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    Summary
    EudraCT Number:2011-000242-38
    Sponsor's Protocol Code Number:BEL114674
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-10-22
    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 number2011-000242-38
    A.3Full title of the trial
    A 2 year study of efficacy and safety of
    intravenous belimumab versus placebo in subjects with
    idiopathic membranous nephropathy
    Estudio de eficacia y seguridad de belimumab intravenoso frente a placebo, de dos años de duración, en sujetos con nefropatía membranosa idiopática
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 2 year study to investigate belimumab in membranous nephropathy
    Estudio de 2 años de duración para investigar belimumab en nefropatía membranosa
    A.3.2Name or abbreviated title of the trial where available
    GSK1550188 in membranous nephropathy
    A.4.1Sponsor's protocol code numberBEL114674
    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 Research & Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & 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 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44208990 4466
    B.5.5Fax number+44208990 1234
    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 Yes
    D.2.1.1.1Trade name BENLYSTA®
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBENLYSTA®
    D.3.2Product code GSK1550188 (Belimumab)
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBELIMUMAB
    D.3.9.1CAS number 356547-88-1
    D.3.9.2Current sponsor codeGSK1550881
    D.3.9.4EV Substance CodeSUB25607
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Idiopathic Membranous Nephropathy (IMN)
    Nefropatía membranosa idiopática (NMI)
    E.1.1.1Medical condition in easily understood language
    Idiopathic Membranous Nephropathy (IMN)
    Nefropatía membranosa idiopática (NMI)
    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 10027170
    E.1.2Term Membranous nephropathy
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of 10mg/kg belimumab for the treatment of IMN.
    Evaluar la eficacia de 10 mg/kg de belimumab para el tratamiento de la NMI.
    E.2.2Secondary objectives of the trial
    - To evaluate the safety and tolerability of belimumab 10mg/kg over a 2 year period in IMN.
    - To evaluate the pharmacokinetics of belimumab in IMN.
    - To evaluate the effect of belimumab on pharmacodynamic markers and other markers of autoimmunity and their relationship with clinical efficacy in IMN.
    - To evaluate the effect of belimumb on quality of life in IMN.
    - To evaluate the benefit of earlier treatment with belimumab compared to delayed treatment with current immunosuppressive treatment regimens.
    - Evaluar la seguridad y tolerabilidad de 10 mg/kg de belimumab durante un periodo de 2 años en la NMI.
    - Evaluar la farmacocinética de belimumab en la NMI.
    - Evaluar el efecto de belimumab sobre marcadores farmacodinámicos y otros marcadores de autoinmunidad y su relación con la eficacia clínica en la NMI.
    - Evaluar el efecto de belimumab sobre la calidad de vida en la NMI.
    - Evaluar el beneficio del tratamiento precoz con belimumab en comparación con el tratamiento tardío con los regímenes inmunosupresores actuales.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A subject will be eligible for inclusion in this study only if all of the following criteria apply:
    1. Age & Gender: Male or female between 18 and 75 years of age inclusive, at the time of signing the informed consent.
    2. Histological diagnosis: Have new clinical diagnosis of IMN, as verified by biopsy (either by light microscope with immuno-fluorescence, or by electron microscope) in the last 3 years (biopsy results should be available for independent evaluation).
    3. Proteinuria: Have clinically active disease (nephrotic range proteinuria) for at least 3 months prior to screening and no improvement (<30% reduction), despite supportive therapy (which must include maximal tolerated doses of ACE inhibitor or
    ARB unless contraindicated, and may include statins, diuretics, dietary salt restriction). During screening proteinuria must be >400mg/mmol by uPCR (equates to >4.0g per 24 h) as measured from a 24 h urine collection and/or spot urine sample (early morning where possible) on 2 occasions at least 7 days apart.
    4. Female Subjects: A female subject is eligible to participate if she is not pregnant or nursing and at least one of the following conditions apply:
    a. Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with
    simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol < 40 pg/mL (<147 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow
    confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
    b. Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimise the risk
    of pregnancy at that point. Female subjects must agree to use contraception until 16 weeks after the last dose.
