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    Summary
    EudraCT Number:2012-004385-17
    Sponsor's Protocol Code Number:MEA115921
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-12-05
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-004385-17
    A.3Full title of the trial
    A Double-blind, Randomised, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard of Care Therapy.
    Estudio doble ciego, aleatorizado, controlado con placebo para evaluar la eficacia y la seguridad de mepolizumab en el tratamiento de la granulomatosis eosinofílica con poliangeítis en sujetos que reciben el tratamiento estándar.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of mepolizumab versus placebo in addition to standard of care for the treatment of Eosinophilic Granulomatosis with Polyangiitis.
    Estudio de mepolizumab frente a placebo, ademas del tratamiento estándar, para el tratamiento de la granulomatosis eosinofílica con poliangeítis.
    A.4.1Sponsor's protocol code numberMEA115921
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGlaxoSmithKline, S.A.
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGlaxoSmithKline
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Reseacrh & Development Ltd
    B.5.2Functional name of contact pointClinical Trials HelpDesk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge road
    B.5.3.2Town/ cityUxbridge
    B.5.3.3Post codeUB11 IBU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+442089904466
    B.5.5Fax number+442089901234
    B.5.6E-mailGSKClinicalSupportHD@gsk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/175/12
    D.3 Description of the IMP
    D.3.1Product nameMepolizumab
    D.3.2Product code SB-240563
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMepolizumab
    D.3.9.1CAS number 196078-29-2
    D.3.9.2Current sponsor codeSB-240563
    D.3.9.3Other descriptive nameRecombinant humanized monoclonal antibody specific for human IL-5
    D.3.9.4EV Substance CodeSUB21650
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInjection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of Eosinophilic Granulomatosis with Polyangiitis in
    Subjects Receiving Standard of Care Therapy.
    Tratamiento de la granulomatosis eosinofílica con poliangeítis en sujetos que reciben el tratamiento estándar.
    E.1.1.1Medical condition in easily understood language
    Eosinophilic Granulomatosis with Polyangiitis also known as Churg-Strauss Syndrome
    Granulomatosis eosinofílica con poliangeítis también denominada Síndrome de Churg-Strauss.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10018701
    E.1.2Term Granulomatous disease
    E.1.2System Organ Class 100000004867
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10072580
    E.1.2Term Granulomatous polyangiitis
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10014956
    E.1.2Term Eosinophilic granuloma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10014957
    E.1.2Term Eosinophilic granulomatous vasculitis
    E.1.2System Organ Class 100000004870
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10056218
    E.1.2Term Necrotising granulomatous vasculitis
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10068462
    E.1.2Term Eosinophilic asthma
    E.1.2System Organ Class 100000004855
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10036023
    E.1.2Term Polyangiitis
    E.1.2System Organ Class 100000004866
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose <=4 mg/day prednisolone/prednisone, in subjects with relapsing or refractory
    eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.
    - To investigate the durability of response to treatment with mepolizumab plus standard of care compared with placebo plus standard of care, assessed by the proportion of subjects in remission at both Weeks 36 and 48.
    - Investigar la eficacia del mepolizumab más el tratamiento convencional en comparación con un placebo más el tratamiento convencional en la duración de la remisión clínica, definida como la duración acumulada en semanas en la que un sujeto alcanza una puntuación BVAS = 0 y una dosis de corticosteroides <=4 mg/día de prednisolona/prednisona en sujetos con granulomatosis eosinofílica con poliangeítis (GEPA) recidivante o resistente que reciben tratamiento convencional que incluye la reducción/retirada de los corticosteroides.
    - Investigar la durabilidad de la respuesta al tratamiento con mepolizumab más el tratamiento convencional en comparación con un placebo más el tratamiento convencional, evaluada por la proporción de pacientes sujetos en remisión tanto en la semana 36 como en la semana 48.
    E.2.2Secondary objectives of the trial
    - To investigate the efficacy of mepolizumab compared with placebo on time to relapse in subjects with EGPA on background standard of care treatment including corticosteroid therapy reduction/withdrawal.
    - To compare the average daily dose of corticosteroid required during the last 4 weeks of the study treatment period.
    - To evaluate the proportion of subjects who achieve remission within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.
    - To investigate the safety of mepolizumab compared with placebo in subjects with EGPA on background standard of care treatment.
    View protocol page 28 for further information.
    - Investigar la eficacia del mepolizumab en comparación con un placebo en el tiempo transcurrido hasta la recidiva en sujetos con GEPA que reciben el tratamiento convencional de base que incluye la reducción/retirada del tratamiento con corticosteroides.
    - Comparar la dosis diaria media de corticosteroides necesaria durante las últimas 4 semanas del periodo de tratamiento del estudio.
    - Evaluar la proporción de sujetos que logran una remisión en las 24 primeras semanas del estudio y siguen en remisión durante el resto del periodo de tratamiento del estudio.
    - Investigar la seguridad del mepolizumab en comparación con un placebo en sujetos con GEPA que reciben el tratamiento convencional de base.
    Ver página apartado 2. OBJETIVOS del Protocolo para más información.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend,
    and write at a level sufficient to complete study related materials.
    2. Age and gender: Male or female subjects age 18 years or older.
    3. EGPA diagnosis: subjects who have been diagnosed with EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia (>1.0x109/L and/or >10% of leucocytes) plus at least two of the following additional features of EGPA.
    - a biopsy showing histopathological evidence of eosinophilic vasculitis, or perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation;
    - neuropathy, mono or poly (motor deficit or nerve conduction abnormality);
    - pulmonary infiltrates, non-fixed;
    - sino-nasal abnormality;
    - cardiomyopathy (established by echocardiography or MRI);
    - glomerulonephritis (haematuria, red cell casts, proteinuria);
    - alveolar haemorrhage (by bronchoalveolar lavage);
    - palpable purpura;
    - ANCA positive (MPO or PR3).
    4. History of relapsing OR refractory disease defined as:
    - Relapsing disease:
    Subject must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation/increased dose of immunosuppressive therapy or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of >=7.5 mg/day.
    - Refractory disease:
    - Either: Failure to attain remission (BVAS=0 and OCS dose <=7.5 mg/day prednisolone or equivalent) within the last 6 months following induction treatment with a standard regimen, administered for at least 3 months.
    Note: a. Subjects who have received a cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed IV CYC prior to Baseline (Visit 2), if their total WBC is >=4x109/L (tested at the local laboratory, if necessary) prior to randomisation.
    b. Subjects who have received a methotrexate, azathioprine, or
    mycophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to Baseline (Visit 2).
    c. Subjects who have received an induction regimen comprising
    corticosteroids alone may be included only if they have failed to attain remission after 3 months of treatment AND the corticosteroid dose is >=15 mg/day prednisolone or equivalent for the 4 weeks prior to Baseline (Visit 2).
    - Or: Within 6 months prior to Screening (Visit 1), recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse) whilst tapering OCS, occurring at any dose level >=7.5 mg/day prednisolone or equivalent.
    5. Corticosteroid therapy: Subject must be on a stable dose of oral prednisolone or prednisone of >=7.5 mg/day (but not >50 mg/day) for at least 4 weeks prior to Baseline (Visit 2).
    6. Immunosuppressive therapy: If receiving immunosuppressive therapy (excluding cyclophosphamide) the dosage must be stable for the 4 weeks prior to Baseline (Visit 2) and during the study (dose reductions for safety reasons will be permitted).
    7. ECG measurements: QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle branch block.
    - The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread.
    - For subject eligibility and withdrawal decisions, QTcF will be used.
    - For purposes of data analysis, QTcF will be used as primary though data using both correction formulas will be collected and analysed. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.
    8. Female subjects: To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control (Appendix 4; see Section 11.4) beginning with consent, for the duration of the trial and for 4 months after the last study drug administration.
    French subjects: 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.
    1. Consentimiento informado: Capacidad de dar el consentimiento informado por escrito antes de participar en el estudio, que incluirá la capacidad de cumplir los requisitos y las restricciones enumeradas en el documento de consentimiento. Los sujetos deberán ser capaces de leer, comprender y escribir en un nivel suficiente para cumplimentar los materiales relacionados con el estudio.
