Glomerulonephritis, MembranousPhase 2NCT01762852
Efficacy and Safety Study of Intravenous Belimumab Versus Placebo in Subjects With Idiopathic Membranous Nephropathy
A Phase 2 study testing Belimumab 10 mg in people with Glomerulonephritis, Membranous, run by GlaxoSmithKline at 30 sites in 10 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Glomerulonephritis, Membranous
- What is being tested?
- Belimumab 10 mg
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 30 sitesin 10 countries
- Study dates
- Apr 2013to Jan 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 IMN, as verified by biopsy (either by light microscope with immuno-fluorescence, or by electron microscope) in the last 3 years (biopsy results [and slides where possible] should be available for independent evaluation). For patients with relapsed disease, a biopsy should be available within the preceding 7 years.
- 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 must include maximal tolerated doses of ACE inhibitor or ARB unless contraindicated, and may include statins, diuretics, dietary salt restriction). During screening proteinuria must be >400 mg/mmol by uPCR (or >4.0 g per 24 hrs) as measured from a 24 hrs urine collection and/or spot urine sample (early morning where possible) on 2 occasions at least 7 days apart.
- Proteinuria in patients with relapsed disease: Patients who previously achieved proteinuria <2 g per 24h for at least 6 months and have subsequently relapsed with proteinuria levels as documented above, may be eligible providing recurrence has been within the previous 3 years and patient is known to be anti-PLA2R positive.
- Female Subject is eligible to participate if she is not pregnant or nursing; is non-childbearing potential. Females of child-bearing potential must agree to use one of the approved contraception methods 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.
- French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
- Inclusion Criteria for Long Term Follow-up: Subjects who have signed informed consent for the Long Term Follow-up and have completed 2 years study treatment and the 16 week follow-up visit, or who have withdrawn early from study treatment but completed the Week 104 Withdrawn visit.
Who cannot join
- Non-Idiopathic MN or other condition affecting the kidney: If the diagnosis of MN is secondary to other conditions, or the subject has renal impairment from a condition that is not MN. Causes of secondary MN 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-versus-host-disease, Guillain-Barre syndrome); or Infectious or parasitic diseases (Hepatitis B; Hepatitis C, syphilis, filariasis, hydatid disease, schistosomiasis, malaria, leprosy); or Drugs and toxins (Gold, penicillamine, non-steroidal anti-inflammatory agents, mercury, captopril, formaldehyde, hydrocarbons, bucillamine); or Miscellaneous(Tumors excluded with reasonable diligence, renal transplantation, sarcoidosis, sickle cell disease, Kimura disease, angiofollicular lymph node hyperplasia).
- Anti-PLA2R autoantibody: Patients known to be negative for anti-PLA2R autoantibody.
- Severely reduced or deteriorating kidney function: An eGFR at screening <40 mL/min/1.73m^2 (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).
- Blood Pressure: Uncontrolled hypertension defined as blood pressure (BP) >150/90 mmHg (treatment target <=140/80)
- 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], BLyS-receptor fusion protein [BR3], TACI 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). 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 30mg/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.
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- 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 such as currently on any suppressive therapy for a chronic infection such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria); or hospitalisation for treatment of infection within 60 days prior to Day 0; or use of parenteral (IV or IM) 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 IMN (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 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. Positive test for Hepatitis C antibody confirmed on the same sample with a Hepatitis C RIBA immunoblot assay if available.
- Liver function tests: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >=2x upper limit of normal (ULN); alkaline phosphatase and bilirubin >1.5xULN (isolated bilirubin >1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- Immunodeficiency: Have an IgA deficiency (IgA level < 10 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.
- Suicidality: Subjects who have evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicide ideation of type 4 or 5 on the Columbia Suicide-Severity Rating Scale (C-SSRS) in the last 2 months or who in the investigator's judgement, pose a significant suicide risk.
- 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.
Trial locations and contacts
30 sites in 10 countries.
