Clinical Trial: Efficacy and Safety Study of Intravenous Belimumab Versus Placebo in Subjects With Idiopathic Membranous Nephropathy

Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Interventional

Official Title: BEL114674: A 2 Year Study of Efficacy and Safety of Intravenous Belimumab Versus Placebo in Subjects With Idiopathic Membranous Nephropathy

Brief Summary: 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 Subjects who are withdrawn from study treatment at any time during the study, eg for rescue therapy, will participate in follow-up visits every 12 weeks up to week 104.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 i

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome: Incidence of remission (complete [CR] or partial [PR]) at Week (WK) 104 [ Time Frame: 104 weeks ]

Original Primary Outcome: Incidence of remission (complete or partial) at Week 104 [ Time Frame: 104 weeks ]

Current Secondary Outcome:

• Incidence of progression of IMN or failure to respond [ Time Frame: Upto Week 104 ]
  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 to complete remission [ Time Frame: Up to 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 to partial remission [ Time Frame: Up to Week 104 ]
  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)
• Change from baseline in proteinuria levels at Week 104 [ Time Frame: Week 0 and Week 104 ]
  Mean uPCR from 2 consecutive 24 hr urine collections (pre and post dose or pre and post visit)
• Change from baseline in serum albumin levels at Week 104 [ Time Frame: Week 0 and 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.
• Change from baseline in eGFR at Week 104 [ Time Frame: Week 0 and 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 to first thromboembolic event [ Time Frame: Up to Week 104 ]
  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.
• Change from baseline in KDQOL-36 score at Week 104 [ Time Frame: Week 0 and 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.
• Incidence of partial remission at Week 104 [ Time Frame: 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)
• Incidence of complete remission at Week 104 [ Time Frame: 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)
• Duration of remission (complete or partial) [ Time Frame: Up to Week 104 ]
  The duration of remission (complete or partial) will be assessed to evaluate length of effect of belimumab.
• Risk-benefit calculation based on key efficacy and safety endpoints using a clinical utility index [ Time Frame: Up to Week 104 ]
  A clinical utility index will be developed to objectively measure benefit over standard practice in a quantitative manner.
• Incidence of serious adverse events (SAEs) [ Time Frame: Up to Week 104 ]
  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'
• Incidence of adverse events (AEs) of special interest [ Time Frame: Up to Week 104 ]
  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
• Safety assessed by evaluation of Adverse events, clinical laboratory assessments, vital signs and immunogenicity [ Time Frame: Up to 116 Weeks ]
• Incidence of progression of IMN or failure to respond [ Time Frame: Upto Week 104 ]
  Defined as: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.Thromboembolism. 4.Death
• Time to complete remission [ Time Frame: Up to 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 to partial remission [ Time Frame: Up to Week 104 ]
  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)
• Change from baseline in proteinuria levels at Week 104 [ Time Frame: Week 0 and Week 104 ]
  Mean uPCR from 2 consecutive 24 hr urine collections (pre and post dose or pre and post visit)
• Change from baseline in serum albumin levels at Week 104 [ Time Frame: Week 0 and Week 104 ]
  Albumin levels will be measured to determine hypoalbuminaemia.
• Change from baseline in eGFR at Week 104 [ Time Frame: Week 0 and Week 104 ]
  For the week 104 assessment, eGFR will be analyzed at both weeks 100 and 104.
• Time to first thromboembolic event [ Time Frame: Up to Week 104 ]
  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.
• Change from baseline in KDQOL-36 score at Week 104 [ Time Frame: Week 0 and 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.
• Incidence of partial remission at Week 104 [ Time Frame: 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)
• Incidence of complete remission at Week 104 [ Time Frame: 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)
• Duration of remission (complete or partial) [ Time Frame: Up to Week 104 ]
  The duration of remission (complete or partial) will be assessed to evaluate length of effect of belimumab.
• Risk-benefit calculation based on key efficacy and safety endpoints using a clinical utility index [ Time Frame: Up to Week 104 ]
  A clinical utility index will be developed to objectively measure benefit over standard practice in a quantitative manner.
• Incidence of serious adverse events (SAEs) [ Time Frame: Up to Week 104 ]
  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'
• Incidence of serious infections [ Time Frame: Up to Week 104 ]
  Serious infections will be assessed as those SAEs which are classified as Infections in MedDRA.
• Safety assessed by evaluation of Adverse events, clinical laboratory assessments, vital signs and immunogenicity [ Time Frame: Up to 116 Weeks ]
  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

Dates:
Date Received: January 4, 2013
Date Started: April 2013
Date Completion: January 2014
Last Updated: March 21, 2017
Last Verified: March 2017