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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
The primary efficacy endpoint is Primary Efficacy Renal Response (PERR) at week 104
active lupus nephritis
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 the screening visit or during the screening period. The local biopsy report will be used to confirm subject eligibility. A tissue sample from the renal biopsy used to qualify the subject for randomization needs to be sent to a central reading center after Day 0 (baseline).
4. Have unequivocally positive anti-nuclear antibody (ANA) test results defined as an ANA titer ? 1:80 (based on Hep-2 immunofluorescence assay or equivalence by enzyme immunoassay 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’s central laboratory results.
5. Have documentation of active renal disease at screening requiring induction therapy with high dose corticosteroids (HDCS) with either IV cyclophosphamide (CYC) or mycophenolate mofetil (MMF) or other oral forms of mycophenolate. The following factors will be used to define active renal disease at screening:
· 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
- > 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 following criteria:
- Have a confirmatory biopsy performed within 3 months prior to the screening visit or during the screening period meeting the criteria outlined in Inclusion Criterion 3.
- Have proteinuria ? 3.5 grams/day (or urinary protein:creatinine ratio? 3.5).
6. Have active renal disease defined as above which requires 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 may begin before Screening but should be initiated within 60 days prior to or on Day 0 (baseline). Initiation of induction is when both HDCS and either MMF or CYC have been started.
The study recommended doses for induction therapy are as follows, adjustments may be made for tolerability issues (refer to Section 5.5.1 Standard of Care Medication for details):
- MMF 1-3g/day orally or Mycophenolate sodium 720 - 2160 mg/day orally
- corticosteroids: 0-3 IV pulses of methylprednisolone 500 -1000 mg/pulse
followed by oral prednisone 0.5-1.0 mg/kg/day with total daily dose up to 60 mg/day (or equivalence)
- CYC 500 mg by IV infusion every 2 weeks (± 3 days) for 6 infusions
Subjects who have been on MMF for SLE including lupus renal disease may be eligible if they have received, or will receive, the following induction therapy within 60 days prior to or on Day 0 (baseline):
- initiation of HDCS with MMF dose increase to reach the target dose for induction in the subject (if the subject did not previously fail MMF induction based on the investigator’s opinion), OR
- initiation of HDCS with discontinuation of MMF and initiation of CYC.
Note: It is recommended that subject eligibility should be discussed with the Medical Monitor if a subject initiated but did not complete an induction therapy within 6 months prior to the initiation of current induction therapy for the study.
7. 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% per year;
◦ 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 sterilisation with documentation of azoospermia prior to the female subject’s entry into the study, and this male is the sole partner for that subject. The documentation on male sterility can come from the site personnel’s review of subject’s medical records, medical examination and/or semen analysis, or medical history interview provided by her or her partner.
Note: If stricter female or male contraception requirements are specified in the country-specific label for induction and/or maintenance standard of care medications, they must be followed.
8. 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 visits).
4.2. Exclusion Criteria
Subjects will be excluded from participating in the study if they meet any of the following exclusion criteria:
1. Subjects who have previously failed both CYC and MMF (or other forms of mycophenolate) induction therapies based on the investigator’s opinion. If a subject has failed only 1 of the 2 therapies for induction, they may be eligible for study inclusion if the other induction therapy is initiated within 60 days prior to or on Day 0 (ie, a subject who failed MMF is eligible if newly initiating induction therapy with CYC or a subject who failed CYC is eligible if newly initiating induction therapy with MMF).
2. Subjects who received an induction therapy with CYC within 3 months prior to the planned initiation of the current induction for the study.
3. Subjects who receive CYC whose pre-induction leukocyte count is Grade 3 or 4 based on the Adverse Event Severity Grading Tables (Appendix 7).
4. Known hypersensitivity or contraindication to any drug products or any component of these drug products they plan to receive (eg, CYC, MMF, AZA, corticosteroids).
5. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
6. Have received treatment with belimumab within 364 days of baseline (Day 0).
7. Received the following within 364 days of baseline (Day 0): - Nitrogen mustard
- Treatment with any B cell targeted therapy (eg, rituximab, other anti-CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], TACI-Fc, or LY2127399 [anti-BAFF])
- A biologic investigational agent (eg, abetimus sodium, anti-CD40L antibody [BG9588/ IDEC-131]). Investigational agent applies to any drug not approved for sale in the country in which it is being used.
- Treatment with interleukin-6 targeted therapy (e.g., tocilizumab, sirukumab).
8. Received any of the following within 90 days of baseline (Day 0):
- Anti-TNF therapy (eg, adalimumab, etanercept, infliximab, certolizumab,
- Interleukin-1 receptor antagonist (anakinra).
- Intravenous immunoglobulin (IVIG).
9. Received a non-biological investigational agent within 60 days of baseline (Day 0).
10. Received a live vaccine within 30 days of baseline (Day 0).
11. Have severe active central nervous system (CNS) lupus (including seizures, psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis, or CNS vasculitis) requiring therapeutic intervention within 60 days of baseline (Day 0).
12. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant or are due to receive transplantation.
13. Subjects who have been on dialysis within 364 days of baseline (Day 0).
14. An estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the screening visit (using the simplified Modification of Diet in Renal Disease [MDRD] equation).
15. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to SLE (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy, or infectious diseases) which, in the opinion of the principal investigator, could confound the results of the study or put the subject at undue risk.
16. Have a planned surgical procedure or a history of any other medical disease
(eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, in the opinion of the principal investigator, makes the subject unsuitable for the study.
17. 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.
18. Have acute or chronic infection requiring management, as follows:
- Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria).
- Hospitalization for treatment of infection within 60 days of baseline (Day 0).
- Have had infection requiring treatment with parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of baseline (Day 0).
19. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to baseline (Day 0).
20. Have a historically positive test or test positive at screening for HIV antibody.
21. Hepatitis B: Serologic evidence of Hepatitis B (HB) infection based on the results of
testing for HBsAg, anti-HBc and anti-HBs as follows:
- Patients positive for HBsAg are excluded.
- Patients negative for HBsAg but positive for Anti-HBc, regardless of Anti-HBs antibody status, will require clarification of their status by testing for HBV DNA
- o if HBV DNA positive, patients will be excluded from participation
- o if HBV DNA negative, patients will be eligible to enrol.
- NOTE: For those subjects randomised, additional ongoing assessment during the study is required (see Section 6.7.5).
22. Hepatitis C: Positive test for Hepatitis C antibody confirmed on a subsequent blood sample by RNA-PCR assay. Subjects who are positive for Hepatitis C antibody and negative when the Hepatitis C RNA-PCR assay is performed on a subsequent sample will be eligible to participate. Subjects who are positive for Hepatitis C antibody and have a positive result for the HCV when the Hepatitis C RNA-PCR assay is performed on the subsequent sample will not be eligible to participate. Subjects in China with positive test for Hepatitis C antibody will be excluded without confirmatory Hepatitis C RNA-PCR testing.
23. Have an IgA deficiency (IgA level < 10 mg/dL).
24. Have a Grade 3 or greater laboratory abnormality (including serum IgG level) based on the Adverse Event Severity Grading Tables (Appendix 7) except for the following that are allowed:
- Urinalysis (eg, proteinuria)
- Hypoalbuminemia due to lupus nephritis.
- Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.