E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with Severe Asthma |
Pacientes con asma grave |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003553 |
E.1.2 | Term | Asthma |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To provide extended treatment with mepolizumab to subjects with a history of lifethreatening or seriously debilitating asthma and a history of improved disease control while receiving mepolizumab as defined by this protocol |
Proporcionar tratamiento prolongado con mepolizumab a los sujetos que tengan una antecedentes de asma que pone en peligro la vida o asma gravemente debilitante y antecedentes de mejoría en el control de la enfermedad con mepolizumab según se define en el presente protocolo. |
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E.2.2 | Secondary objectives of the trial |
To further describe the long-term clinical experience of mepolizumab in a subset of subjects who demonstrated significant clinical benefit since receiving mepolizumab |
Describir más detalladamente la experiencia clínica a largo plazo con mepolizumab en un subgrupo de pacientes que han manifestado un beneficio clínico importante mientras recibían mepolizumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must additionally meet all of the following criteria: 1. Informed Consent: Prior to commencing any study related activities, subjects must be able and willing to provide written informed consent. 2. Male or Eligible Female Subjects: To be eligible for the study, females of child-bearing potential must commit to consistent and correct use of an acceptable method of birth control and for 4 months after the last study drug administration. Methods of acceptable birth control and the definitions for child-bearing and non-child bearing potential are provided in Appendix 1 of study protocol. A urine pregnancy test is required of all females of childbearing potential at the initial Baseline Visit (Visit 1). 3. French Subjects Only: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
4. MEA115661 Participation: Subjects must have completed Visit 14 of MEA115661.
5. Current Anti-Asthma Therapy: The subject?s asthma has been treated with an ICS controller medication for the last 8 months with fluticasone propionate (FP) >=500 mcg/day (or equivalent).
6. Disease Severity: Subjects must be assessed as having life-threatening /serious debilitating asthma in order to enroll, as defined by the following:
Subjects enrolled in MEA115588 must meet one of the following criteria: a) Subject has a history of at least one intubation during their lifetime b) >=3 asthma exacerbations in the 12 months prior to screening for MEA115588 c) >=1 or more hospitalization for asthma exacerbation in the 12 months prior to screening for MEA115588.
Subjects enrolled in MEA115575 must meet one of the following criteria: d) Subject has a history of at least one intubation during their lifetime e) Their optimized dose at randomization in MEA115575 was >=10mg of prednisone f) >=1 or more hospitalization for asthma exacerbation in the 12 months prior to screening for MEA115575
7. Clinical Benefit: Subjects must have experienced documented clinical benefit to enroll. Subjects must meet the following criteria demonstrating clinical benefit:
Subjects enrolled in MEA115588 who received mepolizumab must meet all of the following criteria: a) Subject must have had a reduction in their exacerbation frequency by >=50% during MEA115588. The baseline for comparison is the total number of exacerbations reported in the 12 months prior to screening for MEA115588.
b) The investigator response on the ?Clinician-Rated Response to Therapy? questionnaire at Visit 10 was either: mildly improved, moderately improved or significantly improved
Subjects enrolled in MEA115588 who received placebo must meet all of the following criteria:
c) Subject must have had a reduction in their exacerbation frequency by >=50% during the first 8 months of MEA115661. The baseline for comparison is the total number of exacerbations reported in the 12 months prior to screening for MEA115588. d) The investigator confirms that the subject demonstrated improvement during MEA115661
Subjects enrolled in MEA115575 who received mepolizumab must meet all of the following criteria:
e) Subject must have reduced their oral corticosteroid dose by >= 50% during MEA115575. The baseline for comparison is the subject?s optimized OCS dose at randomization in MEA115575
f) The investigator response on the ?Clinician-Rated Response to Therapy? questionnaire at Visit 9 was either: mildly improved, moderately improved or significantly improved
Subjects enrolled in MEA115575 who received placebo must meet all of the following criteria:
g) Subject must have reduced their oral corticosteroid dose at randomization by >=50% in the first 6 months of MEA115661. The baseline for comparison is the subject?s optimized OCS dose at randomization in MEA115575. h) The investigator confirms that the subject demonstrated improvement during MEA115661 |
Podrán participar en el estudio los sujetos que cumplan además todos los criterios siguientes: 1. Consentimiento informado: Antes de iniciar cualquier actividad relacionada con el estudio, el sujeto debe tener disposición y capacidad para otorgar el consentimiento informado por escrito. 2. Varones y mujeres elegibles: Para ser elegibles para el estudio, las mujeres potencialmente fértiles deben comprometerse a usar correctamente y sin interrupción un método anticonceptivo aceptable durante todo el estudio y hasta 4 meses después de la última dosis del fármaco del estudio. Los métodos anticonceptivos aceptable y las definiciones de mujer potencialmente fértil y no fértil se facilitan en el Apéndice 1. Todas las mujeres potencialmente fértiles deberán realizar una prueba de embarazo en orina en la visita basal de inicio (Visita 1). 3. Solo para pacientes franceses: En Francia, solo podrán participar en este estudio sujetos afiliados o beneficiarios de algún régimen de la seguridad social. 4. Participación en el estudio MEA115661: Los sujetos tendrán que haber completado la Visita 14 del estudio MEA115661. 5. Tratamiento antiasmático actual: tratamiento para el control del asma con un CI a base de propionato de fluticasona (PF) >= 500 ?g/día (o equivalente) al menos durante los últimos 8 meses. . 6. Intensidad de la enfermedad: Para poder participar, los pacientes deberán tener un diagnóstico de asma que pone en peligro la vida o gravemente debilitante, definido como:
Los sujetos participantes en el estudio MEA115588 deberán cumplir alguno de los siguientes criterios: a) Antecedentes de al menos una intubación a lo largo de la vida b) >= 3 exacerbaciones del asma en los 12 meses previos a la selección para el estudio MEA115588 c) >= 1 hospitalizaciones por exacerbación del asma en los 12 meses previos a la selección para el estudio MEA115588.
Los sujetos participantes en el estudio MEA115575 deberán cumplir alguno de los siguientes criterios: d) Antecedentes de al menos una intubación a lo largo de la vida e) La dosis optimizada en el momento de la aleatorización del estudio MEA115575 fue >= 10 mg de prednisona f) >= 1 hospitalizaciones por exacerbación del asma en los 12 meses previos a la selección para el estudio MEA115575.
7. Beneficio clínico: Para poder participar, los sujetos tienen que haber experimentado un beneficio clínico documentado. Deben cumplir los siguientes criterios para demostrar el beneficio clínico: Los sujetos participantes en el estudio MEA115588 que recibieron mepolizumab deben cumplir todos los criterios siguientes: a) Haber tenido una reducción >= 50% en la frecuencia de exacerbaciones durante el estudio MEA115588. La referencia de comparación es el número total de exacerbaciones comunicado en los 12 meses previos a la selección del estudio MEA115588. b) La evaluación del investigador en el cuestionario de "Respuesta al tratamiento valorada por el médico" de la visita 10 deberá ser: mejoría leve, mejoría moderada o mejoría significativa
Los sujetos participantes en el estudio MEA115588 que recibieron placebo deben cumplir todos los criterios siguientes: c) Haber tenido una reducción >= 50% en la frecuencia de exacerbaciones durante los 8 primeros meses del estudio MEA115661. La referencia de comparación es el número total de exacerbaciones comunicado en los 12 meses previos a la selección del estudio MEA115588. d) El investigador deberá confirmar que el paciente manifestó mejoría durante el estudio MEA115661.
Los sujetos participantes en el estudio MEA115575 que recibieron mepolizumab deben cumplir todos los criterios siguientes: e) Haber tenido una reducción >= 50% en la dosis de corticosteroides orales durante el estudio MEA115575. La referencia de comparación es la dosis de corticoides orales optimizada en el momento de la aleatorización del estudio MEA115575. f) La evaluación del investigador en el cuestionario de "Respuesta al tratamiento valorada por el médico" de la visita 9 deberá ser: mejoría leve, mejoría moderada o mejoría intensa
Los sujetos participantes en el estudio MEA115575 que recibieron placebo deben cumplir todos los criterios siguientes: g) Haber tenido una reducción >= 50% en la dosis de corticosteroides orales, con respecto a la aleatorización, durante los 6 primeros meses del estudio MEA115661. La referencia de comparación es la dosis de corticoides orales optimizada en el momento de la aleatorización del estudio MEA115575. h) El investigador deberá confirmar que el paciente manifestó mejoría durante el estudio MEA115661. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study: 1. Health Status: Clinically significant change in health status during MEA115661 which in the opinion of the investigator would make the subject unsuitable for participation in this long-term study. 2. Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation. 3. Exacerbation History: Subjects who received placebo in MEA115588 and had NO exacerbations during the study. 4. Oral Corticosteroid Use: Subjects who received placebo in MEA115575 and were able to discontinue oral corticosteroid therapy by the end of the study. 5. Smoking Status: Current smokers 6. Previous Significant Protocol Deviation: Subjects who were excluded from the per protocol analysis due to significant protocol deviations in either study MEA115575 or MEA115588. 7. ECG Assessment: A clinically significant ECG abnormality at the exit visit of MEA115661, as determined by the investigator. |
No podrán participar en el estudio los sujetos que cumplan alguno de los criterios siguientes. 1. Estado de salud: Cualquier cambio clínicamente relevante del estado de salud ocurrido durante el estudio MEA115661 que, en opinión del investigador, haga al sujeto no elegible para participar en este estudio a largo plazo. 2. Embarazo: Mujeres embarazadas o lactantes. Las mujeres no podrán ser incluidas en el estudio si tienen previsto quedarse embarazadas durante el periodo de participación en el estudio. 3. Historia de exacerbaciones: Los sujetos que recibieron placebo en el estudio MEA115588 y no sufrieron exacerbaciones durante el estudio. 4. Uso de corticosteroides orales: Los sujetos que recibieron placebo en el estudio MEA115575 y estaban en condiciones de prescindir del tratamiento con corticosteroides orales al final del estudio. 5. Tabaquismo.: Fumadores activos 6. Desviaciones importantes del protocolo ocurridas previamente: Los sujetos que quedaron excluidos del análisis del protocolo debido a desviaciones importantes de dicho protocolo en los estudios MEA115575 o MEA115588. 7. Evaluación ECG: Cualquier anomalía del ECG de importancia clínica en la visita de salida del estudio MEA115661, determinada por el investigador. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Annualized rate of exacerbations - Frequency of adverse events |
- Tasa anual de exacerbaciones - Frecuencia de los acontecimientos adversos |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis will be performed as needed in order to provide open-label safety data to inform the risk-benefit assessment of mepolizumab in severe asthma |
Se realizará un análisis intermedio en la medida necesaria para proporcionar datos abiertos de la seguridad que conformen la evaluación del balance riesgo-beneficio de mepolizumab en el asmagrave. |
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E.5.2 | Secondary end point(s) |
- Asthma Control Questionnaire-5 score - Forced expiratory volume in 1 second (FEV1) - Number of withdrawals due to lack of efficacy - Number of withdrawals due to adverse events - Number of hospitalizations due to adverse events including asthma exacerbations - Frequency of both systemic (i.e., allergic and non-allergic) and local site reactions - 12-lead ECG parameters - Vital signs - Frequency of positive anti-mepolizumab binding antibodies/neutralizing antibodies - Clinical Laboratory Parameters |
- Cuestionario sobre el control del asma, versión de 5 ítems - Volumen espiratorio forzado en 1 segundo (FEV1) - Número de retiradas por falta de eficacia - Número de retiradas por acontecimientos adversos - Número de hospitalizaciones por acontecimientos adversos, incluidas las exacerbaciones del asma - Frecuencia de reacciones sistémicas (de tipo alérgico y no alérgico) y locales - Parámetros del ECG de 12 derivaciones - Constantes vitales - Frecuencia de detección de anticuerpos anti-mepolizumab/ anticuerpos neutralizantes - Parámetros de análisis clínicos |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Interim analysis will be performed as needed in order to provide open-label safety data to inform the risk-benefit assessment of mepolizumab in severe asthma |
Se realizará un análisis intermedio en la medida necesaria para proporcionar datos abiertos de la seguridad que conformen la evaluación del balance riesgo-beneficio de mepolizumab en el asmagrave. |
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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 | No |
E.6.3 | Therapy | No |
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 | 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 | 54 |
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 |
Italy |
Japan |
Netherlands |
Argentina |
Australia |
Chile |
Czech Republic |
Germany |
Korea, Republic of |
Spain |
Mexico |
Poland |
Russian Federation |
Ukraine |
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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LSLV |
Última visita del último paciente |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |