E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe Hemophilia-A (< 1% FVIII:C) |
Hemofilia A grave, definida como una FVIII:C < 1 %, |
|
E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is an X-linked congenital bleeding disorder causing frequent bleedings and recurrent spontaneous bleeds into the soft tissue and joints, leading to joint damage and severe disability. |
La hemofilia A es un trastorno hemorrágico hereditario ligado al cromosoma X que afecta a tejidos blandos y articulaciones, provocando daño articular y discapacidad grave. |
|
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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
|
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 |
The primary objective is to evaluate the safety and efficacy of the treatment with BAY 81-8973 for prophylaxis and treatment of breakthrough bleeds in children with severe hemophilia A. |
El objetivo principal es evaluar la seguridad y la eficacia del tratamiento con BAY 81-8973 para la profilaxis y el tratamiento de las hemorragias intercurrentes en niños con hemofilia A grave |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are - To assess the safety and efficacy of BAY 81-8973 during surgeries. - To assess incremental recovery of BAY 81-8973. - To assess pharmacokinetic parameters in a subset of children. |
Los objetivos secundarios son: - Evaluar la seguridad y la eficacia de BAY 81-8973 durante intervenciones quirúrgicas. - Evaluar la recuperación incremental de BAY 81-8973. - Evaluar los parámetros farmacocinéticos en un subconjunto de niños. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part A 1. Male, age <= 12 years. Enrollment will begin with subjects 6-12 years before it is opened to all age groups. 2. Severe hemophilia A defined as < 1% factor VIII concentration (FVIII:C) based on documented prior testing or screening laboratory 3. >/= 50 ED with any FVIII concentrate 4. No current evidence of inhibitor antibody measured using the Nijmegen modified Bethesda assay [<0.6 Bethesda units (BU)/mL] within 2-3 weeks of last FVIII administration. 5. No history of FVIII inhibitor formation. Documentation of negative result in medical records required. [Subjects with a maximum historical titer of 1.0 BU on no more than 1 occasion with the classical Bethesda assay but at least 3 successive negative (<0.6 BU) results thereafter are eligible.] 6. Willingness and ability of subjects and/or parents to complete training in the use of the electronic patient diary (EPD) and to document infusions during the study. 7. Written informed consent by parent/legal representative. Assent should be sought from subjects if appropriate
Part B (PUPs) 1. Male, < 6 years 2. Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing or confirmed on screening laboratory 3. No previous exposure to any FVIII product 4. PUPs may be included if they will receive their first FVIII dose with BAY 81-8973 for treatment of first bleeds and agree to start prophylaxis as part of their care. 5. Willingness and ability of parents to complete training in the use of the electronic patient diary (EPD) and to document all treatment during the study. 6. Written informed consent by parent/legal representative. |
Parte A: 1. Pacientes varones <= 12 años de edad. La inclusión de pacientes de 6 - 12 años de edad precederá a la de todos los demás grupos de edad. 2. Hemofilia A grave, definida como una concentración de factor VIII (FVIII:C) < 1 %, documentada a partir de un análisis previo o en las pruebas analíticas de selección 3. >/= 50 DE con cualquier concentrado de FVIII 4. Ausencia de anticuerpos inhibidores determinada mediante el ensayo de Bethesda modificado por Nijmegen [< 0,6 unidades Bethesda (UB)/ml] realizado en las 2 - 3 semanas posteriores a la última administración de FVIII. 5. Sin antecedentes de formación de inhibidores del FVIII. Es necesario un resultado negativo documentado en la historia clínica. [Puede incluirse también a los pacientes con un valor histórico máximo de 1,0 UB en el ensayo de Bethesda clásico obtenido como máximo en una única ocasión, pero por lo menos con 3 resultados negativos sucesivos (< 0,6 UB) posteriores] 6. Disposición y capacidad de los pacientes y/o sus progenitores para completar la formación sobre el uso del diario electrónico del paciente (DEP) y anotar las infusiones durante el estudio. 7. Consentimiento informado por escrito firmado por uno de los progenitores/representante legal. Asentimiento de los pacientes, si procede.
