A Study to Evaluate the Efficacy and Safety of Belimumab Administered in Combination With Rituximab to Adult Subjects With Systemic Lupus Erythematosus (SLE) - BLISS-BELIEVE
A Study to Evaluate the Efficacy and Safety of Belimumab Administered in Combination With Rituximab to Adult Subjects With Systemic Lupus Erythematosus (SLE) - BLISS-BELIEVE
The purpose of this study is to assess whether co-administration of belimumab and a single
 cycle of rituximab will optimize treatment with belimumab, which will result in improvements
 of clinical status with a favorable safety profile, by comparing subjects randomized to
 belimumab plus rituximab versus belimumab plus rituximab-placebo. Approximately 280 subjects
 will be randomized in a 1:2:1 ratio to 1 of 3 treatment arms; belimumab plus
 rituximab-placebo (Arm A, control), belimumab plus rituximab (Arm B, combination), or
 belimumab plus standard therapy (Arm C, reference). Arm A and Arm B will be double-blinded
 and Arm C will be open-labeled. The open-label arm will provide a qualitative reference to
 standard therapy. Belimumab will be administered as subcutaneous (SC) and rituximab-placebo
 or rituximab will be administered by intravenous (IV) infusions. The total duration of the
 study is for 104 weeks. Double-blinded phase will be for 52-weeks with subjects from Arm A
 and B who cannot tolerate discontinuation of immunosuppressant or taper of corticosteroids.
 Subjects in Arm C will continue to receive belimumab SC and their stable immunosuppressant
 during Weeks 53 through 104.
Inclusion Criteria:

 -  Subjects must be >=18 years of age at the time of signing the informed consent.

 -  Subjects who have clinical diagnosis of SLE based on 4 or more of the 11 American
 College of Rheumatology (ACR) criteria.

 -  Subjects who have a screening SLEDAI-2K score >=6 (This refers to the total score.
 Serological activity, i.e., anti-double stranded deoxyribonucleic acid [dsDNA])
 positivity and/or hypocomplementemia is not required to be present in SLEDAI-2K
 assessment, but are scored if present).

 -  Subjects who have unequivocally positive autoantibody test results defined as an
 anti-nuclear (ANA) titer >=1:80 and/or a positive anti-dsDNA (>=30 International Units
 per milliliter [IU/mL]) serum antibody test from 2 independent time points as follows:
 Positive test results from 2 independent time points within the study screening
 period. Screening results must be based on the study's central laboratory results. Or,
 one positive historical test result and 1 positive test result during the screening
 period.

 -  Subjects who are on a stable SLE treatment regimen consisting of any of these
 medications (alone or in combination) for a period of at least 30 days prior to Day 1
 (i.e. day of first dose of study treatment) with the exception that switching one
 agent for another of the same class for tolerability or availability reasons, which
 will be allowed within 30 days of Day 1: Corticosteroids (prednisone or prednisone
 equivalent); For those subjects on alternating daily doses of steroids, use the
 average of 2 daily doses to calculate the average daily steroid dose; Any
 immunosuppressant or immunomodulatory agents including methotrexate, azathioprine,
 leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil
 hydrochloride, and mycophenolate sodium), calcineurin inhibitors (example [e.g.]
 tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine,
 mizoribine, or thalidomide; Anti-malarials (e.g., hydroxychloroquine, chloroquine,
 quinacrine); Non steroidal anti-inflammatory drugs (NSAIDs).

 -  Male and/or female. A female subject is eligible to participate if she is not pregnant
 not breastfeeding, and at least one of the these conditions applies: Not a woman of
 childbearing potential (WOCBP) or A WOCBP who agrees to follow the contraceptive
 guidance during the treatment period and for at least 16 weeks after the last dose of
 belimumab, or at least 12 months after the last dose of rituximab or
 rituximab-placebo.

 -  Capable of giving signed informed consent which includes compliance with the
 requirements and restrictions listed in the informed consent form (ICF) and in this
 protocol.

 Exclusion Criteria:

 -  Symptomatic herpes zoster within 3 months prior to screening.

 -  Evidence of active or latent tuberculosis (TB). Documentation may include medical
 history and examination, chest X-rays (posterior, anterior, and lateral), and TB
 testing: either a positive tuberculin skin test (TST; defined as a skin induration ≥5
 mm at 48 to 72 hours, regardless of Baccillus Calmette-Guerin (BCG) or other
 vaccination history) or a positive (not indeterminate) QuantiFERON-TB Gold Plus test.

 -  Significant allergies to humanized monoclonal antibodies.

 -  History of hypersensitivity to belimumab and/or rituximab or known to have titers of
 human anti-mouse antibody or history of hypersensitivity reactions when treated with
 other diagnostic or therapeutic monoclonal antibodies.

 -  Lymphoma, leukemia, or any malignancy within the past 5 years (yrs) except for basal
 cell or squamous epithelial carcinomas of the skin that have been resected with no
 evidence of metastatic disease for 3 yrs.

 -  Alanine transferase (ALT) greater than 2 times upper limit of normal (ULN).

