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

NCT01762852 | Withdrawn Phase 2 DMC

• 1 other identifier: 114674
• Study Type: interventional
• Target: N/A
• Locations: 10 countries
• Sites: 30

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 Subjects who are withdrawn from study treatment at any time during the study, eg for rescue therapy, will participate in follow-up visits every 12 weeks up to week 104.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

Keywords

Benlysta; efficacy; proteinuria; Idiopathic membranous nephropathy; GSK1550188; anti-phospholipase A2 receptor antibodies; safety; placebo; BLyS; belimumab; Lymphostat-B; membrane attack complex

Outcome Measures

Primary Outcomes (1)

• 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

  104 weeks

Secondary Outcomes (16)

• Incidence of progression of IMN or failure to respond

  Upto Week 104

• Time to complete remission

  Up to Week 104

• Time to partial remission

  Up to Week 104

• Change from baseline in proteinuria levels at Week 104

  Week 0 and Week 104

• Change from baseline in serum albumin levels at Week 104

  Week 0 and Week 104

Study Arms (2)

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.

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.

Drug: Placebo

Interventions

Belimumab 10 mg DRUG

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

Belimumab Arm

Placebo DRUG

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

Placebo Arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (30)

GSK Investigational Site

St Louis, Missouri, 63110, United States

Location

GSK Investigational Site

Chapel Hill, North Carolina, 27599, United States

Location

GSK Investigational Site

New Lambton, New South Wales, 2305, Australia

Location

GSK Investigational Site

Edmonton, Alberta, T6G 2B7, Canada

Location

GSK Investigational Site

London, Ontario, N6A 5A5, Canada

Location

GSK Investigational Site

Prague, 128 08, Czechia

Location

GSK Investigational Site

Amiens, 80054, France

Location

GSK Investigational Site

Créteil, 94010, France

Location

GSK Investigational Site

Paris, 75743, France

Location

GSK Investigational Site

Toulouse, 31059, France

Location

GSK Investigational Site

Mannheim, Baden-Wurttemberg, 68167, Germany

Location

GSK Investigational Site

Ulm, Baden-Wurttemberg, 89081, Germany

Location

GSK Investigational Site

Munich, Bavaria, 80336, Germany

Location

GSK Investigational Site

Würzburg, Bavaria, 97080, Germany

Location

GSK Investigational Site

Aachen, North Rhine-Westphalia, 52074, Germany

Location

GSK Investigational Site

Solingen, North Rhine-Westphalia, 42653, Germany

Location

GSK Investigational Site

Berlin, State of Berlin, 10117, Germany

Location

GSK Investigational Site

Lecco, Lombardy, 23900, Italy

Location

GSK Investigational Site

Lido Di Camaiore (LU), Tuscany, 55041, Italy

Location

GSK Investigational Site

Amsterdam, 1081 HV, Netherlands

Location

GSK Investigational Site

Nijmegen, 6525 GA, Netherlands

Location

GSK Investigational Site

L'Hospitalet de Llobregat, 08907, Spain

Location

GSK Investigational Site

Madrid, 28041, Spain

Location

GSK Investigational Site

Valencia, 46017, Spain

Location

GSK Investigational Site

Cardiff, CF14 4XW, United Kingdom

Location

GSK Investigational Site

Gloucester, GL1 3NN, United Kingdom

Location

GSK Investigational Site

Leicester, LE5 4PW, United Kingdom

Location

GSK Investigational Site

London, NW3 2QG, United Kingdom

Location

GSK Investigational Site

London, SE5 9RS, United Kingdom

Location

GSK Investigational Site

Reading, RG1 5AN, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 34778952 DERIVED

MeSH Terms

Conditions

Glomerulonephritis, Membranous; Proteinuria

Interventions

belimumab

Condition Hierarchy (Ancestors)

Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Autoimmune Diseases; Immune System Diseases; Urination Disorders; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2013
• First Posted: January 8, 2013
• Study Start: April 1, 2013
• Primary Completion: January 1, 2014
• Study Completion: January 1, 2014
• Last Updated: March 22, 2017

Record last verified: 2017-03

Locations

CA (2); ES (3); IT (2); DE (7); NL (2); US (2); FR (4); GB (6); CZ (1); AU (1)