    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.
    Un sujeto sólo será elegible para participar en el estudio si cumple todos los criterios siguientes:
    1. Edad y sexo: Hombres o mujeres de edad comprendida entre 18 y 75 años inclusive en el momento de la firma del consentimiento informado.
    2. Diagnóstico histológico: Nuevo diagnóstico clínico de NMI, verificado mediante biopsia (con microscopio de luz con inmunofluorescencia o con microscopio electrónico) en los 3 últimos años (los resultados de la biopsia deben estar disponibles para una evaluación independiente).
    3. Proteinuria: Los sujetos deben tener enfermedad clínicamente activa (proteinuria en el rango nefrótico) al menos durante 3 meses antes de la selección y sin mejoría (<30% de reducción), a pesar de la terapia de soporte (que debe incluir dosis máximas toleradas de un inhibidor de la ECA o BRA a menos que esté contraindicado, y puede incluir estatinas, diuréticos y restricción de sal de la dieta). Durante la selección la proteinuria debe ser >400 mg/mmol mediante P/Cr en orina (que equivale a >4 g/24h) medido en orina de 24 horas y/o en una muestra de orina aislada (siempre que sea posible de primera hora de la mañana) en 2 ocasiones con un intervalo mínimo de 7 días.
    4. Mujeres: Una mujer será elegible para participar si no está embaraza o en periodo de lactancia y cumple al menos una de las siguientes condiciones:
    a) Mujeres no potencialmente fértiles definidas como, premenopáusicas con ligadura de trompas o histerectomía documentadas; o posmenopáusicas con 12 meses de amenorrea espontánea [en los casos dudosos unos valores en sangre de hormona folículo estimulante (FSH) >40 MUI/mL y de estradiol <40 pg/mL (<147 pmol/L) son confirmatorios]. Las mujeres sometidas a terapia de sustitución hormonal (TSH) y aquellas en las que el estado menopáusico sea dudoso tendrán que utilizar uno de los métodos anticonceptivos que se describen en la Sección 8.1 si desean continuar su TSH durante el estudio. De lo contrario, deben interrumpir la TSH para permitir la conformación del estado posmenopáusico antes del reclutamiento en el estudio. Con la mayoría de las formas de TSH, transcurrirán al menos 2-4 semanas entre el cese del tratamiento y la menstruación; este intervalo depende del tipo y la dosis de la TSH. Tras la confirmación de su estado posmenopáusico, podrán reanudar su TSH durante el estudio sin tener que utilizar ningún método anticonceptivo.
    b) Mujeres potencialmente fértiles y que estén de acuerdo en utilizar uno de los métodos anticonceptivos descritos en la Sección 8.1 durante un periodo de tiempo apropiado (determinado por la ficha técnica del producto y el investigador) antes de comenzar la administración del tratamiento del estudio para minimizar suficientemente el riesgo de embarazo en ese momento. Las mujeres deben estar de acuerdo en utilizar anticonceptivos hasta 16 semanas después de la última dosis.
    Sujetos franceses: En Francia, un sujeto sólo será elegible para participar en este estudio si está afiliado o es beneficiario de una categoría de la seguridad social.
    E.4Principal exclusion criteria
    1. Non-Idiopathic MN or other condition affecting the kidney: If the diagnosis of MGN is secondary to other conditions, or the subject has renal impairment from a condition that is not MN.
    Causes of secondary MN include (but are not limited to):
    Immune diseases: Systemic lupus erythematosus, diabetes mellitus; rheumatoid arthritis, Hashimoto?s disease, Grave?s disease, mixed connective tissue disease, Sjogren?s syndrome, primary biliary cirrhosis, bullous pemphigoid, small bowel
    enteropathy syndrome, dermatitis herpetiformis, ankylosing spondylitis, graft-versushost- disease, Guillain-Barre syndrome.
