| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hemophilia A is a genetic disorder that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. |
| la hemofilia A es un desorden genético que afecta a la abilidad del cuerpo para controlar la coagulación, que es utilizada para detener una hemorragia cuando un vaso sanguineo se rompe. |
|
| 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 | 10053753 |
| E.1.2 | Term | Hemophilia A without inhibitors |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 | 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 of the study is to evaluate the safety of rFVIIIFc in previously untreated subjects with severe hemophilia A. |
| El objetivo principal del ensayo es evaluar la seguridad de rFVIIIFc en pacientes no tratados previamente con hemofilia A severa |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of rFVIIIFc in the prevention and treatment of bleeding episodes in PUPs
-To evaluate rFVIIIFc consumption for the prevention and treatment of bleeding episodes in PUPs
-To describe experience with the use of rFVIIIFc for immune tolerance induction (ITI) in subjects with inhibitors |
| Evaluar la eficacia de rFVIIIFc en la prevención y tratamiento de episodios de sangrado en pacientes pediatricos no tratados previamente.. Evaluar el consumo de rFVIIIFc para la prevención y tratamiento de episodios de sangrado en pacientes pediatricos no tratados previamente. Describir la experiencia con el uso de rFVIIIFc para indución de tolerancia inmune (ITI) en sujetos con inhibidores. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Ability of the subject or his parent or legal guardian to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations. Subjects may provide assent in addition to the parental/guardian consent, if appropriate.
2. Male, age <18 years at the time of informed consent.
3. Weight ?3.5 kg at the time of informed consent.
4. Severe hemophilia A defined as <1 IU/dL (<1%) endogenous FVIII documented in the medical record or as tested during the Screening Period. Any subject who is enrolled based on results of the local laboratory must be withdrawn if the central laboratory screening results indicate a baseline FVIII activity level ?1% of normal. |
1. Capacidad del sujeto o de su progenitor o tutor legal de comprender el objetivo y los riesgos del estudio y de dar el consentimiento informado firmado y fechado, y la autorización para usar información de salud protegida (PHI), de acuerdo con la
normativa nacional y local sobre la privacidad de los sujetos. Los sujetos podrán otorgar su asentimiento además del consentimiento del progenitor/tutor, si es pertinente. 2. Hombre, edad < 18 años en el momento del consentimiento informado. 3. Peso ? 3,5 kg en el momento del consentimiento informado. 4.
Hemofilia A grave definida como ? 1 UI/dl (? 1 %) de FVIII endógeno documentado en la historia clínica o como se haya analizado durante el período de selección.
Cualquier sujeto que sea inscrito basándose en los resultados del laboratorio local debe ser retirado si los resultados de selección del laboratorio central indican un nivel de actividad del FVIII al inicio > 1 % de lo normal. |
|
| E.4 | Principal exclusion criteria |
1. Prior history of inhibitor as defined by the reporting laboratory. The historical positive inhibitor test is defined as per local laboratory Bethesda value for a positive inhibitor test (i.e., equal to or above lower level of detection).
2. Measurable inhibitor activity at the Screening Visit, measured using the Nijmegen-modified Bethesda assay performed at the central laboratory. A negative inhibitor test result at the local laboratory may be used initially to determine subject eligibility; however, any subject who is enrolled based on results of the local laboratory must be withdrawn if the central laboratory screening results indicate a positive inhibitor. Subjects actively bleeding and requiring emergent treatment may be enrolled and receive study drug after samples for inhibitor testing at the central laboratory have been obtained, with results pending. However, any such subject must be withdrawn if the central laboratory screening results indicate a positive inhibitor.
3. History of hypersensitivity reactions associated with any IV immunoglobulin administration.
4. Injection with any FVIII replacement product or any blood component prior to confirmation of eligibility.
5. Injection with rFVIIIFc prior to confirmation of eligibility.
6. Other coagulation disorder(s) in addition to hemophilia A.
7. Any concurrent clinically significant major disease that, in the opinion of the Investigator, would make the subject unsuitable for enrollment.
8. Current systemic treatment with chemotherapy and/or other immunosuppressant drugs. Use of corticosteroids for the treatment of asthma or management of acute allergic episodes is allowed with the exception of systemic corticosteroid treatment given to children daily or on alternate days at ?2 mg/kg per day of prednisone or its equivalent or ?20 mg/day if they weigh more than 10 kg with a duration of longer than 14 days.
