A 2 year study to investigate belimumab in membranous nephropathy

• Register: EUCTR
• Last refreshed on: 4 November 2013
• Main ID: EUCTR2011-000242-38-DE
• Date of registration: 25/09/2012
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: A 2 year study to investigate belimumab in membranous nephropathy
• Scientific title: BEL114674: A 2 year study of efficacy and safety of intravenous belimumab versus placebo in subjects with idiopathic membranous nephropathy - GSK1550188 in membranous nephropathy
• Date of first enrolment: 09/01/2013
• Target sample size: 94
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-000242-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Australia, Canada, Czech Republic, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trials HelpDesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: Clinical Trials HelpDesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Age & Gender: Male or female between 18 and 75 years of age inclusive, at the time of signing the informed consent.
2. 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 (see inclusion 3), a biopsy should be
available within the preceding 7 years.
3. 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 >400mg/mmol by uPCR (equates to >4.0g per 24 h) 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.
Proteinuria in patients with relapsed disease: Patients who previously
achieved proteinuria <2g 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.
4. 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:
a. 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) > 40 MlU/mL and estradiol < 40 pg/mL (<147 pmol/L) 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 Section 8.1 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 enrolment. 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.
b. Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 74
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion criteria:
1. 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-versushost- disease, Guillain-Barre syndrome.
Infectious or parasitic diseases: Hepatitis B; Hepatitis C, syphilis, filariasis, hydatid disease, schistosomiasis, malaria, leprosy.
Drugs and toxins: Gold, penicillamine, non-steroidal anti-inflammatory agents, mercury, captopril, formaldehyde, hydrocarbons, bucillamine. Miscellaneous: Tumors (excluded with reasonable diligence), renal transplantation, sarcoidosis, sickle cell disease, Kimura disease, angiofollicular lymph node hyperplasia.
2. Anti-PLA2R autoantibody: Patients known to be negative for anti-PLA2R autoantibody.
3. Severely reduced or deteriorating kidney function: An eGFR at screening < 40 mL/min/1.73m2 (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).
4. Blood Pressure: Uncontrolled hypertension defined as blood pressure (BP) > 150/90 mm Hg (treatment target = 140/80) as assessed by either:
a. 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 >50% of measurements being >150/90 or
b. Average daytime blood pressure on a 24 hour ambulatory blood pressure monitor.
5. Prior Therapy: Have received treatment with the following therapies at the times specified prior to Day 0:(please see protocol page 42 for further information)
6. Transplantation: Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
7. 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.
8. Acute or chronic infection: Have required management of acute or chronic infections, please view section 5.2.2 of the protocol for further information.
9. 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).
10. 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. Please view section 5.2.2 of the protocol for further information.
11. 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 please view section 5.2.2 of the protocol for further information.
12. Liver function tests: Aspartate aminotransferase (AST) and alanine aminotransferas

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Idiopathic Membranous Nephropathy (IMN)
MedDRA version: 16.0 Level: LLT Classification code 10027170 Term: Membranous nephropathy System Organ Class: 100000004857

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Trade Name: BENLYSTA®
Product Name: BENLYSTA®
Product Code: GSK1550188 (Belimumab)
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: BELIMUMAB
CAS Number: 356547-88-1
Current Sponsor code: GSK1550881
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: To evaluate the efficacy of 10mg/kg belimumab for the treatment of IMN as measured by remission of proteinuria at 2 years.

Secondary Objective: • To evaluate the safety and tolerability of belimumab 10mg/kg over a 2 year period in IMN.
• To evaluate efficacy through other measures of disease activity over a 2 year period.
• To evaluate the pharmacokinetics of belimumab in IMN over a 2 year period.
• To evaluate the effect of belimumab on pharmacodynamic markers and other markers of autoimmunity and their relationship with clinical efficacy in IMN over a 2 year period.
• To evaluate the effect of belimumb on quality of life in IMN over a 2 year period.
• To evaluate the benefit of earlier treatment with belimumab compared to delayed treatment with current immunosuppressive treatment regimens during 2 years in the treatment period of the main clinical study and whether there is a positive effect following 2 years treatment in a 5 year off investigational drug follow-up period.

Primary end point(s): Incidence of remission (complete or partial) at Week 104
(complete remission [CR] is defined as uPCR < 30mg/mmol (proteinuria <0.3g protein/24h) with no worsening of renal function (less than 15% reduction in eGFR from baseline); partial remission [PR] is defined as uPCR < 350mg/mmol [proteinuria <3.5g /24hrs] but = 30mg/mmol [proteinuria =0.3g /24hrs] 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]).