    Infectious or parasitic diseases: Hepatitis B; Hepatitis C, syphilis, filariasis, hydatid disease, schistosomiasis, malaria, leprosy.
    Drugs and toxins: Gold, penicillamine, non-steroidal anti-inflammatory agents, mercury, captopril, formaldehyde, hydrocarbons, bucillamine. Miscellaneous: Tumors (excluded with reasonable diligence), renal transplantation, sarcoidosis, sickle cell disease, Kimura disease, angiofollicular lymph node hyperplasia.
    2. Anti-PLA2R autoantibody: Patients known to be negative for anti-PLA2R autoantibody.
    3. Severely reduced or deteriorating kidney function: An eGFR at screening < 40 mL/min/1.73m2 (as determined by 4 variable version MDRD equation) or kidney function not stable (as defined by > 15% decrease in eGFR in 3 months before screening).
    4. Blood Pressure: Uncontrolled hypertension defined as blood pressure (BP) > 150/90 mm Hg (treatment target <= 140/80) as assessed by either:
    a. Blood pressures measured 3 times on each of at least 2 clinic visits during screening, after the patient has sat quietly for at least 5 minutes, with >50% of measurements being >150/90 or
    b. Average daytime blood pressure on a 24 hour ambulatory blood pressure monitor.
    5. Prior Therapy: Have received treatment with the following therapies at the times specified prior to Day 0:(please see protocol page 42 for further information)
    6. Transplantation: Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
    7. Cancer: Have a history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
    8. Acute or chronic infection: Have required management of acute or chronic infections, please view section 5.2.2 of the protocol for further information.
    9. Liver disease: Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
    10. Other diseases/conditions: Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to IMN (i.e., cardiovascular, pulmonary, haematologic, gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which, in the opinion of the investigator, could confound the
    results of the study or put the subject at undue risk. Please view section 5.2.2 of the protocol for further information.
    11. Positive serology: Have a historically positive HIV test or test positive at screening for HIV. Serologic evidence of Hepatitis B (HB) infection based on the results of testing for HBsAg, anti-HBc and anti-HBs please view section 5.2.2 of the protocol for further information.
    12. Liver function tests: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >=2x upper limit of normal (ULN); alkaline phosphatase and bilirubin >1.5xULN (isolated bilirubin >1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
    13. Immunodeficiency: Have an IgA deficiency (IgA level < 10 mg/dL) or have IgG level <250 mg/dL and have previously received any non-glucocorticoid immunosuppression during the previous 6 months.
    14. Laboratory test abnormalities: Have clinically significant abnormalities in screening laboratory assessments (not related to the disease), as judged by investigator.
    15. Drug sensitivity / Anaphylaxis: History of sensitivity or intolerance to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their
    participation. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
    16. Suicidality: Subjects who have evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicide ideation of type 4 or 5 on the Columbia Suicide-Severity Rating Scale (C-SSRS) in the last 2 months or
    who in the investigator?s judgement, pose a significant suicide risk.
    17. Substance abuse: Evidence of current drug or alcohol abuse or dependence.
    18. Blood donation: Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
    1. NM no idiopática u otra enfermedad que afecte al riñón: Si el diagnóstico de glomerulonefritis membranosa (GNM) es secundario a otra patología, o el sujeto tiene afectación renal por otra enfermedad distinta de la NM.
    Las causas de NM secundaria incluyen (pero no se limitan a):
    Enfermedades inmunes: Lupus eritematoso sistémico, diabetes mellitus, artritis reumatoide, enfermedad de Hashimoto, enfermedad de Graves enfermedad mixta del tejido conjuntivo, síndrome de Sjögren, cirrosis biliar primaria, pénfigo ampolloso, enteropatía del intestino delgado, dermatitis herpetiforme, espondilitis anquilosante, enfermedad de injerto contra huésped, síndrome de Guillain-Barre.
    Enfermedades infecciosas o parasitarias: Hepatitis B, hepatitis C, sífilis, filariasis, hidatidosis, esquistosomiasis, malaria, lepra.