9. Participation within the past 30 days in any other clinical study involving investigational treatment.
10. Current enrollment in any other clinical study involving investigational treatment.
11. Inability to comply with study requirements.
12. Other unspecified reasons that, in the opinion of the Investigator or Biogen Idec, make the subject unsuitable for enrollment. |
1. Antecedentes previos de inhibidor, tal como lo define el laboratorio que informa. La prueba histórica de inhibidor positiva se define como un valor de Bethesda del laboratorio local para una prueba positiva de inhibidor (es decir, igual o por encima del nivel inferior de detección). 2. Actividad inhibidora medible en la visita de selección, medida usando el ensayo de Bethesda modificado por Nijmegen realizado en el laboratorio central. Un resultado negativo de inhibidor en el laboratorio local puede utilizarse inicialmente para determinar la idoneidad del sujeto; sin embargo, todo sujeto que sea inscrito basándose en los resultados del laboratorio local debe ser retirado si los resultados de la selección del laboratorio
central indican un inhibidor positivo. Los sujetos con sangrado activo y que requieran un tratamiento de emergencia pueden inscribirse y recibir el fármaco del estudio después de que se hayan obtenido las muestras para la prueba del inhibidor en el laboratorio central, con resultados pendientes. Sin embargo, si los resultados de detección del laboratorio central indican un inhibidor positivo, los sujetos deben ser retirados. 3. Antecedentes de reacciones de hipersensibilidad
asociadas con alguna administración i.v. de inmunoglobulina. 4. Inyección con cualquier producto de reemplazo de FVIII o cualquier componente de la sangre antes de la confirmación de la idoneidad. 5. Inyección con rFVIIIFc antes de la confirmación de la idoneidad. 6. Otros trastornos de la coagulación además de la hemofilia A. 7. Cualquier enfermedad importante y clínicamente significativa
concurrente que, en opinión del investigador, podría hacer que el sujeto no fuera apto para la inscripción. 8. Tratamiento sistémico actual con quimioterapia u otros fármacos inmunosupresores. Se permite el uso de corticosteroides para el tratamiento del asma o el control de episodios alérgicos agudos con la excepción del tratamiento con corticosteroides sistémicos que se da los niños diariamente o
en días alternos de ? 2 mg/kg por día de prednisona o su equivalente, o ? 20 mg/día si pesan más de 10 kg, con una duración de más de 14 días. 9. Participación en los últimos 30 días en cualquier otro estudio clínico con algún tratamiento en investigación. 10. Inscripción actual en algún otro estudio clínico con un tratamiento en investigación. 11. Incapacidad para cumplir con los requisitos del estudio. 12. Otra razón no especificada que, en opinión del investigador o de Biogen Idec, haga que el sujeto no sea apto para la inscripción. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the occurrence of inhibitor development. |
| l criterio de valoración principal del estudio es la aparición de desarrollo de inhibidores. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects will be tested for inhibitor formation:
- at each clinic visit including screening and baseline.
- 5 (±1), 10-15, 20-25, 50, 75, and 100 EDs
- 2 to 4 weeks prior to elective major surgery, preoperatively, postoperatively, and at the Last Postoperative Visit (see Section 4.2.2 of protocol).If this does not align with a scheduled visit, an additional visit must be scheduled. For minor surgeries, testing for inhibitors will only be performed if indicated by the nature of the procedure, according to local standard of care.
- if inhibitor development is suspected at any time during the study the subject will be tested for inhibitors by the central lab
Additional unscheduled testing for inhibitors may be performed, if required by local standards of care |
Se evaluará la formación de inhibidores en sujetos:
- en cada visita clinica incluyendo basal y screening
5(+/1), 10-15, 20-25,50,75, and 100 EDs
-2 a 4 semanas antes de elección de cirugía mayor, preoperatorio y posteroperatorio, y en la última visita postoperatoria (ver seccion 4.2.2. del protocolo) Si no coincide con una visita programada una visita adicional deberá programarse. Para cirugías menores, la evaluación de inhibidores será realizada solo si está indicada por la naturaleza del procedimiento de acuerdo a los estandares habituales de cuidado. Si se sospecha un desearrollo de inhibidores en algún momento durante la duración del estudio el sujeto será sometido a una evaluación de inhibidores por el lab. central |
|
| E.5.2 | Secondary end point(s) |
-The annualized number of bleeding episodes per subject
- The annualized number of spontaneous joint bleeding episodes per subject
- The number of injections and dose per injection of rFVIIIFc required to resolve a bleeding episode
- Assessments of response to treatment with rFVIIIFc for bleeding episodes, using the 4-point bleeding response scale
- The total number of EDs per subject per year
- Total annualized rFVIIIFc consumption per subject for the prevention and treatment of bleeding episodes
- rFVIIIFc incremental recovery (IR)
- Response to ITI with rFVIIIFc (success, partial success, failure, early withdrawal) |
| ? El número de episodios de sangrado anualizados por sujeto ? El número de episodios de sangrado articular espontáneos anualizados por sujeto ? El número de inyecciones y dosis por inyección de rFVIIIFc necesario para resolver un episodio de sangrado ? Las evaluaciones de la respuesta al tratamiento con rFVIIIFc para los episodios de sangrado, utilizando la escala de respuesta de sangrado de 4 puntos ? El número total de DE por sujeto por año ? El consumo total anualizado de rFVIIIFc por sujeto para la prevención y el tratamiento de los episodios de sangrado ? La recuperación incremental (RI) de rFVIIIFc ? La respuesta a la ITI con rFVIIIFc (éxito, éxito parcial, fracaso, retirada anticipada) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Incidence of bleeding episodes, dose and number of injections, and response to treatment will be monitored by the physician on an ongoing basis and will be obtained from electronic patient diaries (EPDs), electronic case report forms (eCRFs), and medical records. During clinic visits when rFVIIIFc is injected, blood samples will be taken to assess incremental recovery. |
| La incidencia de episodios de sangrado, dosis y número de inyecciones y respuesta al tratamiento serán monitorizadas por el médico de manera regular y se obtendrán del diario de paciente (DPs), el cuaderno de recogida de datos electronico (eCRF) yarchivos médicos.Durante las visitas clínicas al inyectar rFVIIIFc, se tomarán muestras para evaluar la tasa incremental de respuesta. |
|
| 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) | 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
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| 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
|
| The end of the study will occur when at least 100 subjects have reached at least 100 EDs with rFVIIIFc. Once this milestone has been achieved, any additional study subjects who have not reached 100 EDs will be required to attend the study center for the Early Termination/End of Study Visit assessments. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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