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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01762852




Registration number
NCT01762852
Ethics application status
Date submitted
4/01/2013
Date registered
8/01/2013
Date last updated
22/03/2017

Titles & IDs
Public title
Efficacy and Safety Study of Intravenous Belimumab Versus Placebo in Subjects With Idiopathic Membranous Nephropathy
Scientific title
BEL114674: A 2 Year Study of Efficacy and Safety of Intravenous Belimumab Versus Placebo in Subjects With Idiopathic Membranous Nephropathy
Secondary ID [1] 0 0
114674
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glomerulonephritis, Membranous 0 0
Condition category
Condition code
Renal and Urogenital 0 0 0 0
Kidney disease
Inflammatory and Immune System 0 0 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Belimumab 10 mg
Treatment: Drugs - Placebo

Experimental: Belimumab Arm - 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.

Placebo Comparator: Placebo Arm - 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.


Treatment: Drugs: Belimumab 10 mg
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

Treatment: Drugs: Placebo
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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of remission (complete [CR] or partial [PR]) at Week (WK) 104
Timepoint [1] 0 0
104 weeks
Secondary outcome [1] 0 0
Incidence of progression of IMN or failure to respond
Timepoint [1] 0 0
Upto Week 104
Secondary outcome [2] 0 0
Time to complete remission
Timepoint [2] 0 0
Up to Week 104
Secondary outcome [3] 0 0
Time to partial remission
Timepoint [3] 0 0
Up to Week 104
Secondary outcome [4] 0 0
Change from baseline in proteinuria levels at Week 104
Timepoint [4] 0 0
Week 0 and Week 104
Secondary outcome [5] 0 0
Change from baseline in serum albumin levels at Week 104
Timepoint [5] 0 0
Week 0 and Week 104
Secondary outcome [6] 0 0
Change from baseline in eGFR at Week 104
Timepoint [6] 0 0
Week 0 and Week 104
Secondary outcome [7] 0 0
Time to first thromboembolic event
Timepoint [7] 0 0
Up to Week 104
Secondary outcome [8] 0 0
Change from baseline in KDQOL-36 score at Week 104
Timepoint [8] 0 0
Week 0 and Week 104
Secondary outcome [9] 0 0
Incidence of partial remission at Week 104
Timepoint [9] 0 0
Week 104
Secondary outcome [10] 0 0
Incidence of complete remission at Week 104
Timepoint [10] 0 0
Week 104
Secondary outcome [11] 0 0
Duration of remission (complete or partial)
Timepoint [11] 0 0
Up to Week 104
Secondary outcome [12] 0 0
Risk-benefit calculation based on key efficacy and safety endpoints using a clinical utility index
Timepoint [12] 0 0
Up to Week 104
Secondary outcome [13] 0 0
Incidence of serious adverse events (SAEs)
Timepoint [13] 0 0
Up to Week 104
Secondary outcome [14] 0 0
Incidence of adverse events (AEs) of special interest
Timepoint [14] 0 0
Up to Week 104
Secondary outcome [15] 0 0
Safety assessed by evaluation of Adverse events, clinical laboratory assessments, vital signs and immunogenicity
Timepoint [15] 0 0
Up to 116 Weeks
Secondary outcome [16] 0 0
Survival without renal progression
Timepoint [16] 0 0
From start of treatment up to 7 years

Eligibility
Key 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 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.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- 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.

- 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
1/04/2013
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/01/2014
Actual
Sample size
Target
Accrual to date
Final
0
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
GSK Investigational Site - New Lambton
Recruitment postcode(s) [1] 0 0
2305 - New Lambton
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Missouri
Country [2] 0 0
United States of America
State/province [2] 0 0
North Carolina
Country [3] 0 0
Canada
State/province [3] 0 0
Alberta
Country [4] 0 0
Canada
State/province [4] 0 0
Ontario
Country [5] 0 0
Czech Republic
State/province [5] 0 0
Praha 2
Country [6] 0 0
France
State/province [6] 0 0
Amiens cedex 1
Country [7] 0 0
France
State/province [7] 0 0
Créteil Cedex
Country [8] 0 0
France
State/province [8] 0 0
Paris Cedex 15
Country [9] 0 0
France
State/province [9] 0 0
Toulouse Cedex 9
Country [10] 0 0
Germany
State/province [10] 0 0
Baden-Wuerttemberg
Country [11] 0 0
Germany
State/province [11] 0 0
Bayern
Country [12] 0 0
Germany
State/province [12] 0 0
Nordrhein-Westfalen
Country [13] 0 0
Germany
State/province [13] 0 0
Berlin
Country [14] 0 0
Italy
State/province [14] 0 0
Lombardia
Country [15] 0 0
Italy
State/province [15] 0 0
Toscana
Country [16] 0 0
Netherlands
State/province [16] 0 0
Amsterdam
Country [17] 0 0
Netherlands
State/province [17] 0 0
Nijmegen
Country [18] 0 0
Spain
State/province [18] 0 0
L'Hospitalet de Llobregat
Country [19] 0 0
Spain
State/province [19] 0 0
Madrid
Country [20] 0 0
Spain
State/province [20] 0 0
Valencia
Country [21] 0 0
United Kingdom
State/province [21] 0 0
Cardiff
Country [22] 0 0
United Kingdom
State/province [22] 0 0
Gloucester
Country [23] 0 0
United Kingdom
State/province [23] 0 0
Leicester
Country [24] 0 0
United Kingdom
State/province [24] 0 0
London
Country [25] 0 0
United Kingdom
State/province [25] 0 0
Reading

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01762852
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01762852