    Fármacos y toxinas: Sales de oro, penicilamina, antiinflamatorios no esteroideos, mercurio, captopril, formaldehído, hidrocarburos, bucilamina.
    Miscelánea: Tumores (excluidos con una atención razonable), trasplante renal, sarcoidosis, anemia de células falciformes, enfermedad de Kimura, hiperplasia linfoide folicular.
    2. Autoanticuerpos anti-PLA2R: Pacientes que se sabe que son negativos para autoanticuerpoa anti-PLA2R.
    3. Función renal muy reducida o deteriorada: FGc en la selección <40 mL/min/1,73m2 (determinada por la ecuación de MDER de 4 variables) o función renal no estable (definida por >15% de incremento de FGc en 3 meses anteriores a la selección).
    4. Presión arterial: Hipertensión no controlada definida como presión arterial (PA) >150/90 mmHg (objetivo de tratamiento <=140/80) evaluada por:
    a) Presión arterial medida 3 veces al menos en cada una de 2 visitas a la clínica durante la selección, después de que el sujeto haya permanecido sentado al menos durante 5 minutos, siendo el 50% de las mediciones >150/90, o
    b) Promedio de la presión arterial diurna medida en un monitor de presión arterial durante 24 horas.
    5. Terapia anterior: Haber recibido tratamiento con las siguientes medicaciones en los momentos especificados antes del Día 0 (consulte la página 47 protocolo para más información).
    6. Trasplante: Antecedentes de trasplante de órgano principal o trasplante de células madre hematopoyéticas o de médula ósea.
    7. Cáncer: Antecedentes de neoplasia maligna en los 5 últimos años, excepto las neoplasias adecuadamente tratadas de piel (basalioma o carcinoma epidermoide) o carcinoma in situ de cuello de útero.
    8. Infección aguda o crónica: Haber necesitado tratamiento para infecciones agudas o crónicas, ver apartado 5.2.2 del Protocolo para más información.
    9. Hepatopatía: Historia actual o crónica de hepatopatía, o anomalías hepáticas o biliares conocidas (excepto el síndrome de Gilbert o la litiasis biliar asintomática).
    10. Otras enfermedades/trastornos: Evidencia clínica de enfermedades agudas o crónicas inestables o incontroladas significativas no debidas a NMI que, a juicio del investigador, podrían confundir los resultados del estudio o poner al sujeto en un riesgo indebido. Ver apartado 5.2.2 del Protocolo para más información.
    11. Serología positiva: Tener antecedentes de VIH positivo o prueba de VIH positiva en la selección. Evidencia serológica de hepatitis B (HB) basada en los resultados de las pruebas de HBsAg, anti-HBc y anti-HBs, apartado 5.2.2 del Protocolo para más información.
    12. Pruebas de función hepática: Aspartato aminotransferasa (AST) y alanina aminotrasnferasa (ALT) >=2 x límite superior normal (LSN); fosfatasa alcalina y bilirrubina >1,5 x LSN (la bilirrubina aislada >1,5 LSN es aceptable si se fracciona y la bilirrubina directa es <35%).
    13. Inmunodeficiencia: Tener deficiencia de IgA (nivel de IgA<10 mg/dL) o tener un nivel de IgG <250 mg/dL y haber recibido anteriormente cualquier inmunosupresión no glucocorticoidea durante los 6 meses anteriores.
    14. Tener anomalías clínicamente significativas en pruebas de laboratorio (no relacionadas con la enfermedad), a juicio del investigador.
    15. Antecedentes de sensibilidad o intolerancia a cualquiera de las medicaciones del estudio o de sus componentes, o antecedentes de alergia al fármaco u otro tipo de alergia que, a juicio del investigador o del Monitor Médico de GSK, contraindique la participación del sujeto en el estudio.
    Antecedentes de reacción anafiláctica a la administración parenteral de agentes de contraste, proteínas humanas o murinas o anticuerpos monoclonales.
