NCT01610492 - A Study of Belimumab in Idiopathic Membranous Glomerulonephropathy | Crick

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

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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.

Outcomes

Primary Outcomes

Change From Baseline in Proteinuria Levels at Week 28

Proteinuria based on urinary protein creatinine ratio (PCR) was measured from 2 consecutive 24 hour (h) urine collection pre and post dosing at Baseline and Week 28 and the mean PCR was determined at each time point. Baseline is defined as the mean of the pre and post dosing Day 0 values. The ratio is defined as the Week 28 value divided by the Baseline value. Ratio to Baseline: Estimated value = 0.76, 2-sided 95% confidence interval (CI)=0.57 to 1.01. The geometric mean method was used to calculate the CI. The analysis was performed on Intent-to-treat (ITT) Population which comprised of all eligible participants who received at least one dose of investigational drug. Only those participants available at the indicated time point (Week 28) were analyzed.

Time frame: Baseline and Week 28

Change From Baseline in Anti-phospholipase A2 Receptor (PLA2R) Autoantibody Titers at Week 28

PLA2R autoantibody titers in serum were analyzed at Baseline and Week 28 by means of a validated anti- PLA2R enzyme linked immunosorbent assay (ELISA) from EuroImmun. Baseline is defined as the Day 0 value and change from Baseline was calculated as ratio to Baseline by dividing the Week 28 values with the Baseline values. Ratio to Baseline: Estimated value = 0.27, 2-sided 95% CI=0.12 to 0.58. The geometric mean method was used to calculate the CI.

Time frame: Baseline and Week 28

Secondary Outcomes

Proteinuria Levels at the Indicated Time Points

Proteinuria based on urinary protein creatinine ratio (PCR) measured from 2 consecutive 24h urine collections at Baseline and Week 28, from a pre-intervention spot urine sample and 24 hour urine collection after visit at Weeks 12, 52, 76 and 104, and from a spot urine sample at week 128. Mean PCR was calculated at each time point where there were 2 samples. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Baseline and Week 12, 28, 52, 76, 104 and 128/6 month follow-up

Change From Baseline in Proteinuria Levels at the Indicated Time Points

Proteinuria based on urinary protein creatinine ratio (PCR) measured from 2 consecutive 24h urine collections at Baseline and Week 28, from a pre-intervention spot urine sample and 24 hour urine collection after visit at Weeks 12, 52, 76 and 104, and from a spot urine sample at week 128. Mean PCR was calculated at each time point where there were 2 samples. Baseline is defined as Day 0 value and change from Baseline was calculated as ratio of post-Baseline value divided by the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Baseline and Week 12, 28, 52, 76, 104 and Week 128/6 month follow up

Anti-phospholipase A2 Receptor (PLA2R) Autoantibody Levels at Indicated Time Points

Anti-PLA2R autoantibody titers in serum were analyzed by means of a validated anti-PLA2R enzyme linked immunosorbent assay (ELISA) assay from Euroimmun. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Baseline and Week 12, 28, 52, 76, 104 and 128/6 month follow-up

Change From Baseline in Anti-PLA2R Autoantibody Titers at the Indicated Time Points

Anti-PLA2R autoantibody titers in serum were analyzed by means of a validated anti- PLA2R enzyme linked immunosorbent assay (ELISA) from Euroimmun. Baseline is defined as the Day 0 value and change from Baseline was calculated as ratio of post-Baseline value divided by the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Baseline and Weeks 12, 28, 52, 76, 104 and 128.

Number of Participants With Complete or Partial Remission

Complete remission is defined as PCR \<30 mg/mmol (proteinuria \<0.3grams \[g\]/24 h) with no worsening in renal function (estimated glomerular filtration rate \[eGFR\] reduction from Baseline \<15 percent). Partial remission is defined as PCR \<350 mg/mmol (proteinuria \<3.5 g/24 h) but \>= 30 mg/mmol (proteinuria \>= 0.3g/24h) and decrease of \>50 percent from Day 0 Baseline, together with no consistent worsening in renal function (eGFR reduction from Baseline \<15percent). Only those participants available at the specified time points were analyzed (represented by n=X in category titles).

Time frame: Baseline and Weeks 12, 28, 52, 76, 104 and 128

Time to Complete or Partial Remission

Time to complete or partial remission was estimated using the Kaplan-Meier method. Complete remission is defined as PCR \<30 mg/mmol (proteinuria \<0.3g/24 h) with no worsening in renal function (eGFR reduction from Baseline \<15 percent ). Partial remission is defined as PCR \<350 mg/mmol (proteinuria \<3.5 g/24 h) but \>= 30 mg/mmol (proteinuria \>= 0.3g/24h) and decrease of \>50 percent from Day 0 Baseline, together with no consistent worsening in renal function (eGFR reduction from Baseline \<15 percent). Only 1 participant reached complete remission. Hence, statistical analysis for complete remission was not performed.

Time frame: Baseline and up to Week 128/6 month follow up

Duration of Complete or Partial Remission

Complete remission is defined as PCR \<30 mg/mmol (proteinuria \<0.3g/24 h) with no worsening in renal function (eGFR reduction from Baseline \<15percent). Partial remission is defined as PCR \<350 mg/mmol (proteinuria \<3.5 g/24 h) but \>= 30 mg/mmol (proteinuria \>= 0.3g/24h) and decrease of \>50% from Day 0 Baseline, together with no consistent worsening in renal function (eGFR reduction from Baseline \<15percent). Only those participants available at the specified time points were analyzed (represented by n=X in category titles). NA indicates that data was not available as only 1 participant reached complete remission. Hence, standard deviation for complete remission was not calculated.

Time frame: Baseline and up to Week 128/6 month follow up

Number of Participants With PLA2R Autoantibody Remission

Incidence of anti-PLA2R autoantibody remission were evaluated by full response and partial response. Full response is defined as antibody undetectable, partial response is defined as reduction in titers by 50 percent. For anti PLA2R autoantibody data, log transformation was applied before the formal analyses. Anti-PLA2R autoantibody blood samples were evaluated at Week 12, 28, 52, 76, 104 and 128/6 week post last-dose. Only those participants available at the specified time points were analyzed (represented by n=X in category titles).

Time frame: Baseline and Weeks 12, 28, 52, 76, 104 and 128

Time to Anti-PLA2R Autoantibody Remission

Time to anti-PLA2R autoantibody remission was estimated using Kaplan-Meier method for full response and partial response full response with antibody undetectable and partial response with reduction in titers by 50 percent.

Time frame: Baseline and up to Week 128/6 month follow up

Number of Participants With Anti-PLA2R Autoantibody Relapse

Incidence of anti-PLA2R autoantibody relapse defined as antibody detectable after previously undetectable. Anti-PLA2R autoantibody blood samples were evaluated at Week 12, 28, 52, 76, 104/4 week post last dose, Only those participants available at the specified time points were analyzed (represented by n=X in category titles).

Time frame: Baseline and up to Week 128/6 month follow up

eGFR Levels at the Indicated Time Points

eGFR was assessed from levels of creatinine using the 4 variable version of the modification of diet in renal disease (MDRD) equation as recommended by National Kidney Foundation-Chronic Kidney Disease (NKF-CKD) guidelines. Baseline for eGFR is defined as the mean of the screening and Day 0 values. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up.

Change From Baseline in eGFR Levels at the Indicated Time Points

eGFR was assessed from levels of creatinine using the 4 variable version of the modification of diet in renal disease (MDRD) equation as recommended by national kidney foundation-chronic kidney disease (NKF-CKD) guidelines. Baseline for eGFR is defined as the mean of the Screening and Day 0 values and change from Baseline was calculated as ratio of post-Baseline value divided by the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Baseline and up to Week 128/6 month follow up

Serum Creatinine Levels at the Indicated Time Points

Serum creatinine was assessed as a clinical chemistry laboratory parameter from Baseline up to Week 128/6 month follow-up visit. Baseline for serum creatinine is defined as the mean of the Screening and Day 0 values. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).