    2. Edad y sexo: Varones o mujeres de 18 años de edad o más.
    3. Diagnóstico de GEPA: Sujetos que hayan sido diagnosticados de GEPA desde hace al menos 6 meses sobre la base de la anamnesis o la presencia de: asma más eosinofilia (>1,0 x 109/l y/o >10% de leucocitos) más al menos dos de las siguientes características adicionales de GEPA:
    - una biopsia que muestre signos histopatológicos de vasculitis eosinofílica, o infiltración eosinofílica perivascular, o inflamación granulomatosa rica en eosinófilos
    - mono o polineuropatía (déficit motor o anomalía de la conducción nerviosa)
    - infiltrados pulmonares no fijos
    - anomalía nasosinusal
    - miocardiopatía (determinada mediante ecocardiografía o RM)
    - glomerulonefritis (hematuria, cilindros de hematíes, proteinuria)
    - hemorragia alveolar (mediante lavado broncoalveolar)
    - púrpura palpable
    - positividad para ANCA (MPO o PR3)
    4. Antecedentes de enfermedad recidivante O resistente conforme a las siguientes definiciones:
    - Enfermedad recidivante: El sujeto debe tener antecedentes de al menos una recidiva de GEPA confirmada (es decir, necesidad de aumento de la dosis de CO, inicio/aumento de la dosis del tratamiento inmunodepresor u hospitalización) en los 2 últimos años que haya tenido lugar al menos 12 semanas antes de la selección (visita 1) y estar recibiendo una dosis de prednisolona (o equivalente) >=7,5mg/día.
    - Enfermedad resistente:
    - O bien: Imposibilidad de lograr la remisión (BVAS=0 y dosis de CO <=7,5mg/día de prednisolona o equivalente) en los últimos 6 meses tras el tratamiento de inducción con una pauta convencional, administrado durante al menos 3 meses.
    Nota:
    a. Los sujetos que hayan recibido un tratamiento de inducción con CYC podrán ser incluidos un mínimo de 2 semanas después de la última dosis diaria de CYC oral, o 3 semanas después de la última dosis de CYC i.v. en pulsos antes de la visita basal (visita 2), si el recuento leucocitario total es >=4 x 109/l (analizado en el laboratorio local, si es necesario) antes de la aleatorización.
    b. Los sujetos que hayan recibido un tratamiento de inducción con metotrexato, azatioprina o micofenolato mofetilo podrán participar si llevan recibiendo una dosis estable durante al menos 4 semanas antes de la visita basal (visita 2).
    c. Los sujetos que hayan recibido un tratamiento de inducción constituido por corticosteroides solos podrán participar únicamente si no han alcanzado la remisión después de 3 meses de tratamiento Y la dosis de corticosteroide es >=15mg/día de prednisolona o equivalente durante las 4 semanas previas a la visita basal (visita 2).
    - O BIEN: En los 6 meses previos a la selección (visita 1), recidiva de los síntomas de GEPA (que no tienen por qué cumplir necesariamente la definición de recidiva establecida en el protocolo) durante la reducción progresiva de los CO que aparece con cualquier dosis >=7,5mg/día de prednisolona o equivalente.
    5. Tratamiento con corticosteroides: El sujeto deberá llevar recibiendo una dosis estable de prednisolona o prednisona oral >=7,5 mg/día (pero no >50 mg/día) durante al menos 4 semanas antes de la visita basal(visita 2).
    6. Tratamiento inmunodepresor: Si el sujeto está recibiendo tratamiento inmunodepresor (excepto ciclofosfamida), la dosis deberá mantenerse estable durante las 4 semanas previas a la visita basal (visita 2) y durante el estudio (se permitirán reducciones de la dosis por motivos de seguridad).
    7. Determinaciones del ECG:QTc(F)<450 ms o QTc(F)<480 ms para pacientes con bloqueo de rama.
    - El QTc es el intervalo QT corregido por la frecuencia cardíaca según la fórmula de Bazett (QTcB), la fórmula de Fridericia (QTcF) u otro método, con interpretación del aparato o manual.