    16. Sujetos que tengan riesgo grave de suicidio que incluya historia de conducta suicida en los 6 últimos meses y/o ideas suicidas de tipo 4 o 5 en la Columbia Suicide-Severity Rating Scale (C-SSRS) en los 2 últimos meses o que, a juicio del investigador, tengan un riesgo significativo de suicidio.
    17. Evidencia de abuso o dependencia actual a drogas o alcohol.
    18. Cuando la participación en el estudio tenga como resultado la donación de sangre o derivados sanguíneos en una cantidad superior a 500 mL en un periodo de 56 días.
    E.5 End points
    E.5.1Primary end point(s)
    Incidence of remission (complete or partial) at Week 104
    (complete remission [CR] is defined as uPCR < 30mg/mmol (proteinuria <0.3g protein/24h) with no worsening of renal function (less than 15% reduction in eGFR from baseline); partial remission [PR] is defined as uPCR < 350mg/mmol [proteinuria <3.5g /24hrs] but >= 30mg/mmol [proteinuria >=0.3g /24hrs] AND a decrease of > 50% from baseline (Day 0) based on uPCR, together with no worsening of renal function [less than 15% reduction in eGFR from baseline]).
    Incidencia de remisión (completa o parcial) en la Semana 104
    (La remisión completa [RC] se define como un P/Cr en orina <30 mg/mmol (proteinuria <0,3 g de proteínas/24 h) sin empeoramiento de la función renal (menos del 15% de reducción de la FGc respecto al valor basal); la remisión parcial [RP] se define como un P/Cr en orina <350 mg/mmol [proteinuria <3,5 g/24 h] pero >=30 mg/mmol [proteinuria >=0,3 g/24 h] Y más del 50% de reducción respecto al valor basal (Día 0) basada en el P/Cr en orina, sin empeoramiento de la función renal [menos del 15% de reducción de la FGc respecto al valor basal]).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 104
    Semana 104
    E.5.2Secondary end point(s)
    ? Incidence of progression of IMN or failure to respond as defined by:
    1. Persistent symptomatic nephrotic syndrome potentially necessitating rescue therapy due to:
    ? Persistent nephrotic range proteinuria with <20% improvement after at least 6 months observation, or deterioration in proteinuria (>20% increase from baseline) at any time OR
    ? Severe symptoms of the nephrotic syndrome- i.e. morbid oedema (defined as oedema that is distressing to a patient because of prolonged duration and inability to achieve adequate control with loop diuretics) or thromboembolism, severe hypoalbuminaemia (reduction by 5g/L from baseline and <20g/L) OR
    ? Deterioration in renal function - decrease in eGFR from baseline by >20%
    ? Persistent severe hypogammaglobulinaemia, <250mg/dL- continuing for >3 months.
    2. ESRD (eGFR <15mL/min/1.73m2, dialysis or transplantation)
    3. Thromboembolism
    4. Death

    Other Secondary Endpoints
    ? Time to complete remission
    ? Time to partial remission
    ? Change from baseline in proteinuria levels at Week 104
    ? Change from baseline in serum albumin levels at Week 104
    ? Change from baseline in eGFR at Week 104
    ? Time to first thromboembolic event
    ? Change from baseline in KDQOL-36 score at Week 104
    ? Incidence of partial remission at Week 104
    ? Incidence of complete remission at Week 104
    ? Duration of remission (complete or partial)
    ? Risk-benefit calculation based on key efficacy and safety endpoints using a clinical utility index
    Key Safety Endpoints
    ? Incidence of serious adverse events (SAEs)
    ? Incidence of serious infections

    Other
    There will be a formal analysis of other endpoints at Weeks 28, 52, 76 and 104, unless otherwise stated or already specified in primary and secondary endpoints. Data from other visits will be provided as supporting/descriptive analyses. For proteinuria, absolute values (by uPCR) will be determined at all time points to model temporal effects.
    ? Change from baseline in proteinuria levels
    ? Incidence of partial remission
    ? Incidence of complete remission
    ? Incidence of complete or partial remission at any time during 104 weeks treatment
    ? Incidence of relapse over 104 weeks
    (relapse is defined as: uPCR>350mg/mmol (proteinuria > 3.5g/24 hrs) AND increase of 50% from lowest remission level, in those patients who had previously achieved any type of remission)
    ? Time to relapse (starting from time of first achievement of any type of remission)
    ? Change from baseline in eGFR
    ? Incidence of >20% decrease in eGFR at any time
    ? Change from baseline in serum creatinine levels
    ? Incidence of >50% increase in serum creatinine any time
    ? Change from baseline in serum albumin levels
    ? Change from baseline in cholesterol levels
    ? Incidence of oedema by severity
    ? Change from baseline in KDQOL-36 questionnaire score by visit
    ? Change from baseline in Membranous Nephropathy Quality of Life (MN QOL) questionnaire score by visit
    ? Change from baseline in Workplace Productivity and Activity Impairment (WPAI) questionnaire score by visit
    ? Change from baseline in 6 minute walk test (6MWT)
    ? Unscheduled healthcare contacts/resource utilisation
    ? Requirement for rescue therapy
    ? Change from baseline in anti-PLA2R antibody levels
    ? Incidence of anti-PLA2R antibody remission.
    ? Full response: Antibody undetectable
    ? Partial response: Reduction in titres by 50%
    ? Time to anti-PLA2R antibody remission
    ? Serum belimumab C(0-30min), Cmin, AUC(0-tau), and urine Ae(0-24)
    ? Pharmacodynamics/biomarkers: May include change in relevant B-cells, urine membrane attack complex (MAC), neutrophil gelatinase-associated lipocalin (NGAL), selective proteinuria, BLyS levels, autoantibody profile, change in transcriptomic profile, by visit, as data permit.
    Incidencia de progresión de la NMI o falta de respuesta definida por:
    1. Síndrome nefrótico sintomático persistente que puede necesitar tratamiento de rescate debido a:
    - Proteinuria persistente en el rango nefrótico con mejoría <20% tras al menos 6 meses de observación, o deterioro de la proteinuria (incremento >20% respecto al valor basal) en cualquier momento, O
    - Síntomas graves de síndrome nefrótico - es decir, edemas mórbidos (definidos como edemas preocupantes para el paciente debido a la duración prolongada o a la incapacidad para conseguir el control adecuado con diuréticos del asa) o tromboembolismo, hipoalbuminemia grave (reducción de 5 g/L respecto al valor basal y <20 g/L), O
    - Deterioro de la función renal - disminución >20% en la FGc respecto al valor basal
    - Hipogammaglobulinemia grave persistente, <250 mg/dL - que se mantiene durante >3 meses.
    2. EREF (FGc <15 mL/min/1,73m2, diálisis o trasplante)
    3. Tromboembolismo
    4. Muerte
    Otras variables secundarias
    - Tiempo hasta la remisión completa
    - Tiempo hasta la remisión parcial
    - Cambio respecto al valor basal en los niveles de proteinuria en la Semana 104
    - Cambio respecto al valor basal en los niveles séricos de albúmina en la Semana 104
    - Cambio respecto al valor basal en la FGc en la Semana 104
    - Tiempo hasta el primer acontecimiento tromboembólico
    - Cambio respecto al valor basal en la puntuación del cuestionario KDQOL-36 en la Semana 104
    - Incidencia de remisión parcial en la Semana 104
    - Incidencia de remisión completa en la Semana 104
    - Duración de la remisión (completa o parcial)
    - Cálculo del riesgo-beneficio basado en las variables clave de eficacia y seguridad utilizando un índice de utilidad clínica
    - Incidencia de acontecimientos adversos graves (AAG)
    - Incidencia de infecciones graves
    Otras:
    Se hará un análisis formal de otras variables en las Semanas 28, 52, 76 y 104, a menos que se establezca lo contrario o ya se especifique en las variables primarias y secundarias. Los datos de otras visitas se proporcionarán como análisis de soporte/descriptivo. Para la proteinuria, se determinarán los valores absolutos (mediante el P/Cr en orina) en todas las fechas de medición para configurar los efectos temporales.
