E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild or moderate hemophilia A |
Hemofilia leve a moderada |
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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 (FVIII), which causes increased bleeding. |
La hemofilia A es una deficiencia genética del factor VIII de coagulación (FVIII) que causa aumento del sangrado |
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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 | 20.0 |
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 |
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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 |
There is no formal hypothesis testing in this study. Safety: To evaluate safety profile of emicizumab in patients with non-severe hemophilia A without inhibitors Primary Efficacy: To evaluate the efficacy of emicizumab on the basis of number of treated bleeds over time |
No hay una hipotesis formal a testar en este ensayo Seguridad: Evaluar el perfil de seguridad de Emicizumab en pacientes con hemofilia A no grave sin inhibidores Eficacia Primaria: Evaluar la eficacia de emicizumab basándose en el número de hemorragias tratadas a lo largo del tiempo |
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E.2.2 | Secondary objectives of the trial |
Secondary Efficacy: 1.To evaluate the efficacy of emicizumab on basis of number of all bleeds, joint bleeds over time, target joint bleeds over time, spontaneous bleeds over time, joint health, health-related quality of life, preference for emicizumab compared with previous FVIII treatment and effect of emicizumab prophylaxis on physical activity compared with physical activity at baseline
Pharmacokinetic: 2.To characterize emicizumab pharmacokinetic profile
Immunogenicity: 3. To evaluate immune response to emicizumab |
Eficacia secundaria: 1. Evaluar la eficacia de emicizumab basandose en el número de todas las hemorragias, Número de hemorragias en articulaciones a lo largo del tiempo, Número de hemorragias en articulaciones diana a lo largo del tiempo, Número de hemorragias espontáneas a lo largo del tiempo, Salud articular, Calidad de vida relacionada con la salud, preferencia por emicizumab en comparación con la pauta previa con FVIII y efecto del tratamiento profiláctico con emicizumab en la actividad física en comparación con la actividad física en el momento basal. Farmacocinetica: 2.Caracterizar el perfil FC de emicizumab. Inmunogenicidad: 3.Evaluar la respuesta inmunitaria a emicizumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Diagnosis of mild (FVIII level between > 5% and < 40%) or moderate (FVIII level between >= 1% and <= 5%) congenital Hemophilia A without FVIII inhibitors - Weight >= 3 kg - Need for prophylaxis based on investigator assessment - A negative test for inhibitor (i.e., < 0.6 BU/mL) within 8 weeks prior to enrollment -No documented inhibitor (i.e., < 0.6 BU/mL), FVIII half-life < 6 hours, or FVIII recovery < 66% in the last 5 years - Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks prior to enrollment -Adequate hematologic hepatic and renal function - For women of childbearing potential: agreement to remain abstinent or use contraception during the treatment period and for at least 24 weeks after the final dose of study drug |
-Diagnóstico de hemofilia A congénita leve (concentración de FVIII del> 5% al < 40%) o moderada (concentración de FVIII del ≥ 1% al < 5%) sin inhibidores del FVIII -Peso ≥ 3 kg -Necesidad de profilaxis basada en la evaluación del investigador -Resultado negativo en la prueba de inhibidores (es decir, < 0,6 UB/ml) en las 8 semanas previas a la inclusión -Ausencia de inhibidores documentados (es decir, < 0,6 UB/ml), semivida del FVIII < 6 horas o recuperación del FVIII < 66 % en los últimos 5 años. -Documentación detallada del tratamiento profiláctico o a demanda con FVIII recibido y del número de episodios hemorrágicos ocurridos en las últimas 24 semanas antes de la inclusión, como mínimo. -Función hematológica , hepatica y renal adecuada -Mujeres en edad fértil: Deberán comprometerse a practicar la abstinencia o a usar métodos anticonceptivos durante al menos 24 semanas después de la dosis final del fármaco del estudio. |
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E.4 | Principal exclusion criteria |