    - A efectos de las decisiones relativas a la elegibilidad y la retirada de sujetos, se utilizará el QTcF.
    - A efectos del análisis de los datos, se utilizará el QTcF como dato principal, aunque se recogerán y analizarán los datos utilizando ambas fórmulas de corrección.
    El QTc deberá basarse en valores únicos o promediados de QTc de ECG por triplicado obtenidos durante un periodo breve de registro.
    8. Mujeres: Para poder participar en el estudio, las MCR deberán comprometerse a utilizar de forma sistemática y correcta un método anticonceptivo aceptable (Apéndice 4; véase el apartado 11.4) a partir del consentimiento, durante el estudio y durante 4 meses después de la última administración del fármaco del estudio.
    Sujetos franceses: En Francia sólo se podrá incluir en este estudio a los sujetos afiliados o beneficiarios de alguna categoría de la seguridad social.
    E.4Principal exclusion criteria
    1. GPA or MPA: Diagnosed with granulomatosis with polyangiitis (GPA; previously known as Wegener's granulomatosis) or microscopic polyangiitis (MPA).
    2. Organ-threatening EGPA: Organ-threatening EGPA as per EULAR criteria, i.e., organ failure due to active vasculitis, creatinine >5.8 g/dL (>513 µmol/L) within 3 months prior to Screening (Visit 1).
    3. Life-threatening EGPA: Imminently life-threatening EGPA disease defined as any of the following within 3 months prior to Screening (Visit 1). Please view protocol page 37 for further information.
    4. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior screening (Subjects that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded).
    5. Liver disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
    6. Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to:
    - Known ejection fraction of <30%, OR
    - Severe heart failure that meets New York Heart Association Class IV (Appendix 5; see Section 11.5), OR
    - Hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III (Appendix 5; see Section 11.5), OR
    - Angina diagnosed less than 3 months prior to or at Visit 1 (Screening).
    7. Other concurrent medical conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment.
    8. Infectious disease: Chronic or ongoing active infectious disease requiring systemic treatment.
    9. Parasitic infection: Subjects with a parasitic infestation within 6 months prior to Screening (Visit 1).
    10. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1).
    11. HIV: Subjects with a known human immunodeficiency virus infection.
    12. Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal antibody or biologic therapy.
    13. Previous mepolizumab: Subjects who have previously received mepolizumab within a 1 year period prior to Screening (Visit 1).
    14. Prohibited medications: Subjects receiving any of the following:
    - OCS: Subject requires an oral corticosteroid dose of >50 mg/day prednisolone/prednisone in the 4-week period prior to Baseline (Visit 2).
    - Intravenous or SC corticosteroids in the 4-week period prior to Baseline (Visit 2).
    - Omalizumab within 130 days prior to Screening (Visit 1).
    - Cyclophosphamide: oral CYC within 2 weeks prior to Baseline (Visit 2) and IV CYC within 3 weeks prior to Baseline (Visit 2), if their total WBC is >=4x109/L (measured using the local laboratory if necessary).
    - Rituximab within 12 months prior to Screening (Visit 1); in addition, the subject must have shown recovery of peripheral B-cell count to within the normal range.
    - IV or SC immunoglobulin within 6 months prior to Screening (Visit 1).
    - Interferon_alpha within 6 months prior to Screening (Visit 1).
    - Anti-TNF therapy within 12 weeks prior to Screening (Visit 1).
    - Anti-CD52 (alemtuzumab) within 6 months prior to Screening (Visit 1).
    15. Other laboratory parameter exclusions:
    - Creatinine > 2.5 mg/dL (221 µmol/L)
    - WBC < 4 x109/L
    - Platelet count <120,000/mm3
    - Haemoglobin <8 g/dL (<80 g/L)
    16. Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation.
