Clinical trial NCT01610492: A Study of Belimumab in Idiopathic Membranous Glomerulonephropathy
Official title: BEL116472. A 2 Year Mechanistic Study of Belimumab in Idiopathic Membranous Glomerulonephropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glomerulonephritis, Membranous
Keywords: IMGN
anti-PLA2R antibodies
pharmacokinetics
belimumab
Benlysta
Idiopathic Membranous Glomerulonephropathy
safety
GSK1550188
Lymphostat-B
membrane attack complex
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-06-04
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Change From Baseline in Proteinuria Levels at Week 28
timeFrame: Baseline and Week 28
measure: Change From Baseline in Anti-phospholipase A2 Receptor (PLA2R) Autoantibody Titers at Week 28
timeFrame: Baseline and Week 28
Secondary outcomes:
measure: Proteinuria Levels at the Indicated Time Points
timeFrame: Baseline and Week 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Change From Baseline in Proteinuria Levels at the Indicated Time Points
timeFrame: Baseline and Week 12, 28, 52, 76, 104 and Week 128/6 month follow up
measure: Anti-phospholipase A2 Receptor (PLA2R) Autoantibody Levels at Indicated Time Points
timeFrame: Baseline and Week 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Change From Baseline in Anti-PLA2R Autoantibody Titers at the Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128.
measure: Number of Participants With Complete or Partial Remission
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128
measure: Time to Complete or Partial Remission
timeFrame: Baseline and up to Week 128/6 month follow up
measure: Duration of Complete or Partial Remission
timeFrame: Baseline and up to Week 128/6 month follow up
measure: Number of Participants With PLA2R Autoantibody Remission
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128
measure: Time to Anti-PLA2R Autoantibody Remission
timeFrame: Baseline and up to Week 128/6 month follow up
measure: Number of Participants With Anti-PLA2R Autoantibody Relapse
timeFrame: Baseline and up to Week 128/6 month follow up
measure: eGFR Levels at the Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up.
measure: Change From Baseline in eGFR Levels at the Indicated Time Points
timeFrame: Baseline and up to Week 128/6 month follow up
measure: Serum Creatinine Levels at the Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Change From Baseline in Serum Creatinine Levels at the Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Serum Albumin Levels at Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up.
measure: Change From Baseline in Levels of Serum Albumin at the Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Serum Cholesterol Levels at Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Change From Baseline in Serum Cholesterol at the Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Serum Immunoglobulin G (IgG) Levels at Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow-up
measure: Change From Baseline in Serum IgG at the Indicated Time Points
timeFrame: Baseline and Weeks 12, 28, 52, 76, 104 and 128/6 month follow up
measure: Number of Participants With Edema and Edema Extending Beyond Calf
timeFrame: Baseline and Weeks 12, 28, 52, 76, and 104
measure: Summary of Maximum Observed Serum Concentration (Cmax) of Belimumab at the Indicated Time Points
timeFrame: Baseline and up to 4 week post last dose
measure: Summary of Minimum Observed Concentration (Cmin) of Belimumab at the Indicated Time Points
timeFrame: Baseline and up to 4 week post last dose
measure: Summary of Area Under the Serum Concentration-time Curve to the Last Quantifiable Concentration (AUC[0-2])
timeFrame: Baseline and up to 4 week post last dose
measure: Summary of Total Amount of Urine Excreted Ae(0-24)
timeFrame: Baseline and Up to 4 week post last dose
measure: Change From Baseline in Short Form (SF)-36 v2 Quality of Life (QoL) Questionnaire Score
timeFrame: Baseline and up to Week 104/4 week post last dose
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline and up to Week 128/6 month follow up
measure: Number of Participants With Abnormal Clinical Chemistry and Hematology Values
timeFrame: Baseline and up to Week 116/16 week follow-up visit
measure: Number of Participants With Urinalysis Dipstick Findings
timeFrame: Baseline and up to Week 116/16 Week follow up
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline and up to week 116/16 week follow-up visit
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline and up to Week 116/16 week follow-up visit
measure: Change From Baseline in Temperature
timeFrame: Baseline and up to Week 116/16 week follow-up visit
measure: Number of Participants With Positive Immunogenicity Findings
timeFrame: Baseline and up to Week 116/16 week follow-up visit
measure: Urine Membrane Attack Complex (MAC) Levels
timeFrame: Baseline and up to 4 week post last dose
measure: Change From Baseline in Urine Membrane Attack Complex (MAC)
timeFrame: Baseline and up to 4 week post last dose
measure: Change From Baseline in B Cell and T Cell Markers Concentration
timeFrame: Baseline and up to Week 128/6 month post last dose
measure: Change From Baseline in Cytokines/Chemokine
timeFrame: Baseline and up to Week 104/4 week post last dose
measure: Serum BLys Levels
timeFrame: Baseline and Week 116/16 week follow-up visit
measure: Urine BLys Levels as a Ratio to Creatinine
timeFrame: Baseline and Week 116/16 week follow-up visit
Other outcomes:
Locations:
city: Exeter
country: United Kingdom
facility: GSK Investigational Site
state: Devon
city: Stevenage
country: United Kingdom
facility: GSK Investigational Site
state: Hertfordshire
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
city: Reading
country: United Kingdom
facility: GSK Investigational Site
city: Salford
country: United Kingdom
facility: GSK Investigational Site
city: Whitechapel, London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: