A Study of Belimumab in Idiopathic Membranous Glomerulonephropathy

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01610492
First received: May 31, 2012
Last updated: October 9, 2014
Last verified: October 2014
  Purpose

This is a phase II, open label, experimental medicine study to evaluate the efficacy, safety and mechanism of action of belimumab in subjects with antiphospholipase A2 receptor (PLA2R) autoantibody positive idiopathic membranous glomerulonephropathy (IMGN), and to profile the relationship between biomarkers, autoantibody status and clinical response. 10 milligrams per kilogram (mg/kg) belimumab intravenous (IV) will be administered at weeks 0, 2, and then every 4 weeks, over a 24-week treatment period in subjects with anti-PLA2R antibody positive IMGN followed by a further long term treatment period until subjects reach remission of proteinuria, up to a maximum of 2 years total treatment. All subjects will receive background supportive therapy throughout the study. 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 1000 milligrams per millimole (mg/mmol) [greater than 10 grams(g)/24 hours (h)], to compensate for loss of belimumab in the urine. Effects on mechanistic markers will be measured by the level of proteinuria, levels of anti-PLA2R antibodies, and various other measures of kidney function. These will be compared to historical data. The pharmacokinetics of belimumab will be measured to confirm dosing in heavily proteinuric subjects. Pharmacodynamic (PD) markers, biomarkers and Quality of Life(QoL) in IMGN subjects will also be investigated. Safety will be assessed by adverse events (AE), clinical laboratory evaluations, and vital signs.


Condition Intervention Phase
Glomerulonephritis, Membranous
Drug: belimumab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: BEL116472. A 2 Year Mechanistic Study of Belimumab in Idiopathic Membranous Glomerulonephropathy

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Change from baseline in proteinuria levels at week 28 [ Time Frame: Weeks 0 and 28 ] [ Designated as safety issue: No ]
    To evaluate whether belimumab can modulate proteinuria in IMGN.

  • Change from baseline in anti-PLA2R autoantibody titres at week 28 [ Time Frame: Weeks 0 and 28 ] [ Designated as safety issue: No ]
    To evaluate whether belimumab can modulate anti-PLA2R autoantibodies in patients with detectable baseline levels of these antibodies.


Secondary Outcome Measures:
  • Change from baseline in proteinuria levels [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Change from baseline in anti-PLA2R autoantibody titres [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Change from baseline in urine levels of belimumab [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Incidence of complete or partial remission [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
    Complete remission: PCR <30mg/mmol (proteinuria <0.3g/24h) with no worsening in renal function (estimated glomerular filtration rate (eGFR) reduction from baseline <15%). Partial remission: PCR <350mg/mmol (proteinuria <3.5g/24h) but >= 30mg/mmol (proteinuria >=0.3g/24h) AND decrease of >50% from Day 0 baseline, together with no worsening in renal function (eGFR reduction from baseline <15%)

  • Time to complete or partial remission [ Time Frame: Week 0 to Week 104 ] [ Designated as safety issue: No ]
  • Incidence of anti-PLA2R autoantibody remission: [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
    Full response: Antibody undetectable, Partial response: Reduction in titres by 50%.

  • Incidence of anti-PLA2R autoantibody relapse [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
    Antibody detectable after previously undetectable

  • Change from baseline in eGFR levels [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Change from baseline in serum creatinine levels [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Change from baseline in levels of serum albumin [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Change from baseline in levels of cholesterol [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Incidence of oedema (extending beyond calf) [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Serum belimumab Cmax, Cmin, AUC(0-2), and urine Ae(0-24) [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
  • Change from baseline in SF-36 v2 QoL questionnaire score [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
    To evaluate the effect of belimumab on quality of life in IMGN

  • PD/biomarker endpoints may include Urine membrane attack complex (B Cell and T Cell sub-populations, B lymphocyte stimulator levels cytokines/chemokines antigen specific lymphocyte response, autoantibody profile, change in transcriptomics profile [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
    may include but not limited to Interleukin (IL)-21, IL-17, IL-4, IL-10,Interferon (IFN)-Gamma), or other markers of IMGN or autoimmune pathology, as data permits

  • Safety and tolerability [ Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104 and 112 ] [ Designated as safety issue: No ]
    AEs, clinical laboratory assessments (clinical chemistry, haematology and urinalysis), vital signs and immunogenicity

  • Duration of complete or partial remission [ Time Frame: Week 0 to Week 104 ] [ Designated as safety issue: No ]
  • Incidence of proteinuria relapse [ Time Frame: Weeks 0, 12, 28, 52, 76 and 104 ] [ Designated as safety issue: No ]
    PCR >350mg/mmol AND increase of 50% from lowest remission level, in those subjects who had previously achieved any type of remission

  • Time to anti-PLA2R autoantibody remission [ Time Frame: Week 0, to Week 104 ] [ Designated as safety issue: No ]

Enrollment: 14
Study Start Date: July 2012
Estimated Study Completion Date: August 2016
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
10mg/kg belimumab intravenous (IV) administered at weeks 0 and 2, and then every 4 weeks, over a 24-week treatment period, resulting in a total of 8 doses, and will be assessed for the primary endpoint at week 28. Subjects will then enter the long term phase of the study and receive 10mg/kg belimumab every 4 weeks until week 100,or until they have been in complete remission for at least 3 months, resulting in up to 27 doses.
Drug: belimumab
10mg/kg administered intravenously

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01610492

Locations
United Kingdom
GSK Investigational Site
Exeter, Devon, United Kingdom, EX2 5DW
GSK Investigational Site
Stevenage, Hertfordshire, United Kingdom, SG1 4AB
GSK Investigational Site
Cambridge, United Kingdom, CB2 0QQ
GSK Investigational Site
Glasgow, United Kingdom, G11 6NT
GSK Investigational Site
Manchester, United Kingdom, M13 9WL
GSK Investigational Site
Reading, United Kingdom, RG1 5AN
GSK Investigational Site
Salford, United Kingdom, M6 8HD
GSK Investigational Site
Whitechapel, London, United Kingdom, E1 1BB
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01610492     History of Changes
Other Study ID Numbers: 116472
Study First Received: May 31, 2012
Last Updated: October 9, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by GlaxoSmithKline:
Idiopathic Membranous Glomerulonephropathy
IMGN
GSK1550188
Lymphostat-B
anti-PLA2R antibodies
belimumab
Benlysta
safety
pharmacokinetics
membrane attack complex

Additional relevant MeSH terms:
Glomerulonephritis
Glomerulonephritis, Membranous
Nephritis
Kidney Diseases
Urologic Diseases
Autoimmune Diseases
Immune System Diseases
Belimumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 19, 2014