    17. Alcohol/substance abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Screening (Visit 1).
    18. Other investigational product: Subjects who have received treatment with an investigational drug within the past 30 days or 5 terminal phase half-lives of the drug whichever is longer, prior to Screening (Visit 1) (this also includes investigational formulations of marketed products).
    19. Other clinical study: Subject is currently participating in any other interventional clinical study.
    20. Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.
    1. GPA o PAM: Diagnóstico de granulomatosis con poliangeítis (GPA; antiguamente conocida como granulomatosis de Wegener) o poliangeítis microscópica (PAM).
    2. GEPA que pone en peligro órganos: GEPA que pone en peligro órganos de acuerdo con los criterios de la EULAR, es decir, insuficiencia orgánica debida a vasculitis activa, creatinina >5,8 g/dl (>513 µmol/l) en los 3 meses previos a la selección (visita 1).
    3. GEPA que pone en peligro la vida: GEPA que supone un peligro inminente para la vida en los 3 meses previos a la selección (visita 1). Para más información consultar el Protocolo.
    4. Neoplasias malignas: Neoplasia maligna actual o antecedentes de cáncer en remisión durante menos de 12 meses antes de la selección (no se excluirá a los sujetos que hayan tenido un carcinoma localizado [es decir, basocelular o epidermoide] de la piel que se extirpó con fines curativos).
    5. Hepatopatía: Hepatopatía inestable (definida por la presencia de ascitis, encefalopatía, coagulopatía, hipoalbuminemia, varices esofágicas o gástricas o ictericia persistente), cirrosis y anomalías biliares confirmadas (a excepción del síndrome de Gilbert o de colelitiasis asintomática).
    6. Aparato cardiovascular: Sujetos que presenten enfermedad cardiovascular grave o de importancia clínica no controlada con el tratamiento habitual que presenten, entre otras, las siguientes características:
    - fracción de eyección <30%, O BIEN
    - insuficiencia cardíaca grave que cumpla los criterios de clase IV de la New York Heart Association (Apéndice 5; apartado 11.5), O BIEN
    - hospitalización en los 12 meses previos a la visita 1 por insuficiencia cardíaca grave que cumpla los criterios de clase III de la New York Heart Association (Apéndice 5; véase el apartado 11.5), O BIEN
    - angina diagnosticada menos de 3 meses antes de la visita 1 (selección)
    7. Otras afecciones médicas concurrentes: Sujetos que padecen anomalías preexistentes clínicamente significativas endocrinas, autoinmunitarias, metabólicas, neurológicas, renales, digestivas, hepáticas, hematológicas, respiratorias o de otra naturaleza no asociadas a la GEPA y que no se controlen con el tratamiento habitual.
    8. Enfermedades infecciosas: Enfermedad infecciosa activa crónica o en curso que requiera tratamiento sistémico.
    9. Infecciones parasitarias: Sujetos con una infestación parasitaria en los 6 meses previos a la selección (visita 1).
    10. Situación con respecto a la hepatitis: Diagnóstico de hepatitis B crónica, basado en la positividad para el antígeno de superficie del virus de la hepatitis B (HBsAg) en la visita de selección (visita 1).
    11. VIH: Sujetos con infección conocida por el virus de la inmunodeficiencia humana.
    12. Hipersensibilidad: Sujetos con alergia o intolerancia conocidas a un anticuerpo monoclonal o tratamiento biológico.
    13. Tratamiento previo con mepolizumab: Sujetos que hayan recibido previamente mepolizumab en el periodo de 1 año antes de la selección (visita 1).
    14. Medicamentos prohibidos: Sujetos que reciban cualquiera de los siguientes medicamentos:
    - CO: El sujeto requiere una dosis de corticosteroides orales >50 mg/día de prednisolona/prednisona durante el periodo de 4 semanas previo a la visita basal (visita 2).
    - Corticosteroides intravenosos o subcutáneos durante el periodo de 4 semanas previo a la visita basal (visita 2).
    - Omalizumab en los 130 días previos a la selección (visita 1).
    - Ciclofosfamida: CYC oral en las 2 semanas previas a la visita basal (visita 2) y CYC i.v. en las 3 semanas previas a la visita basal (visita 2), si el recuento de leucocitos total es ? 4 x 109/l (medido en el laboratorio local si es necesario).
