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    Summary
    EudraCT Number:2012-000385-38
    Sponsor's Protocol Code Number:BEL116472
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-04-02
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-000385-38
    A.3Full title of the trial
    BEL116472. A 2 year mechanistic study of belimumab in
    Idiopathic Membranous Glomerulonephropathy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate belimumab in IMGN
    A.4.1Sponsor's protocol code numberBEL116472
    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 Research and Development Ltd
    B.1.3.4CountryUnited Kingdom
    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
    B.5.2Functional name of contact pointClinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street Address1-3, Iron Bridge Road
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BU
    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 Yes
    D.2.1.1.1Trade name BENLYSTA® (belimumab)
    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 (belimumab)
    D.3.2Product code GSK1550188
    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 codeGSK1550188
    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) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Idiopathic Membranous Glomerulonephropathy (IMGN)

    E.1.1.1Medical condition in easily understood language
    Idiopathic Membranous Glomerulonephropathy (IMGN)

    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 16.1
    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
    The primary objective of this study is:
    To evaluate whether belimumab can modulate proteinuria in IMGN.
    To evaluate whether belimumab can modulate anti-PLA2R autoantibodies in patients with detectable baseline levels of these antibodies.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    To evaluate the safety and tolerability of belimumab 10mg/kg over a 2 year period in
    IMGN.
    To assess the pharmacokinetics (PK) of belimumab 10mg/kg in patients with IMGN.
    To evaluate the effect of belimumab on pharmacodynamic (PD) markers and other markers of autoimmunity and their relationship with clinical measures in IMGN.
    To evaluate the effect of belimumab on quality of life in IMGN.
    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 clinical diagnosis of IMGN, as verified by
    biopsy (either by light microscope with immuno-fluorescence, or by
    electron microscope) in the last 7 years with non-active disease >3
    years (non-active defined as subject not on immunosuppressants and proteinuria <2g per 24h) (biopsy results and
    slides should be available for independent evaluation).
    3. Autoantibody: Have positive anti-PLA2R autoantibody test results at screening.
    4. 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 should 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 PCR (or >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.
    5. 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 enrollment. 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 of Protocol 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.
    E.4Principal exclusion criteria
    A subject will not be eligible for inclusion in this study if any of the following criteria apply:
    1. Non-Idiopathic MGN 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 MGN. Causes of secondary MGN 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-Barré 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: Tumours (excluded with reasonable diligence), renal transplantation, sarcoidosis, sickle cell disease, Kimura disease, angiofollicular lymph node hyperplasia.
    2.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, unless due to medication change).
    3. 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.
    4. Prior Therapy: Have received treatment with the therapies (as per protocol page 39-see table) at the times specified prior to Day 0:
    Corticosteroid dose represents prednisolone or prednisolone equivalent.
    5. Transplantation: Have history of a major organ transplant (e.g heart, lung, kidney,liver) or hematopoietic stem cell/marrow transplant.
    6. 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.
    7. Acute or chronic infection: Have required management of acute or chronic infections, as follows:
    • Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).
    • Hospitalisation for treatment of infection within 60 days prior to Day 0.
    • Use of parenteral (IV or IM) antibiotics (anti-bacterials, anti-virals, antifungals, or anti-parasitic agents) within 60 days prior to Day 0.
    8. 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).
    9. Other diseases/conditions: Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to IMGN (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.
    or
    Have a planned surgical procedure or a history of any other medical disease (e.g. cardiopulmonary), laboratory abnormality, or condition (e.g. poor venous access) that, in the opinion of the investigator, makes the subject unsuitable for the study.
    10. 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 as follows:
    • Patients positive for HBsAg are excluded.
    • Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody and with no history of Hepatitis B vaccination are excluded.
    • Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies are excluded.
    • Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody are excluded.
    Positive test for Hepatitis C antibody confirmed on the same sample with a Hepatitis C RIBA immunoblot assay if available. Subjects who are positive for hepatitis C antibody, and who are negative when the Hepatitis C RIBA immunoblot assay is performed on the same sample, will be eligible to participate.
    Subjects who are positive for Hepatitis C antibody and who have a
    positive or indeterminate result when the Hepatitis C RIBA immunoblot assay is performed on the same sample, or where the Hepatitis C RIBA assay is not available, will not be eligible to participate. For remaining list of exclusion criteria see Protocol page 39
    E.5 End points
    E.5.1Primary end point(s)
    • Change from baseline in proteinuria levels at week 28
    • Change from baseline in anti-PLA2R autoantibody titres at week 28
    E.5.1.1Timepoint(s) of evaluation of this end point
    week28
    E.5.2Secondary end point(s)
    • Change from baseline in proteinuria levels
    • Change from baseline in anti-PLA2R autoantibody titres
    • Change from baseline in urine levels of belimumab
    • Incidence of complete or partial remission
    -Complete remission: PCR <30mg/mmol (proteinuria <0.3g/24h) with no worsening in renal function (estimated glomerular filtration rate (eGFR) reduction from baseline <15%)
    -Partial remission: PCR <350mg/mmol (proteinuria <3.5g/24h) but ≥30mg/mmol (proteinuria ≥0.3g/24h) AND decrease of >50% from Day 0 baseline, together with no worsening in renal function (eGFR reduction from baseline <15%)
    • Time to complete or partial remission
    • Duration of complete or partial remission
    • Incidence of proteinuria relapse (PCR >350mg/mmol AND increase of 50% from lowest remission level, in those subjects who had previously achieved any type of remission)
    • Incidence of anti-PLA2R autoantibody remission:
    -Full response: Antibody undetectable
    -Partial response: Reduction in titres by 50%
    • Time to anti-PLA2R autoantibody remission
    • Incidence of anti-PLA2R autoantibody relapse (antibody detectable after previously undetectable)
    • Change from baseline in eGFR levels
    • Change from baseline in serum creatinine levels
    • Change from baseline in levels of serum albumin
    • Change from baseline in levels of cholesterol
    • Incidence of oedema (extending beyond calf)
    • Serum belimumab Cmax, Cmin, AUC(0-2), and urine Ae(0-24)
    • Change from baseline in SF-36 v2 Quality of Life (QoL) questionnaire score
    • Pharmacodynamic/biomarker endpoints may include Urine membrane attack complex (MAC), B Cell and T Cell sub-populations, BLyS levels, cytokines/chemokines (may include but not limited to IL-21, IL-17, IL-4, IL-10, IFN-Gamma), antigen specific lymphocyte response, autoantibody profile, change in transcriptomic profile or other markers of IMGN or autoimmune pathology, as data permit.
    • Safety and tolerability as assessed by evaluation of adverse events (AE), clinical laboratory assessments (clinical chemistry, haematology and urinalysis), vital signs and immunogenicity.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 12, 28, 52, 76 and 104 (dependent on endpoint)
    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 No
    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 No
    E.6.11Pharmacogenomic Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the last subject’s last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months3
    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: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 18
    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.
    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 Decision2012-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-05-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-09-14
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