    - Cambio respecto al valor basal en los niveles de proteinuria
    - Incidencia de remisión parcial
    - Incidencia de remisión completa
    - Incidencia de remisión completa o parcial en cualquier momento durante las 104 semanas de tratamiento
    - Incidencia de recidiva durante las 104 semanas
    (La recidiva se define como: P/Cr en orina >350 mg/mmol (proteinuria >3,5 g/24 h) Y más del 50% de incremento desde el nivel de remisión más bajo, en pacientes que anteriormente habían alcanzado cualquier tipo de remisión)
    - Tiempo hasta la recidiva (comenzando desde la fecha en la que se consiguió por primera vez cualquier tipo de remisión)
    - Cambio respecto al valor basal en la FGc
    - Incidencia de disminución >20% en la FGc en cualquier momento
    - Cambio respecto al valor basal en los niveles séricos de creatinina
    - Incidencia de aumento >50% en la creatinina sérica en cualquier momento
    - Cambio respecto al valor basal en los niveles séricos de albúmina
    - Cambio respecto al valor basal en los niveles de colesterol
    - Incidencia de edema según la gravedad
    - Cambio respecto al valor basal en la puntuación del cuestionario KDQOL-36 por visita
    - Cambio respecto al valor basal en la puntuación del cuestionario Membranous Nephropathy Quality of Life (MN QOL) por visita
    - Cambio respecto al valor basal en el cuestionario Workplace Productivity and Activity Impairment (WPAI) por visita
    - Cambio respecto al valor basal en la prueba de marcha de 6 minutos (TM 6?)
    - Utilización de recursos/contactos sanitarios no programados
    - Necesidad de medicación de rescate
    - Cambio respecto al valor basal en los niveles de anticuerpos anti-PLA2R
    - Incidencia de remisión de anticuerpos anti-PLA2R
    * Respuesta completa: anticuerpos indetectables
    * Respuesta parcial: reducción del 50% en el título
    - Tiempo hasta la remisión de anticuerpos anti-PLA2R
    - Concentración sérica de belimumab (0-30 min), Cmin, AUC (0-tau) y Ae(0-24)
    - Farmacodinamia/biomarcadores: Puede incluir cambio en las células B relevantes, complejo de ataque a la membrana (MAC) en orina, lipocalina asociada a la gelatinasa de los neutrófilos (NGAL), proteinuria selectiva, niveles de BLyS, perfil de autoanticuerpos, cambio en el perfil transcriptómico, por visita, como permitan los datos.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 104
    Semana 104
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    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
    Canada
    Czech Republic
    France
    Germany
    Italy
    Netherlands
    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
    Last Subject Last Visit
    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 months4
    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 months4
    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: 74
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 67
    F.4.2.2In the whole clinical trial 94
    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)
    Subjects will not receive any additional treatment from GSK after completion of the study because other treatment options are available and for subjects in remission, the value of belimumab maintenance therapy is unclear. Equally for subjects who have not achieved remission with belimumab by two years, the value of extending therapy beyond two years is unclear. The investigator is responsible for ensuring that consideration has been given to the poststudy care of the patient?s medical condition.
    Los sujetos no recibirán tratamiento adicional de GSK después de completar el estudio porque existen otras opciones de tratamiento y en los sujetos en remisión, no está claro el valor de la terapia de mantenimiento con belimumab. Los sujetos que no hayan alcanzado una remisión con belimumab en 2 años, no está claro el valor de prolongar el tratamiento. El investigador tiene que asegurarse de que se ha considerado el tratamiento posterior al estudio del paciente, aunque GSK no sea el proveedor.
    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 Decision2012-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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