 -  Bilirubin greater than 1.5 times ULN (isolated bilirubin greater than 1.5 times ULN is
 acceptable if bilirubin is fractionated and direct bilirubin less than 35%).

 -  Immunoglobulin A (IgA) deficiency (IgA level less than 10 milligram per decilitre
 [mg/dL]).

 -  Immunoglobulin G (IgG) less than 250 mg/dL. For Germany only, IgG less than 400mg/dL.

 -  Neutrophils less than 1.5 times 10^9.

 -  Current unstable liver or biliary disease per investigator assessment defined by the
 presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or
 gastric varices, persistent jaundice, or cirrhosis.

 -  Severe heart failure (New York Heart Association Class IV) or other severe,
 uncontrolled cardiac disease.

 -  QT interval corrected (QTc) greater than 450 millisecond (msec) or QTc greater than
 480 msec in subjects with bundle branch block.

 -  Subjects who have a history of a major organ transplant (e.g., heart, lung, kidney,
 liver) or hematopoietic stem cell/marrow transplant.

 -  Subjects who have clinical evidence of significant unstable or uncontrolled acute or
 chronic diseases not due to SLE (i.e., cardiovascular, pulmonary, hematologic,
 gastrointestinal, hepatic, renal, neurological, psychiatric, 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.

 -  Subjects who have an acute or chronic infection requiring management as : Currently on
 any suppressive therapy for a chronic infection such as pneumocystis, cytomegalovirus,
 herpes simplex virus, herpes zoster, or atypical mycobacteria); Hospitalization for
 treatment of infection within 60 days of Day 1; subjects who had infection requiring
 treatment with parenteral (IV or IM) antibiotics (antibacterials, antivirals,
 anti-fungals, or anti-parasitic agents) within 60 days of Day 1. Prophylactic
 anti-infective treatment is allowed.

 -  Subjects who have severe lupus kidney disease (defined by proteinuria greater than 6
 gram (g)/24 hr or equivalent using spot urine protein to creatinine ratio, or serum
 creatinine greater than 2.5 mg/dL), or have severe active nephritis requiring
 induction therapy not permitted by protocol (e.g., IV cyclophosphamide), or have
 required hemodialysis or high dose prednisone or equivalent (greater than 100 mg/day)
 within 90 days of Day 1.

 -  Subjects who 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
 Day 1.

 -  Subjects who have a planned surgical procedure, laboratory abnormality, or condition
 (e.g., poor venous access) that, in the opinion of the principal investigator, makes
 the subject unsuitable for the study.

 -  Subjects who have evidence of serious suicide risk, including any history of suicidal
 behavior in the last 6 months and/or any suicidal 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 opinion, pose a significant suicide risk.

 -  Subjects who have a history of an anaphylaxis reaction to parenteral administration of
 contrast agents, human or murine proteins, or monoclonal antibodies.

 -  Subjects who have received live vaccine(s) within 1 month prior to screening, or plans
 to receive such vaccines during the screening period or during the study.

 -  Subjects who have received any of the these prior/concomitant therapy within 364 days
 of Day 1: Belimumab; Rituximab; Abatacept; Any B cell targeted therapy (anti-cluster
 of differentiation-20 [CD] agents other than rituximab, anti CD22 [epratuzumab],
 anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], Trans-membrane activator
 and calcium-modulator and cytophilin ligand interactor [TACI] Fc, anti B-cell
 activating factor [BAFF] (LY2127399), anti-Interferon alpha agents or anti-BLyS other
 than belimumab); A biologic investigational agent other than B cell targeted therapy
 (e.g., abetimus sodium, anti CD40L antibody [BG9588/ IDEC 1311]). (Investigational
 agent applies to any drug not approved for sale in the country in which it is being
 used).

 -  Subjects who have required 3 or more courses of systemic corticosteroids within 364
 days of Day 1. (Topical or inhaled steroids are permitted).

 -  Subjects who have received any of these within 90 days of Day 1: Anti-TNF therapy
 (e.g., adalimumab, etanercept, infliximab); Interleukin-1 receptor antagonist
 (anakinra); Intravenous immunoglobulin (IVIG); High dose prednisone or equivalent
 (greater than 100 mg/day); Plasmapheresis.

 -  Subjects who have received any of the these within 60 days of Day 1: A non-biologic
 investigational agent (Investigational agent applies to any drug not approved for sale
 in the country in which it is being used); IV cyclophosphamide and, for Germany only,
 oral cyclophosphamide; Any steroid injection (e.g., intramuscular [IM],
 intraarticular, or IV).

 -  Positive immunodeficiency virus (HIV) antibody test.

 -  Positive serology for Hepatitis B (HB), defined as HB surface antigen positive
 (HBsAg+) OR HB core antibody positive (HBcAb+).

 -  Positive Hepatitis C (HCV) antibody test.

 -  Subjects who have current drug or alcohol dependence, or a history of drug or alcohol
 abuse or dependence within 364 days prior to Day 1.

 -  Sensitivity to any of the study treatments, or components thereof, or drug or other
 allergy that, in the opinion of the investigator, contraindicates participation in the
 study.

 -  Unable to administer study treatment (belimumab) by SC injection and has no other
 reliable resource to administer the injection.