-Inherited or acquired bleeding disorder other than mild (FVIII level between > 5% and < 40%) or moderate (FVIII level between >= 1% and <= 5%) congenital hemophilia A - History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator’s judgment - Previous (within the last 12 months) or current treatment for thromboembolic disease or signs of thromboembolic disease - Other conditions that may currently increase the risk of bleeding or thrombosis - History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection - Planned surgery during the emicizumab loading dose phase. Surgeries in patients on emicizumab from Week 5 onwards are allowed - Known HIV infection with CD4 counts < 200 cells/micro L - Concomitant disease, condition, significant abnormality on screening evaluation or laboratory tests, or treatment that could interfere with the conduct of the study, or that would in the opinion of the investigator, pose an additional unacceptable risk in administering study drug to the patient - Receipt of any of the following: o An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration with the exception of prior emicizumab prophylaxis o A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter o Any other investigational drug currently being administered or planned to be administered - Inability to comply with the study protocol in the opinion of the investigator - Pregnant or breastfeeding, or intending to become pregnant during the study - Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug |
-Trastorno hemorrágico hereditario o adquirido distinto de la hemofilia A congénita leve (concentración de FVIII del > 5% al < 40%) o moderada (concentración de FVIII del ≥ 1% al ≤ 5%) -Antecedentes de alcoholismo o toxicomanía en las 48 semanas previas a la selección, a criterio del investigador. -Tratamiento previo (en los últimos 12 meses) o actual por enfermedad tromboembólica o signos de enfermedad tromboembólica. -Otras enfermedades que puedan aumentar actualmente el riesgo de hemorragia o trombosis -Antecedentes de hipersensibilidad clínicamente significativa asociada a tratamiento con anticuerpos monoclonales o componentes de la inyección de emicizumab -Intervención quirúrgica programada durante la fase de dosis de carga de emicizumab. Se permiten las intervenciones quirúrgicas en pacientes en tratamiento con emicizumab desde la semana 5 en adelante. -Infección conocida por el VIH con un recuento de CD4 < 200 células/μl. -Enfermedad, trastorno, anomalía importante en la evaluación de selección o en los análisis clínicos o tratamiento concomitantes que podrían interferir en la realización del estudio o que, en opinión del investigador, supondrían un riesgo inaceptable adicional en la administración del fármaco del estudio al paciente. -Recepción de cualquiera de los siguientes medicamentos: o Fármaco en investigación para tratar o reducir el riesgo de hemorragias hemofílicas durante 5 semividas desde la última administración del fármaco, a excepción de la profilaxis previa con emicizumab o Tratamiento con un fármaco en investigación no relacionado con la hemofilia durante los últimos 30 días o 5 semividas, lo que sea más corto. o Cualquier otro fármaco en investigación administrado actualmente o programado para administrarse. -Incapacidad para cumplir el protocolo del estudio, en opinión del investigador. -Mujer embarazada o en período de lactancia o con intención de quedarse embarazada durante el estudio. -Las mujeres con capacidad de procrear deberán obtener un resultado negativo en una prueba de embarazo en suero realizada en los 7 días previos al comienzo del tratamiento con el fármaco del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety: 1.Incidence and severity of adverse events 2.Incidence of thromboembolic events and thrombotic microangiopathy 3.Incidence of laboratory abnormalities, injection-site reactions, adverse events leading to drug discontinuation, severe hypersensitivity, anaphylaxis, and anaphylactoid events 4.Change from baseline in physical examination findings, vital signs and ECG parameters Primary Efficacy: 5.Number of treated bleeds over time |
