The main clinical study will be a randomized, double-blind, placebo-controlled, long term study involving a 100 week treatment period. The purpose of this study is to test for superiority of treatment with belimumab 10 mg/kg plus supportive therapy compared to placebo plus supportive therapy in idiopathic membranous nephropathy (IMN). The purpose of this study is also to investigate the effect of initiating earlier treatment with belimumab compared to delayed treatment with current immunosuppressive treatment regimens. The study will also determine the pharmacokinetic (PK) profile of belimumab and further explore the mechanism of action of Belimumab as well as effects on quality of life. All subjects (on either active treatment or placebo) will receive background supportive therapy throughout the main clinical study, which includes angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs) unless contraindicated and may include statins, diuretics, dietary salt restriction but excludes immunosuppressants (except low dose corticosteroids). Screening will be done within 5 to 2 weeks before the first scheduled dose of study treatment. A total of 94 evaluable subjects will be randomized in a 1:1 ratio such that 47 subjects receive intravenous belimumab 10 mg/kg and 47 receive intravenous placebo. Subjects will be dosed on Days 0, 14, 28 and then every 4 weeks through to, and including, Week 100, resulting in a total of 27 doses (giving 104 weeks of drug exposure). 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 1000mg/mmol (greater than 10 g/24 h), to compensate for loss of belimumab in the urine. Subjects who are withdrawn from study treatment at any time during the study, eg for rescue therapy, will participate in follow-up visits every 12 weeks up to week 104. A subject will be regarded as having completed the main clinical study if they complete all phases of the main clinical study (screening, treatment period, 4 week and 16 week post last dose short term safety follow-up). Subjects who complete the main clinical study will therefore participate in the main clinical study for approximately 28 months. After the main clinical study, there will be a 5 year (long term) follow-up phase to assess long term outcomes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Belimumab is Lyophilised powder for reconstitution in 4.8 mL sterile water for injection (SWFI) and diluted in normal saline (250 mL). 400 mg per vial plus excipients (citric acid/sodium citrate/sucrose/polysorbate). Belimumab 10 mg/kg intravenous infusion (will last for 1 hr) on Day 0, Week 2, Week 4, then every 4 weeks for up to 100 weeks
Normal saline solution (sodium chloride 154 mmol/L). Intravenous infusion (will last for 1 hr) on Day 0, Week 2, Week 4, then every 4 weeks for up to 100 weeks
GSK Investigational Site
St Louis, Missouri, United States
GSK Investigational Site
Chapel Hill, North Carolina, United States
GSK Investigational Site
New Lambton, New South Wales, Australia
GSK Investigational Site
Edmonton, Alberta, Canada
GSK Investigational Site
London, Ontario, Canada
Incidence of remission (complete [CR] or partial [PR]) at Week (WK) 104
CR: urine protein to creatinine ratio (uPCR) \<30 mg/mmol (proteinuria \<0.3 g/24 hr) with no worsening of renal function (\<15% estimated glomerular filtration rate \[eGFR\] reduction from baseline \[BL\]).PR: uPCR \<350 mg/mmol (proteinuria \<3.5g/24 hrs) but \>=30 mg/mmol (proteinuria \>=0.3g/24 hrs) AND a decrease of \>50% from BL based on uPCR, with no worsening of renal function. uPCR: Mean from 2 consecutive 24 hr urine collections (pre and post dose or pre and post visit). eGFR: BL will be defined as mean of screening and Day 0 values. For WK 104 assessment, will be analysed at both WK 100 and 104
Time frame: 104 weeks
Incidence of progression of IMN or failure to respond
Defined by at least one of the following:1.Persistent symptomatic nephrotic syndrome potentially necessitating rescue therapy 2.End Stage Renal Disease (eGFR \<15 mL/min/1.73m\^2,dialysis or transplantation).3.Clinical thromboembolic events. 4.Death
Time frame: Upto Week 104
Time to complete remission
Complete Remission (CR) is defined as uPCR \<30 mg/mmol (proteinuria \<0.3 g/24 hrs) with no worsening of renal function (less than 15% reduction in estimated eGFR from baseline)
Time frame: Up to Week 104
Time to partial remission
Partial Remission (PR) is defined as uPCR \<350 mg/mmol (proteinuria \<3.5 g/24 hrs) but \>=30 mg/mmol (proteinuria \>=0.3g/24 hrs) 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)
Time frame: Up to Week 104
Change from baseline in proteinuria levels at Week 104
Mean uPCR from 2 consecutive 24 hr urine collections (pre and post dose or pre and post visit)
Time frame: Week 0 and Week 104
Change from baseline in serum albumin levels at Week 104
Albumin levels will be measured to determine hypoalbuminaemia. Baseline will be defined as mean of screening and Day 0 values. For the week 104 assessment, albumin will be analyzed at both weeks 100 and 104.