Parte B (PNTP) 1. Varón, < 6 años 2. Hemofilia A grave, definida como una FVIII:C < 1 %, documentada a partir de un análisis previo o confirmada en las pruebas analíticas de selección. 3. Sin exposición previa a ningún producto de FVIII 4. Puede incluirse a PNTP si van a recibir su primera dosis de FVIII con BAY 81-8973 para el tratamiento de las primeras hemorragias y acceden a iniciar la profilaxis como parte de su tratamiento. 5. Disposición y capacidad de los progenitores para completar la formación sobre el uso de diario electrónico del paciente (DEP) y anotar todos los tratamientos durante el estudio. 6. Consentimiento informado por escrito por uno de los progenitores/representante legal. |
|
E.4 | Principal exclusion criteria |
Parts A and B 1. Any individual with another bleeding disorder that is different from Hemophilia A (eg, von Willebrand disease, Hemophilia B) 2. Any individual with thrombocytopenia (platelet count < 100,000/mm3) 3. Creatinine > 2x upper limit of normal or AST/ALT > 5x upper limit of normal 4. Any individual without a negative inhibitor at screening (except for PUPs) 5. Any individual who is receiving chemotherapy, immune modulatory drugs (IVIG, cyclosporine, chronic use of oral or i.v. corticosteroids), has received another investigational FVIII product within the last month, or received another experimental drug within the last 3 months. 6. Any individual who requires any pre-medication to tolerate FVIII treatment (eg, antihistamines). 7. Any individual who is unwilling to comply with study visits or other protocol requirements, for example (eg. prophylaxis treatment) or is not suitable for participation in this study for any reason, according to the Investigator's judgment. 8. Known hypersensitivity to active substance, mouse or hamster protein. 9. Previous participation in this study
Part B only (PUPs): 10. First treatment with BAY 81-8973 for high risk bleeding situations (e.g. surgery, intracranial bleed), or requiring intensive or prolonged treatment. 11. Unable to tolerate volume of blood draws required for study participation. |
Partes A y B: 1. Presencia de otro trastorno hemorrágico (a partir de la Enm. 1) diferente de la hemofilia A (p. ej., enfermedad de von Willebrand, hemofilia B) 2. Trombocitopenia (cifra de plaquetas < 100 000/mm3) 3. Niveles de creatinina > 2 veces por encima del límite superior de la normalidad o niveles de aspartato-aminotransferasa (AST)/alanina-aminotransferasa (ALT) > 5 veces el límite superior de la normalidad (a partir de la Enm. 1) 4. No disponer de una prueba de inhibidores negativa en la selección (salvo para los PNTP) 5. Tratamiento actual con quimioterapia, fármacos inmunomoduladores (inmunoglobulina intravenosa [IgIV], ciclosporina, uso crónico de corticosteroides por vía oral o i.v.), tratamiento con otro producto de FVIII en investigación durante el último mes o tratamiento con otro fármaco experimental en los últimos 3 meses. 6. Necesidad de medicación previa para tolerar el tratamiento con FVIII (p. ej., antihistamínicos). 7. No estar dispuesto a cumplir las visitas del estudio o los demás requisitos del protocolo (p. ej., tratamiento profiláctico) o no ser apto para participar en este estudio por cualquier motivo, según el criterio del investigador 8. Hipersensibilidad conocida al principio activo o a las proteínas de ratón o hámster. 9. Participación previa en este estudio.
Solo para la Parte B (PNTP): 10. Primer tratamiento con BAY 81-8973 para situaciones de alto riesgo de hemorragia (p. ej., intervención quirúrgica, hemorragia intracraneal), o que requieran un tratamiento intensivo o prolongado. 11. Incapacidad para tolerar volumen de las extracciones de muestras de sangre necesarias para la participación en el estudio. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary variable is the annualized number of total bleeds (sum of spontaneous bleeds and traumatic bleeds) during prophylaxis that occur within 48 h of the last prophylaxis infusion. Both joint and non-joint bleeding will be assessed. |
La variable principal de eficacia será el número anualizado del total de hemorragias intercurrentes (suma de las hemorragias espontáneas y las hemorragias por traumatismo) que se hayan producido en el plazo de 48 horas después de la última infusión profiláctica. Se evaluarán las hemorragias articulares y las no articulares. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continuous throughout duration of study |
Continua a lo largo de la duración del estudio |
|
E.5.2 | Secondary end point(s) |
- Subject/parents' assessment of the response of treatment of bleeding events which is assessed as excellent, good, moderately well or poorly. - Annualized number of total bleeds (sum of spontaneous and trauma bleeds) during prophylaxis treatment - Assessment of adequacy of haemostasis during surgical interventions - Number of infusions for the treatment of a bleed - Consumption of FVIII |
- Evaluación por el paciente o sus progenitores de la respuesta al tratamiento de los episodios hemorrágicos, que se calificará como excelente, buena, moderada o mala. - Número anualizado de hemorragias totales (suma de hemorragias espontáneas y hemorragias por traumatismos) durante el tratamiento profiláctico. - Evaluación de la eficacia de la hemostasia durante las intervenciones quirúrgicas. - Número de infusiones realizadas para el tratamiento de una hemorragia. - Consumo de FVIII. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continuous throughout duration of study |
Continua a lo largo de la duración del estudio |
|
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 | Yes |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 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 |
Bulgaria |
Canada |
Denmark |
Ireland |
Italy |
Austria |
Romania |
Sweden |
Argentina |
Hungary |
Latvia |
Lithuania |
Spain |
Israel |
Mexico |
Poland |
Russian Federation |
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
|
End of the trial is the last visit (follow-up phone call 1-2 weeks after end of treatment) of the last subject undergoing study. |
El final del estudio es la última visita (Llamada telefónica de seguimiento 1 - 2 semanas después de la finalización del tratamiento) del último paciente del estudio. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |