A Study of Belimumab in Idiopathic Membranous Glomerulonephropathy
Condition: Glomerulonephritis, Membranous
MeSH terms: Glomerulonephritis; Glomerulonephritis, Membranous
Intervention: belimumab
Intervention description: 10mg/kg administered intravenously
Intervention MeSH terms: Belimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: IMGN; anti-PLA2R antibodies; pharmacokinetics; belimumab; Benlysta; Idiopathic Membranous Glomerulonephropathy; safety; GSK1550188; Lymphostat-B; membrane attack complex

Summary:

      This is a phase II, open label, experimental medicine study to evaluate the efficacy, safety
      and mechanism of action of belimumab in subjects with antiphospholipase A2 receptor (PLA2R)
      autoantibody positive idiopathic membranous glomerulonephropathy (IMGN), and to profile the
      relationship between biomarkers, autoantibody status and clinical response. 10 milligrams per
      kilogram (mg/kg) belimumab intravenous (IV) will be administered at weeks 0, 2, and then
      every 4 weeks, over a 24-week treatment period in subjects with anti-PLA2R antibody positive
      IMGN followed by a further long term treatment period until subjects reach remission of
      proteinuria, up to a maximum of 2 years total treatment. All subjects will receive background
      supportive therapy throughout the study. The dosing frequency will be adjusted to every 2
      weeks if the subject's proteinuria as assessed by urinary protein creatinine ratio (PCR) is
      greater than 1000 milligrams per millimole (mg/mmol) [greater than 10 grams(g)/24 hours (h)],
      to compensate for loss of belimumab in the urine. Effects on mechanistic markers will be
      measured by the level of proteinuria, levels of anti-PLA2R antibodies, and various other
      measures of kidney function. These will be compared to historical data. The pharmacokinetics
      of belimumab will be measured to confirm dosing in heavily proteinuric subjects.
      Pharmacodynamic (PD) markers, biomarkers and Quality of Life(QoL) in IMGN subjects will also
      be investigated. Safety will be assessed by adverse events (AE), clinical laboratory
      evaluations, and vital signs.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age & Gender: Male or female between 18 and 75 years of age inclusive, at the time of
             signing the informed consent.

          -  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).

          -  Autoantibody: Have positive anti-PLA2R autoantibody test results at screening.

          -  Proteinuria: Have clinically active disease (nephrotic range proteinuria) for at least
             3 months prior to screening and no improvement (less than 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 greater than 400mg/mmol by PCR (or
             greater than 4.0g per 24h) 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.

          -  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: 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) greater than 40
             Milli-International Units per millilitre(MlU/mL) and estradiol less than 40 picograms
             per milliliter (less than 147 picomoles per liter) 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 the protocol 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. Child-bearing potential and agrees to use
        one of the contraception methods listed in the protocol for an appropriate period of time
        (as determined by the product label or investigator) prior to the start of dosing to
        sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to
        use contraception until 16 weeks after the last dose

        Exclusion Criteria:

          -  Non-Idiopathic membranous glomerulonephropathy (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.

          -  Severely reduced or deteriorating kidney function: An eGFR at screening < 40
             millilitres (mL) /minute (min) /1.73 meter (m)^2 (as determined by 4 variable version
             Modification of Diet in Renal Disease equation) or kidney function not stable (as
             defined by > 15% decrease in eGFR in 3 months before screening, unless due to
             medication change).

          -  Blood Pressure: Uncontrolled hypertension defined as blood pressure (BP) greater than
             150/90 millimeters of mercury (mm Hg) (treatment target greater than and equal to
             140/80) as assessed by either : 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 greater than 50% of measurements being greater than 150/90 or average
             daytime blood pressure on a 24 hour ambulatory blood pressure monitor.