Time frame: Week 0 and Week 104
Change from baseline in eGFR at Week 104
Baseline will be defined as mean of screening and Day 0 values. For the week 104 assessment, eGFR will be analyzed at both weeks 100 and 104.
Time frame: Week 0 and Week 104
Time to first thromboembolic event
Thromboembolism is a formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel. Thromboembolic event is a complication of nephrotic syndrome.
Time frame: Up to Week 104
Change from baseline in KDQOL-36 score at Week 104
The Kidney Disease Quality of Life (KDQOL- 36) consists of the SF-12 Physical Health and Mental Health Composite scores along with the Burden of Kidney Disease and Effects of Kidney Disease subscales.
Time frame: Week 0 and Week 104
Incidence of partial remission at Week 104
Partial Remission (PR) is defined as uPCR \<350 mg/mmol (proteinuria \<3.5g/24 hrs) but \>=30 mg/mmol (proteinuria \>=0.3 g/24 hrs) 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)
Time frame: Week 104
Incidence of complete remission at Week 104
Complete Remission (CR) is defined as uPCR \<30 mg/mmol (proteinuria \<0.3 g/24 hrs) with no worsening of renal function (less than 15% reduction in estimated eGFR from baseline)
Time frame: Week 104
Duration of remission (complete or partial)
The duration of remission (complete or partial) will be assessed to evaluate length of effect of belimumab.
Time frame: Up to Week 104
Risk-benefit calculation based on key efficacy and safety endpoints using a clinical utility index
A clinical utility index will be developed to objectively measure benefit over standard practice in a quantitative manner.
Time frame: Up to Week 104
Incidence of serious adverse events (SAEs)
SAEs are medical occurrences not due to the disease (unless more severe than expected), but which result in death, disability, incapacity, are life threatening, require or prolong hospitalization, are associated with specified liver injury/impaired function and other defined criteria. SAEs beyond Week 104 will be assessed as 'Other endpoints' or 'Long Term Follow-up endpoints'
Time frame: Up to Week 104
Incidence of adverse events (AEs) of special interest
AEs of special interest will include: Serious infusion reactions/hypersensitivity/anaphylaxis, fatal events; serious malignancies; serious infections including herpes zoster; cardiovascular SAEs (fatal and non-fatal events) including arrhythmia, congestive heart failure, cerebrovascular accident, deep vein thrombosis, myocardial infarction/unstable angina, peripheral arterial thromboembolism, revascularization; SAEs suggestive of suicidal or self-harming behavior
Time frame: Up to Week 104
Safety assessed by evaluation of Adverse events, clinical laboratory assessments, vital signs and immunogenicity
Safety and tolerability assessed by evaluation of adverse events (AE), clinical laboratory assessments (clinical chemistry, haematology and urinalysis), vital signs and immunogenicity. Including infusion-related and hypersensitivity reactions, infections and malignancies
Time frame: Up to 116 Weeks
Survival without renal progression
Subjects will be followed annually for 5 years after Week 104 in the main clinical study or until ESRD or death, whichever is earlier for analysis of survival without renal progression. Survival without renal progression will be defined as the time from start of treatment until decrease in eGFR from baseline at entry into the study by greater than 20% OR end stage renal disease (eGFR \<15 mL/min/1.73 m\^2, start of dialysis or renal transplantation) OR death.
Time frame: From start of treatment up to 7 years
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GSK Investigational Site
Prague, Czechia
GSK Investigational Site
Amiens, France
GSK Investigational Site
Créteil, France
GSK Investigational Site
Paris, France
GSK Investigational Site
Toulouse, France
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