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 |
Prevención de la formación de inhibidores y de inducción de tolerancia inmunológica en pacientes con hemofilia A grave o moderadamente grave tratados con ADVATE con una pauta profiláctica precoz a baja dosis. |
|
E.1.1.1 | Medical condition in easily understood language |
Coagulation Factor VIII deficiency |
Deficiencia de Factor de coagulación VIII |
|
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 | 14.0 |
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 |
|
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 |
Determinar la tasa de incidencia de formación de inhibidores en PnTP con hemofilia A grave y moderadamente grave durante los 50 primeros días de exposición (DE) al tratamiento, empezando por una pauta profiláctica una vez por semana junto con la minimización de señales de peligro inmunológico |
|
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 |
- Determinar la eficacia y seguridad general de una pauta profiláctica precoz una vez por semana en PnTP con hemofilia A grave y moderadamente grave durante los 50 primeros DE a ADVATE.
- Recopilar información sobre las asociaciones temporales y los mecanismos moleculares y celulares implicados en el desarrollo de una respuesta inmunitaria al factor VIII durante los 50 primeros DE a ADVATE.
|
|
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) |
- Pacientes con hemofilia A grave y moderadamente grave (FVIII =< 2%).
- Determinados tipos de mutaciones del FVIII (como, por ejemplo, grandes deleciones multidominio; mutaciones terminadoras; inserciones/deleciones/inversiones que tienen como resultado un codón de terminación prematura; inversiones del intrón 22) se pueden utilizar para corroborar un fenotipo de hemofilia A grave cuando en las analíticas se evidencian niveles de FVIII >= 1% debido a errores de redondeo o al efecto residual de una administración previa de FVIII; para confirmar que el paciente puede participar en el estudio, los niveles de FVIII se tienen que determinar en el laboratorio central.
- Pacientes < 1 año de edad.
- Los pacientes tienen que tener =< 3 DE a cualquier concentrado de FVIII o producto que contenga FVIII empleado para el tratamiento de hemorragias menores (hemorragias para las que se necesita un máximo de 2 infusiones por caso), o a infusiones preventivas o de precaución tras una posible lesión.
- Se permite participar a pacientes con circuncisión previa sólo si la causa del diagnóstico original de hemofilia A ha sido la aparición de problemas hemorrágicos asociados a la circuncisión y si no han sido necesarios más de 2 DE a tratamiento con FVIII.
- Acceso venoso adecuado (sin necesidad de colocación de un DAVC) determinado por el médico.
- Consentimiento informado por escrito del(de los) representante(s) legalmente autorizado(s). |
|
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 study |
- Enfermedades potencialmente mortales (hemorragia intracraneal, traumatismo grave) o necesidad de cirugía en el momento del reclutamiento.
- Evidencia de nivel de inhibidores >= 0,6 UB en el ensayo Bethesda (método modificado de Nijmegen) al inicio del estudio (las muestras se pueden reanalizar utilizando pruebas de inhibidores insensibles a lupus para reducir el número de resultados falsos positivos).
- Defecto hemostático hereditario o adquirido distinto de hemofilia A.
- Cualquier enfermedad crónica clínicamente significativa distinta de hemofilia A.
- Hipersensibilidad conocida a ADVATE o a cualquiera de sus componentes.
- Toda intervención quirúrgica programada que no pueda posponerse hasta después de los 20 primeros DE.
- Participación en el estudio en PnTP de los inhibidores en la hemofilia (Hemophilia Inhibitor PUP Study [HIPS]).
- Aplicación de concentrados de eritrocitos, plaquetas o leucocitos, o plasma.
- Administración de cualquier medicamento que altere la coagulación o la función plaquetaria.
- Administración sistémica de cualquier fármaco inmunomodulador (como, por ejemplo, quimioterapia, glucocorticosteroides intravenosos).
- La participación en otro estudio clínico de un dispositivo o PEI durante los 30 días anteriores al reclutamiento para participar en este estudio o durante la realización de éste. |
|
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) |
- Incidencia de formación de inhibidores en la hemofilia A grave y moderadamente grave (FVIII =< 2%) durante los 50 primeros DE a ADVATE (se permite la exposición anterior a FVIII hasta un máximo de 3 DE, pero un máximo de 2 exposiciones por caso - a cualquier concentrado de FVIII, y en el cálculo de los 50 DE se incluirán las infusiones para el tratamiento de hemorragias) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
end of study |
final del ensayo |
|
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-alpha], 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 |
- Incidencia de formación de inhibidores en la hemofilia A grave (FVIII =<1%) durante los 50 primeros DE a ADVATE.
- Tiempo hasta la formación de inhibidores.
- Tasa de incidencia de inhibidores de título bajo, de título elevado, transitorios y totales.
- Incidencia de AAG y AA no graves al menos posiblemente relacionados con ADVATE.
- Número, tipo y gravedad de todas las hemorragias experimentadas (p. ej., hemorragia intracraneal, hemartrosis, de partes blandas).
- Número, tipo y gravedad de todas las hemorragias experimentadas en función de la frecuencia de administración del tratamiento profiláctico (una vez por semana en comparación con 2-3 veces por semana).
- Número y tipo de intervenciones quirúrgicas (que no se pueden posponer hasta después de 20 DE).
- Asociación de factores de riesgo de formación de inhibidores conocidos: tipo de mutación del gen del FVIII, haplotipo del FVIII, haplotipos HLA, antecedentes familiares de inhibidores, infecciones, polimorfismos de genes inmunomoduladores (factor de necrosis tumoral alfa [TNF-alpha], interleucina 10 [IL-10], antígeno 4 asociado al linfocito T citotóxico [CTLA4]).
- Consumo total de FVIII (en unidades internacionales [UI]) por cada paciente.
- Isotipo de los anticuerpos específicos del FVIII de todos los pacientes al inicio del estudio y cada 10 DE.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
end of study |
final del ensayo |
|
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 |
Históricamente controlado |
Historically controlled |
|
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
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 |
|
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
|
Last subject / last visit |
Último sujeto / última visita |
|
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 |