    - Rituximab en los 12 meses previos a la selección (visita 1); además, el sujeto debe haber mostrado la recuperación del recuento de linfocitos B periféricos dentro del intervalo normal.
    - Inmunoglobulina i.v. o s.c. en los 6 meses previos a la selección (visita 1).
    - Interferón-alfa en los 6 meses previos a la selección (visita 1).
    - Tratamiento anti-TNF en las 12 semanas previas a la selección (visita 1).
    - Anti-CD52 (alemtuzumab) en los 6 meses previos a la selección (visita 1).
    15. Otras exclusiones basadas en parámetros analíticos:
    -Creatinina >2,5 mg/dl (221 µmol/l)
    - LEU <4 x 109/l
    - Recuento de plaquetas <120.000/mm3
    - Hemoglobina <8 g/dl (<80 g/l)
    16. Embarazo: Mujeres embarazadas o lactantes.
    17. Abuso de alcohol/sustancias: Antecedentes (o sospecha de antecedentes) de consumo abusivo de alcohol o abuso de sustancias en los 2 años previos a la selección (visita 1).
    18. Otros productos en investigación: Sujetos que hayan recibido tratamiento con un fármaco en investigación en los últimos 30 días en 5 semividas de la fase terminal del fármaco, lo que suponga más tiempo, antes de la selección (visita 1).
    19. Otros estudios clínicos: El sujeto está participando actualmente en otro estudio clínico de intervención.
    20. Cumplimiento: Sujetos que tengan indicios conocidos de incumplimiento.
    E.5 End points
    E.5.1Primary end point(s)
    1. Total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose <=4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories:- Zero; >0 to <12 weeks;
    - 12 to <24 weeks;
    - 24 to <36 weeks
    - >=36 weeks.
    2. The proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period.
    - La duración total acumulada de la remisión, es decir, el número acumulado de semanas en las que la puntuación BVAS es 0 y la dosis de prednisolona/prednisona es <=4 mg/día durante el periodo de tratamiento del estudio de 52 semanas, notificada como porcentaje de sujetos que alcancen la remisión en las siguientes categorías: cero, > 0 a < 12 semanas, 12 a < 24 semanas, 24 a < 36 semanas y >= 36 semanas.
    - La proporción de sujetos que están en remisión tanto en la semana 36 como en la semana 48 del periodo de tratamiento del estudio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Over the 52 week treatment period
    Durante las 52 semanas del periodo de tratamiento.
    E.5.2Secondary end point(s)
    - Time to first confirmed EGPA relapse.
    - The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the study treatment period (48 through 52) in each of the following categories: Zero; >0 to <=4.0 mg; >4.0 to <=7.5 mg; >7.5 mg.
    - The proportion of subjects in each treatment group who achieve remission (BVAS=0 and prednisolone/prednisone dose <=4 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period.
    - Tiempo transcurrido hasta la primera recidiva de GEPA confirmada.
    - Proporción de sujetos con una dosis diaria media de prednisolona/prednisona durante las últimas 4 semanas del periodo de tratamiento del estudio (48 a 52) en cada una de las categorías siguientes: cero, >0 a <=4,0 mg, >4,0 a <=7,5 mg y > 7,5 mg.
    - Proporción de sujetos que logran una remisión (BVAS =0 y dosis de prednisolona/prednisona <=4 mg/día) en las 24 primeras semanas del estudio y que siguen en remisión durante el resto del periodo de tratamiento del estudio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    As specified in the endpoint.
    Como se específica en la variable.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    Japan
    Spain
    United Kingdom
    United States
    E.8.7Trial 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
    LVLS
    Última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 130
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The investigator is responsible for ensuring that consideration has been given to the post-study care of the subject's medical condition whether or not GSK is providing specific post-study treatment.
    El investigador es responsable de garantizar que se valore la asistencia posterior al estudio del estado médico del sujeto con independencia de que GSK suministre un tratamiento específico después del ensayo.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-01-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-09-05
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