A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus Standard of Care in Adult Subjects with Active Lupus Nephritis
This is a Phase 3, multi-centre, multi-national, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of IV belimumab 10 mg/kg plus standard of care compared to placebo plus standard of care in adult subjects with active lupus nephritis. Subjects will be randomized to 1 of 2 treatment groups in a 1:1 ratio: 10 mg/kg belimumab plus standard of care or placebo plus standard of care.
Efficacy Endpoints and Analysis:
The primary efficacy endpoint is
Renal response at Week 104 measured as an ordinal response - complete renal response,
partial renal response, or no renal response. Renal response is determined by changes in urinary sediment, proteinuria, and renal function. Renal response at Week 104 will be defined by a response at Week 100 that is confirmed by a repeat measurement at Week 104. Renal response is defined as follows:
* Complete Renal Response:
Calculated glomerular filtration rate (GFR) is no more than 10% below the pre-flare
value or within normal range
Inactive urinary sediment [( and amp;lt; 5 RBCs/hpf and and amp;lt; 5 WBCs/hpf (or within the reference
range of the laboratory)] no cellular casts (no RBC or WBC casts)
Urinary protein:creatinine ratio and amp;lt; 0.5
(Note: For subjects with a normal urinary sediment and GFR at baseline and only the
presence of proteinuria (>= 3.5 grams/day), the urine protein:creatinine ratio should be
and amp;lt; 0.5 to meet the primary endpoint.)
No receipt of prohibited (rescue) therapy (see Sections 5.5 and 5.6). Partial Renal Response:
Estimated or calculated GFR no more than 10% below the baseline value or within
RBCs/hpf >= 50% reduction from baseline or and amp;lt; 5 RBCs/hpf (or within the normal
reference range for the central laboratory) and no RBC casts
>= 50% decrease in the urine protein:creatinine ratio with one of the following:
[?] a urine protein:creatinine ratio of and amp;lt; 1.0, if the baseline ratio was <= 3.0
[?] a urine protein:creatinine ratio of and amp;lt; 3.0, if the baseline ratio was and amp;gt; 3.0
[?] No receipt of prohibited (rescue) therapy (see Sections 5.5 and 5.6).
* No Renal Response:
Not meeting criteria for either complete or partial renal response.
Major Secondary Endpoints:
* Complete renal response at Week 104.
* Renal response (complete, partial or no response) at Week 52.
1. Males or females at least 18 years of age.
2. Have a clinical diagnosis of systemic lupus erythematosus (SLE) according to the
American College of Rheumatology (ACR) criteria (Appendix 1).
3. Have active, biopsy-proven proliferative lupus nephritis Class III or IV [excluding
Class III(C), IV-S(C), and IV-G(C)] either with or without the presence of Class V, or
pure Class V membranous using the 2003 ISN/RPS criteria (Appendix 2); the biopsy must
be performed in the 6 months prior to baseline (Day 0). Whenever possible, a tissue
sample from the renal biopsy used to qualify the subject will be collected and sent to a
central reading center; however, the tissue sample will not be shipped prior to nor be used
for the purposes of randomization.
4. Have unequivocally positive anti-nuclear antibody (ANA) test results defined as an ANA
titer >= 1:80 (based on Hep-2 immunofluorescence assay) and/or a positive anti-dsDNA
(>= 30 IU/mL based on ELISA assay) serum antibody test at the screening visit based on
the study[Single Quote]s central laboratory results.
5. Have documentation of active renal disease at screening requiring initiation of induction
therapy with high dose corticosteroids (HDCS) with either intravenous (IV)
cyclophosphamide (CYC) or mycophenolate mofetil (MMF) or other oral forms of
mycophenolate. Induction therapy should be started no more than 14 days prior to the
baseline visit (Day 0). The following factors will be used to define active renal disease:
* Urinary protein:creatinine ratio of >= 1.0 AND active urinary sediment as defined by at
least 1 of the following (in absence of menses and genitourinary tract infection).
> 5 red blood cell (RBC)/high power field (hpf) or above the laboratory reference
[?] > 5 white blood cell (WBC)/hpf (or above the laboratory reference range).
[?] Presence of cellular casts (RBC or WBC).
* Subjects without active urinary sediment are eligible if they meet at least 1 of the
[?] Have a confirmatory biopsy performed within 3 months prior to the baseline visit
meeting the criteria outlined in Inclusion Criterion 3.
[?] Have proteinuria >= 3.5 grams/day.
6. A female subject is eligible to enter the study if she is:
* Not pregnant or nursing;
* Of non-childbearing potential (ie, women who had a hysterectomy, are
postmenopausal which is defined as 1 year without menses, have both ovaries
surgically removed, or have current documented tubal ligation or any other permanent
female sterilization procedure); or
* Of childbearing potential (ie, women with functional ovaries and no documented
impairment of oviductal or uterine function that would cause sterility). This category
includes women with oligomenorrhoea [even severe], women who are
perimenopausal, or have just begun to menstruate. These women must have a negative
serum pregnancy test at screening, and agree to 1 of the following:
[?] Complete abstinence from intercourse from 2 weeks prior to administration of the
1st dose of study agent until 16 weeks after the last dose of study agent; or
[?] Consistent and correct use of 1 of the following acceptable methods of birth
control for 1 month prior to the start of the study agent, during study, and for
16 weeks after the last dose of study agent:
[?] Implants of levonorgestrel or etonogestrel;
[?] Ethinyl estradiol/Etonogestrel vaginal ring;
[?] Injectable progesterone;
[?] Any intrauterine device (IUD) with a documented failure rate of less than 1%
[?] Oral contraceptives (either combined or progesterone only);
[?] Double barrier method: condom and occlusive cap (diaphragm or cervical/vault
caps) with spermidical foam/gel/film/cream/suppository;
[?] Transdermal contraceptive patch;
[?] Male partner who is sterile prior to the female subject[Single Quote]s entry into the study
and is the sole sexual partner for the female subject.
Note: MMF and other forms of mycophenolate affect the metabolism of oral
contraceptives and may reduce their effectiveness. As such, women receiving
mycophenolate who are using oral contraceptives for birth control should employ
an additional method (eg, barrier method).
7. Have the ability to understand the requirements of the study, provide written informed
consent (including consent for the use and disclosure of research-related health
information), and comply with the study protocol procedures (including required study