E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is a genetic deficiency of blood clotting factor VIII, which causes increased bleeding. |
La Hemofilia A es una deficiencia genetica del factor VIII de coagulación que causa un aumento de las hemorragias |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053751 |
E.1.2 | Term | Hemophilia A with anti factor VIII |
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 evaluate the overall safety and tolerability of prophylactic administration of emicizumab |
Evaluar la seguridad general y la tolerancia de la administración profiláctica de emicizumab |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of prophylactic administration of emicizumab •To evaluate the immunogenicity of emicizumab •To obtain emicizumab PK data |
•Evaluar la eficacia de la administración profiláctica de emicizumab •Evaluar la inmunogenicidad de emicizumab •Obtener datos sobre la FC de emicizumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including the patient-reported outcome (PRO) questionnaires and bleed diaries through the use of an electronic device, as per the investigator’s judgment -Aged 12 years or older at the time of informed consent -Body weight >=40 kg at the time of screening -Diagnosis of congenital hemophilia A with persistent inhibitors against FVIII -Documented treatment with bypassing agents or FVIII concentrates in the last 6 months (on-demand or prophylaxis). Prophylaxis needs to be discontinued the latest by a day before starting emicizumab -Adequate hematologic, hepatic, and renal function -For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of <1% per year during the treatment period and for at least five elimination half-lives (24 weeks) after the last dose of emicizumab |
-Tener disposición y capacidad para cumplir con las visitas planificadas, los planes de tratamiento, las pruebas de laboratorio y otros procedimientos del estudio, incluyendo los cuestionarios de los resultados percibidos por el paciente (PRO) y los diarios de hemorragias utilizando un dispositivo electrónico, de acuerdo con el criterio del investigador -Tener ≥ 12 años de edad en el momento de otorgar el consentimiento informado -Peso corporal ≥40 kg en el período de selección -Hemofilia A congénita diagnosticada, con inhibidores persistentes contra FVIII -Tratamiento documentado con agentes bypass o concentrados de FVIII en los 6 últimos meses (a demanda o con fines profilácticos). El tratamiento profiláctico se debe suspender, como máximo, un día antes de empezar a administrar emicizumab -Función hematológica, hepática y renal adecuada -Para las mujeres potencialmente fértiles: deben comprometerse a practicar la abstinencia sexual (es decir, a no mantener relaciones heterosexuales) o a utilizar un método anticonceptivo altamente eficaz con una tasa de fallos de <1% al año, durante el período de tratamiento y durante al menos cinco vidas medias de eliminación (24 semanas) después de la administración de la última dosis de emicizumab |
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E.4 | Principal exclusion criteria |
-Inherited or acquired bleeding disorder other than hemophilia A -Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy (prophylaxis regimens with FVIII and/or bypassing agents must be discontinued prior to enrollment). Patients receiving ITI therapy will be eligible following the completion of a 72-hour washout period prior to the first emicizumab administration -History of illicit drug or alcohol abuse within 12 months prior to screening, as per the investigator’s judgment -High risk for thrombotic microangiopathy (TMA) (e.g., have a previous medical or family history of TMA), as per the investigator’s judgment -Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease -Other conditions (e.g., certain autoimmune diseases) that may increase the risk of bleeding or thrombosis -History of clinically significant hypersensitivity reaction associated with monoclonal antibody therapies or components of the emicizumab injection -Known human immunodeficiency virus (HIV) infection with CD4 count <200 cells/μL within 6 months prior to screening -Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or planned use during the study, with the exception of antiretroviral therapy -Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the patient’s safe participation in and completion of the study or interpretation of the study results -Receipt of: •Emicizumab in a prior investigational study •An investigational drug to treat or reduce the risk of hemophilic bleeds within five half-lives of last drug administration •A non-hemophilia-related investigational drug within last 30 days or five half-lives, whichever is shorter •Any concurrent investigational drug. -Pregnancy or lactation, or intent to become pregnant during the study -Positive serum pregnancy test result within 7 days prior to initiation of study drug (females only) |
-Presentar trastornos hemorrágicos hereditarios o adquiridos distintos de hemofilia A -Pacientes que estén recibiendo (o que tengan previsto recibir durante el estudio) terapia de inducción de inmunotolerancia (ITI) (el tratamiento profiláctico con FVIII y/o agentes bypass se debe suspender antes de la inclusión en el estudio). Los pacientes que estén recibiendo terapia ITI serán elegibles para el estudio tras completar un período de lavado farmacológico de 72 horas antes de la administración de la primera dosis de emicizumab -Antecedentes de consumo de sustancias ilegales o abuso de alcohol en los 12 meses previos a la selección, de acuerdo con el criterio del investigador -Pacientes con alto riesgo de microangiopatia trombótica (MAT) (p. ej. con antecedentes clínicos o familiares de MAT), de acuerdo con el criterio del investigador -Tratamiento previo (en los 12 últimos meses) o actual para enfermedad tromboembólica (exceptuando trombosis previa asociada a catéter que no esté siendo tratada actualmente con antitrombóticos) o signos de enfermedad tromboembólica en la actualidad -Otros trastornos (p. ej. determinadas enfermedades autoinmunes) que puedan aumentar el riesgo de hemorragia o trombosis -Antecedentes de reacciones de hipersensibilidad clínicamente significativas asociadas con anticuerpos monoclonales o los componentes de la inyección de emicizumab -Infección por virus de inmunodeficiencia humana (VIH) confirmada, con recuento de CD4 <200 células/μl en los 6 meses previos a la selección -Uso de inmunomoduladores sistémicos (p. ej. interferón o rituximab) en el momento de la inclusión en el estudio o previsto durante el estudio, exceptuando terapia antirretroviral -Enfermedad concurrente, tratamiento concomitante o anomalías en las pruebas de laboratorio clínico que podrían interferir en la realización del estudio o que, de acuerdo con la opinión del investigador o el promotor, impedirían al paciente participar con seguridad en el estudio y completarlo o dificultarían la interpretación de los resultados del estudio -Administración de: •Emicizumab en un estudio de investigación previo •Cualquier fármaco en investigación utilizado para tratar o reducir el riesgo de hemorragias hemofílicas durante un período de cinco vidas medias después de la administración de la última dosis del fármaco •Cualquier fármaco en investigación para indicaciones distintas a hemofilia en los 30 últimos días o durante un período de cinco vidas medias, dependiendo de lo que sea más corto •Cualquier fármaco en investigación utilizado de forma concomitante. -Pacientes embarazadas o en período de lactancia o que tengan intención de quedarse embarazadas durante el estudio -Resultado positivo en la prueba de embarazo en suero en los 7 días previos al inicio del tratamiento con el fármaco del estudio (sólo en mujeres) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence and severity of adverse events including thromboembolic, TMA, systemic hypersensitivity, anaphylaxis, and anaphylactoid events 2. Changes in physical examination findings, vital signs, and laboratory parameters |
1. Incidencia y severidad de los acontecimientos adversos, incluyendo eventos tromboembólicos, microangiopatía trombótica (MAT), reacciones sistémicas de hipersensibilidad, anafilácticas y anafilactoides 2. Cambios en los hallazgos de la exploración física, las constantes vitales y los parámetros de laboratorio |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 2 years |
Hasta un máximo de 2 años |
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E.5.2 | Secondary end point(s) |
1. Number of bleeds over time 2. Hemophilia Adult Quality of Life Questionnaire (Haem-A-QoL) (>=18 y) or Hemophilia Quality of Life Short Form (Haemo-QoL-SF) (ages 12−17) scores over time 3. EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) scores over time 4. Patient preference for the emicizumab regimen compared with the previous regimen used 5. The incidence and clinical significance of anti-emicizumab antibodies 6. Pharmacokinetics data for emicizumab at defined timepoints |
1. Número de hemorragias en el transcurso del tiempo 2. Cuestinario de calidad de vida de Hemofilia del adulto (Haem-A-QoL) (pacientes ≥ 18 años) o Formulario corto de calidad de vida de hemofilia (Haemo-QoL-SF )(pacientes de edades comprendidas entre 12 y 17 años) en el transcurso del tiempo 3. Cuestionario EuroQoL de cinco- dimensiones-cinco niveles (EQ-5D-5L) en el transcurso del tiempo 4. Preferencia de los pacientes por el régimen de administración de emicizumab en comparación con el utilizado previamente 5. Incidencia y la significación clínica de los anticuerpos anti-emicizumab 6. Datos Farmacocinéticos de emicizumab en momentos específicos |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Screening (Week-4 to Week 0), Week 1, Week 2, Week 3, Week 5, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 21, Month 24, at safety follow-up 2-3. Week 1, Month 3, Month 6, Month 12, Month 18, Month 24 4. Up to 2 years 5. Week 1, Week 5, Month 3, Month 6, Month 12, Month 18, Month 24, at safety follow-up 6. Week 1, Week 2, Week 3, and Week 5, Month 3, Month 6, Month 12, Month 18, Month 24, at safety follow-up |
1. Screening (Semana 4 a Semana 0), Semana 1, Semana 2, Semana 3, Semana 5, Mes 3, Mes 6, Mes 9, Mes 12, Mes 15, Mes 18, Mes 21, Mes 24 y seguimiento de seguridad 2-3. Semana 1, Mes 3, Mes 6, Mes 12, Mes 18, Mes 24 4. Hasta un máximo de 2 años 5. Semana 1, Semana 5, Mes 3, Mes 6, Mes 12, Mes 18, Mes 24, seguimiento de seguridad 6. Semana 1, Semana 2, Semana 3, y Semana 5, Mes 3, Mes 6, Mes 12, Mes 18, Mes 24 y seguimiento de seguridad |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 |
Brazil |
Bulgaria |
Canada |
Colombia |
Denmark |
Dominican Republic |
Finland |
Germany |
Guatemala |
Hungary |
Israel |
Italy |
Mexico |
Netherlands |
Panama |
Poland |
Portugal |
Romania |
Russian Federation |
Saudi Arabia |
Spain |
Sweden |
Switzerland |
United Kingdom |
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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 end of this study is defined as the date when the last remaining patient has completed the last visit (i.e., LPLV). The study will end when all patients have been treated with emicizumab for 2 years, or earlier, if one of the following is documented: Withdrawal of consent OR Completed the 24 week safety follow-up visit 24 weeks after discontinuing emicizumab OR Lost to follow-up OR Death. |
El final del estudio se define como la fecha cuando el ultimo paciente participante ha completado la última visita (es decir, UVUP). El estudio terminará cuando todos los pacientes hayan sido tratados con emicizumab durante 2 años o antes si uno de los siguientes supuestos se documenta: Retirada de consentimiento O completa la visita de seguimiento de seguridad de 24 semanas 24 semanas después de discontinuar emicizumab O perdida de seguimiento O muerte |
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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 | 3 |
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 | 3 |
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 |