E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of inhibitor formation, and immune tolerance induction in patients with severe and moderately severe hemophilia A by early and low-dose prophylactic ADVATE therapy |
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E.1.1.1 | Medical condition in easily understood language |
Coagulation 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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
Determine the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) to starting with a once weekly prophylactic regimen together with the minimization of immunological danger signals |
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E.2.2 | Secondary objectives of the trial |
•Determine the general safety and efficacy during the first 50 EDs to ADVATE of an once weekly early prophylactic regimen starting once weekly in PUPs with severe and moderately severe hemophilia A
•Gather information about the temporal associations and molecular and cellular mechanisms involved in the development of an immune response to factor VIII (FVIII) during the first 50 EDs to ADVATE |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Subjects who meet all of the following criteria are eligible for this study:
•Subjects with severe and moderately severe hemophilia A (FVIII ≤2%)
Certain FVIII mutation types (eg, large multi-domain deletions; nonsense mutations; insertions/deletions/inversions that result in a premature stop codon; intron 22 inversions) can be used to corroborate a severe hemophilia A phenotype when laboratory assays show FVIII levels ≥1% because of rounding errors or carryover effect from a previous FVIII administration; a central laboratory FVIII assay is required to confirm subject eligibility.
•Subjects < 1 year of age.
•Subjects must have ≤3 EDs to any FVIII concentrate or FVIII-containing product used for treatment of minor bleeds (bleeds requiring no more than 2 infusions per event), or for preventative or precautionary infusions following possible injury.
•Subjects with prior circumcision are allowed to enroll only if bleeding issues related to circumcision were the cause for the original diagnosis of hemophilia A and if no more than 2 EDs of FVIII were required.
•Adequate venous access (without need for central venous access device [CVAD]-placement) as determined by the physician
•Written informed consent from legally authorized representative(s) |
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E.4 | Principal exclusion criteria |
•Life-threatening conditions (intracranial hemorrhage, severe trauma), or requirement for surgery at the time of enrollment
•Evidence of inhibitor ≥0.6 BU in Njimegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitortesting for lupus anticoagulant will be done to eliminate false positives)
•Inherited or acquired hemostatic defect other than hemophilia A
•Any clinically significant, chronic disease other than hemophilia A
•Known hypersensitivity to ADVATE or any of its constituents
•Any planned elective surgery that cannot be postponed until after the first 20 EDs
•Participation in the Hemophilia Inhibitor PUP Study (HIPS)
•Application of red blood cell, platelet, or leukocyte concentrates, or plasma
•Administration of any medication affecting coagulation or platelet function
•Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids)
•Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this studySubjects who meet any of the following criteria are not eligible for this study:
•Life-threatening conditions (intracranial hemorrhage, severe trauma), or requirement for surgery at the time of enrollment
•Evidence of inhibitor ≥0.6 BU in Njimegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitor)
•Inherited or acquired hemostatic defect other than hemophilia A
•Any clinically significant, chronic disease other than hemophilia A
•Known hypersensitivity to ADVATE or any of its constituents
•Any planned elective surgery that cannot be postponed until after the first 20 EDs
•Participation in the Hemophilia Inhibitor PUP Study (HIPS)
•Application of red blood cell, platelet, or leukocyte concentrates, or plasma
•Administration of any medication affecting coagulation or platelet function
•Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids)
•Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this study
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E.5 End points |
E.5.1 | Primary end point(s) |
•Incidence of inhibitor formation in severe and moderately severe hemophilia A (FVIII ≤2%) within the first 50 EDs to ADVATE (prior exposure to FVIII up to a maximum of 3 EDs but maximum 2 exposures per event - to any FVIII concentrate are allowed, and infusions for bleed management will be included in the 50-ED calculation) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Incidence of inhibitor formation in severe hemophilia A (FVIII ≤1% within the first 50 EDs of ADVATE
•Time to inhibitor formation
•Incidence rate for low-titer, high-titer, transient, and all inhibitors
•Incidence of SAEs and non-serious AEs at least possibly related to ADVATE
•Number, type, and severity of all bleeds experienced (eg, intracranial hemorrhage, joint, soft tissue)
•Number, type, and severity of all bleeds experienced when different prophylactic dosing frequencies are used (once per week versus 2-3 times per week)
•Number and type of surgeries (which cannot be postponed until after 20 EDs)
•Association of known risk factors to inhibitor formation: FVIII gene mutation type, FVIII haplotype, HLA haplotypes, family history of inhibitors, infections, immunomodulatory gene polymorphisms (tumor necrosis factor-alpha [TNF-α], interleukin-10 [IL-10], cytotoxic T-lymphocyte antigen 4 [CTLA4])
•Total FVIII consumption (in international units [IU]) for each subject
•FVIII-specific antibody isotype for all subjects at study entry and every 10 ED |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
Austria |
Belgium |
Bulgaria |
Canada |
Denmark |
France |
Germany |
Greece |
Ireland |
Italy |
Latvia |
Lithuania |
Netherlands |
Norway |
Poland |
Portugal |
Romania |
Russian Federation |
Slovakia |
Spain |
Sweden |
Switzerland |
Turkey |
Ukraine |
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 subject / 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 | 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 | 5 |
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 |