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
Condition: Systemic Lupus Erythematosus
MeSH terms: Lupus Erythematosus, Systemic
Intervention: Belimumab; Rituximab; Rituximab-placebo; Standard therapy (Including Immunosuppressants); Standard therapy (Excluding Immunosuppressants); Steroid Taper
Intervention description: Belimumab will be administered as SC injection once weekly via autoinjector in thigh or abdomen; Rituximab will be administered as IV infusion of 1000mg at Week 4 and Week 6; Saline will be administered as IV infusions at Week 4 and Week 6; Standard therapy will contain stable SLE medications including immunosuppressant to be administered from baseline through Week 104.; Standard therapy excluding Immunosuppressant will contain anti-malarials, NSAIDs, and/or corticosteroids with prednisone dose equivalent to <= 5 mg/day will administered through Week 104.; Steroid taper will include prednisone doses equivalent to =< 5 mg/day in all Arms through Week 104.
Intervention MeSH terms: Rituximab; Belimumab; Immunosuppressive Agents
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 292.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: immunosuppressants; Systemic Lupus Erythematosus Disease Activity Index; Belimumab; Lupus Low Disease Activity State; Systemic Lupus Erythematosus

Summary:

      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 292 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). 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.
    

Eligibility criteria:

        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 deciliter
             [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 intramuscular [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 hours 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- Tumor Necrosis
             Factor (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.