Seguridad: 1. Incidencia y seguridad de los efectos adversos 2. Incidencia de eventos tromboembólicos y microangiopatia tromboembolica 3. Incidencia de anomalías analíticas, de las reacciones en el lugar de inyección, acontecimientos adversos que obligan a suspender la medicación, acontecimientos graves de hipersensibilidad, anafilaxia y reacciones anafilactoides. 4. Variación de los hallazgos en la exploración física y los parametros del ECG con respecto al momento basal. Eficacia primaria: 5.Numero de sangrados tratados a lo largo del tiempo |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3. From Screening (Day -28 to -1) to 24 weeks after final dose of emicizumab or Study completion/discontinuation 4. From baseline (Day [D]-28 to -1) to 24 weeks after final dose of emicizumab or Study completion/discontinuation |
1-3. Desde screening (Dia -28 a -1) hasta 24 semanas despues de la dosis final de emicizumab o la finalizacion del estudio/ discontinuación 4. Desde basal (Day [D]-28 a -1) hasta 24 semanas despues de la dosis final de emicizumab o la finalizacion del estudio/ discontinuación |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy: 1.Number of all bleeds (i.e., those treated and untreated with FVIII), joint bleeds, target joint bleeds and spontaneous bleeds over time 2.Joint health, as assessed through use of the Hemophilia Joint Health Score at specified timepoints 3.Health-related quality of life, as assessed through use of the Comprehensive Assessment Tool of Challenges in Hemophilia Questionnaire over time 4.Preference for emicizumab compared with previous FVIII regimen, as assessed through use of the Emicizumab Preference Survey 5.Effect of emicizumab prophylaxis treatment on physical activity compared with physical activity at baseline Pharmacokinetic: 6.Plasma concentration of emicizumab at specified timepoints Immunogenicity: 7.Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study 8.Number and proportion of patients who develop anti-FVIII inhibitors (titer>= 0.6 BU/mL) at specified timepoints |
Eficacia secundaria: 1. Numero total de sangrados (es decir, aquellos tratados y no tratados con FVIII), sangrado articular, sangrado de articulaciones diana, y sangrados espontáneos a lo largo del tiempo 2.Joint health, as assessed through use of the Hemophilia Joint Health Score at specified timepoints 3.Health-related quality of life, as assessed through use of the Comprehensive Assessment Tool of Challenges in Hemophilia Questionnaire over time 4.Preference for emicizumab compared with previous FVIII regimen, as assessed through use of the Emicizumab Preference Survey 5.Effect of emicizumab prophylaxis treatment on physical activity compared with physical activity at baseline Pharmacokinetic: 6.Plasma concentration of emicizumab at specified timepoints Immunogenicity: 7.Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study 8.Number and proportion of patients who develop anti-FVIII inhibitors (titer>= 0.6 BU/mL) at specified timepoints |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At least 52 weeks 2. D-7 to -1, Week 25, 49, at every 24 weeks till Study completion/discontinuation 3. Week 1, 13, 25, 37 and 49; at every 12 weeks (Q12W) till Study completion/discontinuation 4. Week 17 5. Up to week 49 6. Week 1-5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45 and 49, Q12W, at safety follow up (FU), Study completion/discontinuation 7. Week 1, 5, 13, 25, 33, 41 and 49, Q12W, at safety FU, Study completion/discontinuation 8. D-28 to -1, Week 1, 13, 25, 37 and 49, Q12W, at safety FU, Study completion/discontinuation |
1. Al menos 52 semanas 2. D-7 a -1, semanas 25, 49, y cada 24 semanas hasta finalización de estudio / discontinuacion 3. Semanas 1, 13, 25, 37 y 49; cada 12 semanas (Q12W) hasta finalización de estudio / discontinuacion 4. Semana 17 5. Hasta la semana 49 como maximo 6. Semanas 1-5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45 y 49, Q12W, seguimiento de seguridad, finalización de estudio / discontinuacion 7. Semanas 1, 5, 13, 25, 33, 41 y 49, Q12W, seguimiento de seguridad, finalización de estudio / discontinuacion 8. D-28 a -1, Semanas 1, 13, 25, 37 y 49, Q12W, seguimiento de seguridad, finalización de estudio / discontinuacion |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenecity, Biomarkers, Health Status Utility |
Inmunogenicicdad, biomarcadores, utilidad del estado de salud. |
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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 | 15 |
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 |
Belgium |
Canada |
France |
Germany |
Italy |
Netherlands |
Poland |
South Africa |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
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 |