          -  Prior Therapy: Have received treatment with the following therapies at the times
             specified prior to Day 0: Therapy - B-cell targeted therapy except rituximab (e.g.,
             other anti- CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], B
             lymphocyte stimulator-receptor fusion protein [BR3], transmembrane activator and
             calcium modulator and cyclophylin ligand interactor Fc, or belimumab), Time period:
             anytime; Therapy: Rituximab (Subjects with rituximab treatment between 1 and 2 years
             prior to Day 0 are eligible if there is documented evidence of B-cell repopulation to
             >50% of pre-treatment levels.), Period: 2 years; Therapy: Abatacept and any other
             biologic investigational agent other than B cell targeted therapy (i.e. not approved
             for sale in the country in which it is being used), Time Period: 364 days; Therapy:
             Cyclophosphamide or chlorambucil 3 or more courses of systemic corticosteroids for
             concomitant conditions (e.g., asthma, atopic dermatitis). (Topical or inhaled steroids
             are permitted.), Time Period: 180 days; Therapy: Anti-tumour necrosis factor (TNF) or
             anti-IL-6 therapy (e.g. adalimumab, etanercept, infliximab, tocilizumab).
             Interleukin-1 receptor antagonists (e.g. anakinra). Other
             immunosuppressive/immunomodulatory agents (e.g azathioprine, 6-mercaptopurine,
             mycophenolate mofetil (PO)/ mycophenolate mofetil hydrochloride (IV), mycophenolate
             sodium (PO), methotrexate, tacrolimus, sirolimus, thalidomide, leflunomide,
             mizoribine, ciclosporin). Intravenous immunoglobulin (IVIG). Plasmapheresis,
             leukapheresis, Time Period: 90 days; Therapy: A non-biologic investigational agent
             (i.e. not approved for sale in the country in which it is being used). Intravenous
             corticosteroid, Adrenocorticotropic hormone (ACTH). Adenocorticotropic hormone (ACTH),
             aliskiren A change in dose of >50% for angiotensin pathway antihypertensive (e.g., ACE
             inhibitor, angiotensin receptor blocker), Time Period: 60 days; Therapy: A live
             vaccine. Greater than 30 milligrams per day (mg/day) corticosteroid, Time Period: 30
             days; Therapy: Greater than 10mg/day corticosteroid. A change in dose of a
             corticosteroid. Note: Changes to inhaled steroids and new topical immunosuppressive
             agents (e.g., eye drops, topical creams) are allowed, Time Period: 14 days;

          -  Transplantation: Have a history of a major organ transplant (e.g., heart, lung,
             kidney, liver) or hematopoietic stem cell/marrow transplant.

          -  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.

          -  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 intramuscular) antibiotics (anti-bacterials,
             anti-virals, anti-fungals, or anti-parasitic agents) within 60 days prior to Day 0.

          -  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).

          -  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.

          -  Positive serology: Have a historically positive human immunodeficiency virus (HIV)
             test or test positive at screening for HIV. Serologic evidence of Hepatitis B (HB)
             infection based on the results of testing for hepatitis B surface (antigen) (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
             Recombinant Immunoblot Assay (RIBA) immunoblot assay if available. 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.

          -  Liver function tests: Aspartate aminotransferase (AST) and alanine aminotransferase
             (ALT) greater than and equal to 2x upper limit of normal (ULN); alkaline phosphatase
             and bilirubin greater than 1.5xULN (isolated bilirubin greater than 1.5ULN is
             acceptable if bilirubin is fractionated and direct bilirubin < 35%).

          -  Immunodeficiency: Have an IgA deficiency [immunoglobulin (Ig)A level < 10 milligrams
             per deciliter (mg/dL)] or have IgG level < 250 mg/dL and have previously received any
             non-glucocorticoid immunosuppression during the previous 6 months.

          -  Laboratory test abnormalities: Have clinically significant abnormalities in screening
             laboratory assessments (not related to the disease), as judged by investigator.

          -  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.

          -  Substance abuse: Evidence of current drug or alcohol abuse or dependence.

          -  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.