30 sites in 10 countries
Germany7 sites
GSK Investigational Site
Aachen, North Rhine-Westphalia, 52074
GSK Investigational Site
Berlin, State of Berlin, 10117
GSK Investigational Site
Mannheim, Baden-Wurttemberg, 68167
GSK Investigational Site
Munich, Bavaria, 80336
GSK Investigational Site
Solingen, North Rhine-Westphalia, 42653
GSK Investigational Site
Ulm, Baden-Wurttemberg, 89081
GSK Investigational Site
Würzburg, Bavaria, 97080
United Kingdom6 sites
GSK Investigational Site
Cardiff, CF14 4XW
GSK Investigational Site
Gloucester, GL1 3NN
GSK Investigational Site
Leicester, LE5 4PW
GSK Investigational Site
London, NW3 2QG
GSK Investigational Site
London, SE5 9RS
GSK Investigational Site
Reading, RG1 5AN
France4 sites
GSK Investigational Site
Amiens, 80054
GSK Investigational Site
Créteil, 94010
GSK Investigational Site
Paris, 75743
GSK Investigational Site
Toulouse, 31059
Spain3 sites
GSK Investigational Site
L'Hospitalet de Llobregat, 08907
GSK Investigational Site
Madrid, 28041
GSK Investigational Site
Valencia, 46017
United States2 sites
GSK Investigational Site
Chapel Hill, North Carolina, 27599
GSK Investigational Site
St Louis, Missouri, 63110
Canada2 sites
GSK Investigational Site
Edmonton, Alberta, T6G 2B7
GSK Investigational Site
London, Ontario, N6A 5A5
Italy2 sites
GSK Investigational Site
Lecco, Lombardy, 23900
GSK Investigational Site
Lido Di Camaiore (LU), Tuscany, 55041
Netherlands2 sites
GSK Investigational Site
Amsterdam, 1081 HV
GSK Investigational Site
Nijmegen, 6525 GA
About this study
Official title: BEL114674: A 2 Year Study of Efficacy and Safety of Intravenous Belimumab Versus Placebo in Subjects With Idiopathic Membranous Nephropathy
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.
- Conditions
- Glomerulonephritis, Membranous
- Being tested
- Belimumab 10 mg, Placebo
- Keywords
- Benlysta, efficacy, proteinuria, Idiopathic membranous nephropathy, GSK1550188, anti-phospholipase A2 receptor antibodies, safety, placebo, BLyS, belimumab, Lymphostat-B, membrane attack complex
- Medical subject headings
- Glomerulonephritis, Membranous, Proteinuria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Belimumab 10 mgDrug
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
PlaceboDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Belimumab Arm | Experimental | Subjects will receive belimumab 10 mg/kg intravenous infusion [will last for 1 hour (hr)] on Day 0, Week 2, Week 4, then every 4 weeks for up to 100 weeks with frequency adjusted for subjects with >1000 mg/mmol uPCR (>10 g/24 hrs). All subjects will receive background supportive therapy throughout the study. Receives: Drug: Belimumab 10 mg |
| Placebo Arm | Placebo comparator | Intravenous infusion (will last for 1 hr) on Day 0, Week 2, Week 4, then every 4 weeks for up to 100 weeks with frequency adjusted for subjects with >1000 mg/mmol uPCR (>10 g/24 hrs). All subjects will receive background supportive therapy throughout the study. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 104 weeks
Secondary outcomes (16)
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
Measured: 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)
Measured: 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)
Measured: 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)
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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)
Measured: 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)
Measured: 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.
Measured: 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.
Measured: 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'
Measured: 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
Measured: 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
Measured: 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.
Measured: From start of treatment up to 7 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jan 2013 (estimated)
- Study startApr 2013
- Primary completionJan 2014 (estimated)
- Study completionJan 2014 (estimated)
Why it stopped: Withdrawn due to difficulties in to recruiting due to competing studies, changing treatment practices, unavailability of eligible study population
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Glomerulonephritis, MembranousStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01762852
- Sponsor's protocol ID
- 114674
- Status last verified
- Mar 2017
- First submitted
- 4 Jan 2013
- Last updated
- 22 Mar 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD004293. doi: 10.1002/14651858.CD004293.pub4.
PubMed 34778952
Study at a glance
From the registry record, last updated by the sponsor on 22 Mar 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- BEL114674: A 2 Year Study of Efficacy and Safety of Intravenous Belimumab Versus Placebo in Subjects With Idiopathic Membranous Nephropathy
- ClinicalTrials.gov ID
- NCT01762852
- Acronym / sponsor ID
- 114674
- Conditions
- Glomerulonephritis, Membranous
- Keywords
- Benlysta, efficacy, proteinuria, Idiopathic membranous nephropathy, GSK1550188, anti-phospholipase A2 receptor antibodies, safety, placebo
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Withdrawn due to difficulties in to recruiting due to competing studies, changing treatment practices, unavailability of eligible study population
- Enrolment
- 0 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- Apr 2013
- Primary completion
- Jan 2014 (estimated)
- Study completion
- Jan 2014 (estimated)
- First posted
- 8 Jan 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Belimumab Arm | Experimental | Drug: Belimumab 10 mgSubjects will receive belimumab 10 mg/kg intravenous infusion [will last for 1 hour (hr)] on Day 0, Week 2, Week 4, then every 4 weeks for up to 100 weeks with frequency adjusted for subjects with >1000 mg/mmol uPCR (>10 g/24 hrs). All subjects will receive background supportive therapy throughout the study. |
| Placebo Arm | Placebo comparator | Drug: PlaceboIntravenous infusion (will last for 1 hr) on Day 0, Week 2, Week 4, then every 4 weeks for up to 100 weeks with frequency adjusted for subjects with >1000 mg/mmol uPCR (>10 g/24 hrs). All subjects will receive background supportive therapy throughout the study. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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 IMN, as verified by biopsy (either by light microscope with immuno-fluorescence, or by electron microscope) in the last 3 years (biopsy results [and slides where possible] should be available for independent evaluation). For patients with relapsed disease, a biopsy should be available within the preceding 7 years.
- 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 must include maximal tolerated doses of ACE inhibitor or ARB unless contraindicated, and may include statins, diuretics, dietary salt restriction). During screening proteinuria must be >400 mg/mmol by uPCR (or >4.0 g per 24 hrs) as measured from a 24 hrs urine collection and/or spot urine sample (early morning where possible) on 2 occasions at least 7 days apart.
- Proteinuria in patients with relapsed disease: Patients who previously achieved proteinuria <2 g per 24h for at least 6 months and have subsequently relapsed with proteinuria levels as documented above, may be eligible providing recurrence has been within the previous 3 years and patient is known to be anti-PLA2R positive.
- Female Subject is eligible to participate if she is not pregnant or nursing; is non-childbearing potential. Females of child-bearing potential must agree to use one of the approved contraception methods 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.
Key exclusion criteria (18 listed)
- Non-Idiopathic MN or other condition affecting the kidney: If the diagnosis of MN is secondary to other conditions, or the subject has renal impairment from a condition that is not MN. Causes of secondary MN 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-versus-host-disease, Guillain-Barre syndrome); or Infectious or parasitic diseases (Hepatitis B; Hepatitis C, syphilis, filariasis, hydatid disease, schistosomiasis, malaria, leprosy); or Drugs and toxins (Gold, penicillamine, non-steroidal anti-inflammatory agents, mercury, captopril, formaldehyde, hydrocarbons, bucillamine); or Miscellaneous(Tumors excluded with reasonable diligence, renal transplantation, sarcoidosis, sickle cell disease, Kimura disease, angiofollicular lymph node hyperplasia).
- Anti-PLA2R autoantibody: Patients known to be negative for anti-PLA2R autoantibody.
- Severely reduced or deteriorating kidney function: An eGFR at screening <40 mL/min/1.73m^2 (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).
- Blood Pressure: Uncontrolled hypertension defined as blood pressure (BP) >150/90 mmHg (treatment target <=140/80)
- 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], BLyS-receptor fusion protein [BR3], TACI 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). 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 30mg/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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Belimumab 10 mgBelimumab 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 | Drug | Belimumab Arm |
| PlaceboNormal 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 | Drug | Placebo Arm |
Primary outcome
Incidence of remission (complete [CR] or partial [PR]) at Week (WK) 104
Time frame: 104 weeks
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
16 secondary outcomes
Incidence of progression of IMN or failure to respond
Time frame: Upto Week 104
Time to complete remission
Time frame: Up to Week 104
Time to partial remission
Time frame: Up to Week 104
Change from baseline in proteinuria levels at Week 104
Time frame: Week 0 and Week 104
Change from baseline in serum albumin levels at Week 104
Time frame: Week 0 and Week 104
Change from baseline in eGFR at Week 104
Time frame: Week 0 and Week 104
Time to first thromboembolic event
Time frame: Up to Week 104
Change from baseline in KDQOL-36 score at Week 104
Time frame: Week 0 and Week 104
Incidence of partial remission at Week 104
Time frame: Week 104
Incidence of complete remission at Week 104
Time frame: Week 104
Duration of remission (complete or partial)
Time frame: Up to Week 104
Risk-benefit calculation based on key efficacy and safety endpoints using a clinical utility index
Time frame: Up to Week 104
Incidence of serious adverse events (SAEs)
Time frame: Up to Week 104
Incidence of adverse events (AEs) of special interest
Time frame: Up to Week 104
Safety assessed by evaluation of Adverse events, clinical laboratory assessments, vital signs and immunogenicity
Time frame: Up to 116 Weeks
Survival without renal progression
Time frame: From start of treatment up to 7 years
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Mar 2017.
- Derived from this study: PubMed 34778952von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD004293. doi: 10.1002/14651858.CD004293.pub4.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
30 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Belimumab 10 mg in people with Glomerulonephritis, Membranous, run by GlaxoSmithKline at 30 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 22 Mar 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 30 sites in Germany, United Kingdom, France, Spain, United States and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of remission (complete [CR] or partial [PR]) at Week (WK) 104 (time frame: 104 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01762852, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Mar 2017.