Timepoint(s) of evaluation of this end point: Week 104

Secondary Outcome(s)

Secondary end point(s): • Incidence of progression of IMN or failure to respond as defined by:
1. Persistent symptomatic nephrotic syndrome potentially necessitating rescue therapy due to:
• Persistent nephrotic range proteinuria with <30% improvement after at least 6 months observation, or deterioration in proteinuria (>30% increase from baseline) at any time OR
• Symptoms or other clinically significant evidence of severe nephrotic
syndrome- i.e. morbid oedema (defined as oedema that is distressing to a patient because of prolonged duration and inability to achieve
adequate control with loop diuretics) or subclinical evidence of
thromboembolism, severe hypoalbuminaemia (reduction by 5g/L from
baseline and <20g/L) OR
• Deterioration in renal function - decrease in eGFR from baseline by >20% OR
• Persistent severe hypogammaglobulinaemia, <250mg/dL- continuing for >6 months.
2. ESRD (eGFR <15mL/min/1.73m2, dialysis or transplantation)
3. Clinical thromboembolic events
4. Death

Other Secondary Endpoints
• Time to complete remission
• Time to partial remission
• Change from baseline in proteinuria levels at Week 104
• Change from baseline in serum albumin levels at Week 104
• Change from baseline in eGFR at Week 104
• Time to first thromboembolic event
• Change from baseline in KDQOL-36 score at Week 104
• Incidence of partial remission at Week 104
• Incidence of complete remission at Week 104
• Duration of remission (complete or partial)
• Risk-benefit calculation based on key efficacy and safety endpoints using a clinical utility index
Key Safety Endpoints
• Incidence of serious adverse events (SAEs)
• Incidence of AEs of special interest:
• 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 for studies that
are not prospectively assessing for suicidality using the C-SSRS and
Possible Suicidality Related Questionnaire (PSRQ)

Other (Endpoints)
There will be a formal analysis of other endpoints at Weeks 28, 52, 76 and 104/4 week post last dose, unless otherwise stated or already specified in primary and secondary endpoints. Data from other visits will be provided as supporting/descriptive analyses. For proteinuria, absolute values (by uPCR) will be determined at all time points to model temporal effects.
• Change from baseline in proteinuria levels
• Incidence of partial remission
• Incidence of complete remission
• Incidence of complete or partial remission at any time during 104 weeks treatment
• Incidence of relapse over 104 weeks
(relapse is defined as: uPCR>350mg/mmol (proteinuria > 3.5g/24 hrs) AND increase of 50% from lowest remission level, in those patients who had previously achieved any type of remission)
• Time to relapse (starting from time of first achievement of any type of remission)
• Change from baseline in eGFR
• Incidence of >20% decrease in eGFR at any time
• Change from baseline in serum creatinine levels
• Incidence of >50% increase in serum creatinine any time
• Change from baseline in serum albumin levels
• Change from baseline in cholesterol levels
• Incidence of oedema by severity
• Change from baseline in KDQOL-36 questionnaire score by visit
• Change from baseline in Membranous Nephropathy Quality of Life (MN QOL) questionnaire score by visit
• Change from baseline in Workplace Productivity and Activity Impairment (WPAI) questionnaire score by visit
• Change from baseline in 6 minute walk test (6MWT)
• Unscheduled healthcare contacts/resource utilisation
• Requirement for rescue therapy
• Change from baseline in anti-PLA2R antibody levels
• Incidence of anti-PLA2R antibody remission.
• Full response: Antibody undetectable
• Partial response: Reduction in titres by 50%
• Time to anti-PLA2R antibody remission
• Serum belimumab C(0-30min), Cmin, AUC(0-tau), and urine Ae(0-24)
• Pharmacodynamics/biomarkers: May include change in relevant B-cells and other lymphocyte subsets, urine membrane attack complex (MAC), neutrophil gelatinase-associated lipocalin (NGAL), selective proteinuria, BLyS levels, autoantibody profile, change in transcriptomic profile, by visit, as data permit.

Timepoint(s) of evaluation of this end point: Week 104

Secondary ID(s)

BEL114674

Source(s) of Monetary Support

GlaxoSmithKline Research & Development Ltd