 | Secondary end point(s) |
anamnestic response of inhibitor patients, frequency of transient inhibitors, modality of occurrence of inhibitors, clinical factors potentially associated to inhibitor development, lab factors potentially associated to inhibitor development, analyses of FVIII mRNA expression levels, epitope mapping, FII & FV gain-of-function thrombophilic mutations, incidence of all other adverse events related and not related to the products used |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
after development of the inhibitor, first 50 EDs or 3 years from enrolment |
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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 | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
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 |
Brazil |
Chile |
Czech Republic |
Egypt |
France |
Germany |
India |
Iran, Islamic Republic of |
Italy |
Mexico |
Saudi Arabia |
Slovakia |
South Africa |
Spain |
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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The trial ends for each after 50 Exposure Days (treatment of patients with IMP) or 3 years after enrolment, whichever comes first or after inhibitor development. If an inhibitor development occurs (confirmation of the central laboratory), the patient must returs to the site every month for 6 months to verify the inhibitor plasmatic levels. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |