E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe asthma with an eosinophilic phenotype |
Asma severo con fenotipo eosinofílico |
|
E.1.1.1 | Medical condition in easily understood language |
Severe Asthma |
Asma severo |
|
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 | 20.0 |
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 evaluate the efficacy of GSK3511294 100 mg (SC) every 26 weeks versus maintaining existing treatment with either mepolizumab or benralizumab in participants with severe asthma with an eosinophilic phenotype who have previously benefited from anti-IL-5/5R therapy |
Evaluar la eficacia de GSK3511294 100 mg (s.c.) cada 26 semanas en comparación con mantener el tratamiento existente con mepolizumab o benralizumab en los participantes con asma grave con fenotipo eosinofílico que previamente se han beneficiado del tratamiento anti-IL-5/5R |
|
E.2.2 | Secondary objectives of the trial |
To evaluate GSK3511294 100 mg (SC) every 26 weeks versus maintaining existing treatment with either mepolizumab or benralizumab on health related quality of life (HRQoL) and additional efficacy assessments |
Evaluar GSK3511294 100 mg (s.c.) cada 26 semanas en comparación con mantener el tratamiento existente con mepolizumab o benralizumab sobre la calidad de vida relacionada con la salud (CdVRS) y las evaluaciones de eficacia adicionales |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age: Adults and adolescents ≥12 years of age, at the time of signing the informed consent/assent.[For countries where local regulations or the regulatory status of study medication permit enrolment of adults only, participants recruited will be ≥18 years of age] 2. Asthma: Participants who have a documented physician diagnosis of asthma for ≥2 years that meets the National Heart, Lung, and Blood Institute guidelines [NHLBI, 2007] or GINA guidelines [GINA, 2020]. 3. Anti-IL-5/5R Therapy: Receiving either mepolizumab 100 mg SC or benralizumab 30 mg SC for ≥12 months prior to Screening and have a documented benefit to therapy assessed by either: • ≥50% reduction in exacerbation frequency since initiating treatment, OR • ≥50% reduction in maintenance OCS use since initiating treatment, OR • no exacerbations in the past 6 months whilst receiving anti-IL-5/5R therapy and an ACQ-5 score of ≤1.5 at Screening. 4. Inhaled Corticosteroid: A well-documented requirement for regular treatment with medium to high dose ICS in the 12 months prior to Visit 1 with or without maintenance OCS. The maintenance ICS dose must be ≥440 mcg fluticasone propionate [FP] hydrofluoroalkane product [HFA] daily, or clinically comparable [GINA, 2020; see Appendix 10 of the protocol]. Participants who are treated with medium dose ICS will also need to be treated with a Long-acting beta-agonist (LABA) to qualify for inclusion. 5. Additional Controller Medication: Current treatment with at least one additional controller medication, besides ICS [e.g., LABA, LAMA, leukotriene receptor antagonist (LTRA), or theophylline]. 6. Male or eligible female. • A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: o Is a woman of non-childbearing potential (WONCBP) as defined in Section 10.4.1 of the protocol OR o Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4.2 of the protocol from at least 14 days prior to the first dose of study intervention until at least 30 weeks after either: the first dose (if study intervention was permanently discontinued prior to Week 26), or the dose at Week 26. • A WOCBP must have a negative highly sensitive serum pregnancy test at screening Visit 1 and a negative highly sensitive urine pregnancy test within 24 hours before the first dose of study intervention. Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5 of the protocol. • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention). • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 7. Informed Consent: Capable of giving signed informed consent/assent as described in Section 10.1 of the protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. French participants: In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
1. Edad: adultos y adolescentes de 12 años de edad en el momento de firmar el consentimiento/asentimiento informado. [En países donde la normativa local o el estado normativo de la medicación del estudio permite únicamente la inscripción de adultos, los participantes serán de ≥18 años de edad] 2. Asma: participantes con un diagnóstico médico de asma documentado durante ≥2 años que cumpla con las directrices del Instituto Nacional del Corazón, los Pulmones y la Sangre (NHLBI, 2007) o las directrices GINA (GINA, 2020). 3. Tratamiento anti-IL-5/5R: recibir mepolizumab 100 mg s.c. o benralizumab 30 mg s.c. durante ≥12 meses antes de la selección y tener un beneficio del tratamiento documentado evaluado por lo siguiente: • reducción ≥50 % en la frecuencia de exacerbaciones desde el inicio del tratamiento, O • reducción ≥50 % en el uso de corticoesteroides (CO) de mantenimiento desde el inicio del tratamiento, O • ausencia de exacerbaciones en los últimos 6 meses mientras recibe el tratamiento anti-IL-5/5R y una puntuación ACQ-5 de ≤1,5 en la selección. 4. Corticosteroide inhalado: un requisito bien documentado para el tratamiento regular con dosis de media a alta de corticoesteroide inhalado (CSI) en los 12 meses previos a la visita 1 con o sin CO de mantenimiento. La dosis de mantenimiento de CSI debe ser de ≥440 μg de propionato de fluticasona (PF) con hidrofluoroalcano (HFA) al día, o clínicamente comparable (GINA, 2020; consulte el Anexo 10). Los participantes tratados con dosis medias de CSI también tendrán que tratarse con un agonista β2 de acción prolongada (LABA) para ser aptos para su inclusión. 5. Medicación de control adicional: tratamiento actual con al menos un medicamento de control adicional, aparte de los CSI (p. ej., LABA, antagonista muscarínico de acción prolongada [LAMA], antagonista del receptor de leucotrienos [LTRA] o teofilina). 6. Hombre apto o mujer apta. Mujeres participantes: • Una mujer es apta para participar si no está embarazada ni en período de lactancia y si se cumple por lo menos uno de los siguientes requisitos: o No es una mujer en edad fértil (NO MEF) como se define en la sección 10.4.1 O BIEN o Es una mujer en edad fértil (MEF) y usa un método anticonceptivo altamente eficaz, con una tasa de fallo de <1 %, como se describe en la sección 10.4.2 desde al menos 14 días antes de la primera dosis de la intervención del estudio hasta al menos 30 semanas después de la primera dosis (si la intervención del estudio se interrumpió de forma permanente antes de la semana 26) o la dosis de la semana 26. • Las MEF deben presentar una prueba de embarazo en suero de alta sensibilidad negativa en la visita 1 de selección y una prueba de embarazo en orina de alta sensibilidad negativa en el plazo de 24 horas antes de la primera dosis de la intervención del estudio. Los requisitos adicionales para las pruebas de embarazo durante y después de la intervención del estudio se encuentran en la sección 8.3.5. • El uso de anticonceptivos por las mujeres debe ser coherente con las normativas locales relativas a los métodos anticonceptivos para las participantes en estudios clínicos. • El investigador debe evaluar el potencial de fracaso del método anticonceptivo (p. ej., incumplimiento, iniciado recientemente en relación a la primera dosis de la intervención del estudio). • El investigador es responsable de la revisión de los antecedentes médicos, los antecedentes menstruales y la actividad sexual reciente para reducir el riesgo de incluir a una mujer con un embarazo temprano no detectado. 7. Consentimiento informado: con capacidad de dar su consentimiento/asentimiento informado firmado según lo establecido en la sección 10.1, lo que incluye el cumplimiento de los requisitos y las restricciones enumerados en el formulario de consentimiento informado (FCI) y en este protocolo. |
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E.4 | Principal exclusion criteria |
1. Concurrent Respiratory Disease: Presence of a known pre-existing, clinically important lung condition other than asthma. This includes (but is not limited to) current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer. 2. Eosinophilic Diseases: Participants with other conditions that could lead to elevated eosinophils such as hyper-eosinophilic syndromes including (but not limited to) Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly known as Churg-Strauss Syndrome) or Eosinophilic Esophagitis. 3. Parasitic Infection: Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are to be excluded. 4. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus – HIV), other than that explained by the use of CSs taken as therapy for asthma. 5. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening (Participants that had localised carcinoma of the skin which was resected for cure will not be excluded). 6. Liver Disease: Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C) are acceptable if participant otherwise meets entry criteria. 7. Other Concurrent Medical Conditions: Participants who have known, preexisting, clinically significant cardiac, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment. 8. Vasculitis: Participants with current diagnosis of vasculitis. Participants with high clinical suspicion of vasculitis at screening will be evaluated and current vasculitis excluded prior to enrolment. 9. COVID-19: Participants that, according to the investigator's medical judgment, are likely to have active COVID-19 infection should be excluded. Participants with known COVID-19 positive contacts within the past 14 days should be excluded for at least 14 days following the exposure during which the participant should remain symptom-free. 10. Other mAbs used in the treatment of asthma: Participants who have received omalizumab (Xolair), dupilumab (Dupixent) or reslizumab (Cinqair/Cinqaero) within 130 days prior to Visit 1. 11. Other mAbs not used for the treatment of asthma: Participants who have received any mAb within 5 half-lives of Visit 1. 12. Investigational Medications: Participants who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer, prior to visit 1 (this also includes investigational formulations of marketed products). 13. ECG Assessment: QTcF ≥450msec or QTcF ≥480 msec for participants with Bundle Branch Block at screening Visit 1. 14. Smoking history: Current smokers or former smokers with a smoking history of ≥10 pack years (number of pack years = (number of cigarettes per day / 20) x number of years smoked). A former smoker is defined as a participant who quit smoking at least 6 months prior to Visit 1. 15. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1. 16. Hypersensitivity: Participants with allergy/intolerance to a mAb or biologic. 17. Pregnancy: Participants who are pregnant or breastfeeding. Participants should not be enrolled if they plan to become pregnant during the time of study participation. Requirements for pregnancy testing are located in Section 8.3.5 of the protocol. 18. Adherence: Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations. |
1. Enfermedad respiratoria concurrente: presencia de una enfermedad pulmonar clínicamente importante preexistente conocida distinta al asma. Esto incluye (entre otros) infección actual, bronquiectasia, fibrosis pulmonar, aspergilosis broncopulmonar o diagnósticos de enfisema o bronquitis crónica (enfermedad pulmonar obstructiva crónica distinta al asma) o antecedentes de cáncer de pulmón. 2. Enfermedades eosinofílicas: participantes con otras afecciones que podrían dar lugar a aumento de eosinófilos como síndromes hipereosinofílicos, incluidos (entre otros) granulomatosis eosinofílica con poliangeítis (GEPA, anteriormente conocida como síndrome de Churg-Strauss) o esofagitis eosinofílica. 3. Infección parasitaria: debe excluirse a los participantes con una infestación parasitaria conocida, preexistente en los 6 meses anteriores a la visita 1. 4. Inmunodeficiencia: inmunodeficiencia conocida (por ejemplo, virus de la inmunodeficiencia humana, VIH), excepto la que se explique por el uso de los CS tomados como tratamiento para el asma. 5. Neoplasia maligna: neoplasia maligna actual o antecedentes de cáncer en remisión durante menos de 12 meses antes de la selección (los participantes que presentaron carcinoma localizado de la piel que se extirpó para su curación no se excluirán). 6. Enfermedad hepática: cirrosis o enfermedad hepática o biliar actual inestable según la evaluación del investigador definida por la presencia de ascitis, encefalopatía, coagulopatía, hipoalbuminemia, varices esofágicas o gástricas, ictericia persistente. NOTA: La hepatopatía crónica no cirrótica estable (incluidos el síndrome de Gilbert, los cálculos biliares asintomáticos y la hepatitis B o C estable crónica) es aceptable si el participante cumple el resto de los criterios de inclusión. 7. Otras afecciones médicas concurrentes: participantes que tengan anomalías conocidas, preexistentes clínicamente significativas del sistema cardíaco, endocrino, autoinmunitario, metabólico, neurológico, renal, gastrointestinal, hepático, hematológico o de cualquier otro sistema que no estén controladas con tratamiento estándar. 8. Vasculitis: participantes con diagnóstico actual de vasculitis. Los participantes con sospecha clínica alta de vasculitis en el momento de la selección se evaluarán y la vasculitis actual deberá excluirse antes de la inscripción. 9. COVID-19: los participantes que, según el criterio del investigador, probablemente sufran una infección activa por COVID-19, deben ser excluidos. Los participantes con contactos positivos de COVID-19 conocidos en los últimos 14 días deben excluirse durante al menos 14 días después de la exposición durante los cuales el participante debe seguir sin presentar síntomas. 10. Otros ACM usados para el tratamiento del asma:participantes que han recibido omalizumab (Xolair) o dupilumab (Dupixent) o reslizumab (Cinqair/Cinqaero) en los 130 días previos a la visita 1. 11. Otros ACM no usados para el tratamiento del asma: participantes que hayan recibido cualquier ACM en el plazo de 5 semividas antes de la visita 1. 12. Medicamentos en investigación: participantes que hayan recibido tratamiento con un fármaco en investigación en los últimos 30 días o cinco semividas de fase terminal, lo que sea más prolongado, antes de la visita 1 (esto también incluye las formulaciones en investigación de productos comercializados). 13. Evaluaciones de ECG: QTcF ≥450 ms o QTcF ≥480 ms para los participantes con bloqueo de rama en la visita 1 de selección. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Annualised rate of clinically significant exacerbations over 52 weeks |
Tasa anual de exacerbaciones clínicamente significativas durante 52 semanas |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 0 through Week 52 |
Semana 0 a semana 52 |
|
E.5.2 | Secondary end point(s) |
1.Weighted mean change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score calculated over 52 weeks 2.Weighted mean change from baseline in Asthma Control Questionnaire-5 (ACQ-5) score calculated over 52 weeks 3.Weighted mean change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) calculated over 52 weeks |
1.Cambio medio ponderado desde el inicio en la puntuación total del Cuestionario Respiratorio de St. George (SGRQ) calculada durante 52 semanas 2.Cambio medio ponderado desde el valor inicial en la puntuación del Cuestionario de control del asma-5 (ACQ-5) calculada durante 52 semanas 3.Cambio medio ponderado desde el valor inicial en el volumen espiratorio forzado previo al broncodilatador en un segundo (FEV1) calculado durante 52 semanas |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Week 0 through Week 52 2.Week 0 through Week 52 3.Week 0 through Week 52 |
1. Semana 0 a semana 52 2. Semana 0 a semana 52 3. Semana 0 a semana 52 |
|
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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Double dummy design to maintain the blind |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 166 |
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 |
Canada |
Japan |
Taiwan |
United States |
Austria |
Finland |
France |
Germany |
Italy |
Norway |
Poland |
Slovenia |
Spain |
Switzerland |
United Kingdom |
Czechia |
|
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
|
|
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 | 10 |
E.8.9.1 | In the Member State concerned days | 10 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 10 |