Rituximab and Belimumab for Lupus Nephritis
Condition: Lupus Nephritis
MeSH terms: Nephritis; Lupus Nephritis
Intervention: Rituximab; Cyclophosphamide; Prednisone; Methylprednisolone; Diphenhydramine; Acetaminophen; Rituximab; Cyclophosphamide; Prednisone; Methylprednisolone; Diphenhydramine; Acetaminophen; Belimumab
Intervention description: Rituximab 1000mg intravenously (IV) at week 0 and week 2; Cyclophosphamide (750 mg) intravenously (IV) at week 0 and week 2.; Week 0 and Week 2: Prednisone (40 mg/day; taper to 10 mg/day by week 12)
Continue prednisone 10 mg/day to week 96; Week 0 and Week 2:
Solumedrol (100 mg) IV; Diphenhydramine (50 mg, or equivalent dose of similar antihistamine) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.; Acetaminophen (650 mg) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.; Rituximab 1000mg intravenously (IV) at week 0 and week 2.; Cyclophosphamide (750 mg) intravenously (IV) at week 0 and week 2.; Week 0 and Week 2: Prednisone (40 mg/day; taper to 10 mg/day by week 12)
Continue prednisone 10 mg/day to week 96; Week 0 and Week 2: Solumedrol (100 mg) IV; Diphenhydramine (50 mg, or equivalent dose of similar antihistamine) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.; Acetaminophen (650 mg) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.; The RCB Group will receive IV belimumab 10mg/kg at weeks 4, 6, 8, and then every 4 weeks through week 48
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Rituximab; Belimumab; Prednisolone hemisuccinate; Prednisolone phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      In this experimental study, researchers will try to find out if treatment of lupus nephritis
      with a combination of rituximab and cyclophosphamide (CTX), or a combination of rituximab and
      CTX followed by treatment with belimumab is safe and if this drug combination can block the
      immune system attacks.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology
             (ACR) criteria.

          2. Positive antinuclear antibody (ANA) or positive anti-ds DNA test results at visit -1
             or any time within 14 days before visit -1.

          3. Active proliferative lupus nephritis, as defined by either of the following:

               -  Kidney biopsy documentation within the last 3 months of International Society of
                  Nephrology/Renal Pathology Society (ISN/RPS) proliferative nephritis: Class III,
                  Class IV, or Class V in combination with Class III or IV.

               -  Active urinary sediment and kidney biopsy documentation within the last 12 months
                  of ISN/RPS proliferative nephritis: Class III, Class IV, or Class V in
                  combination with Class III or IV. Active urinary sediment is defined as any one
                  of the following:

               -  >5 RBC/hpf in the absence of menses and infection;

               -  >5 White blood cell per high powered field (WBC/hpf) in the absence of infection;
                  or

               -  Cellular casts limited to RBC or WBC casts.

          4. Urine protein-to-creatinine ratio (UPCR) >1 at study entry based on a 24-hour
             collection.

          5. Ability to provide informed consent.

        Exclusion Criteria:

          1. New onset lupus nephritis, defined as lupus nephritis for which the participant has
             not yet been treated with either mycophenolate mofetil or cyclophosphamide.

          2. Neutropenia (absolute neutrophil count <1500/mm^3).

          3. Thrombocytopenia (platelets <50,000/mm^3).

          4. Moderately severe anemia (Hgb < mg/dL).

          5. Moderately severe hypogammaglobulinemia (IgG <450 mg/dL) or Immunoglobulin A (IgA)
             <10mg/dL.

          6. Positive QuantiFERON -Tuberculosis (TB) Gold test results.

          7. Pulmonary fibrotic changes on chest radiograph consistent with prior healed
             tuberculosis.

          8. Active bacterial, viral, fungal, or opportunistic infections.

          9. Evidence of infection with human immunodeficiency virus (HIV), hepatitis B (as
             assessed by HBsAg and anti-HBc) or hepatitis C.

         10. Hospitalization for treatment of infections, or parenteral (IV or IM) antibacterials,
             antivirals, anti-fungals, or anti-parasitic agents within the past 60 days.

         11. Chronic infection that is currently being treated with suppressive antibiotic therapy,
             including but not limited to tuberculosis, pneumocystis, cytomegalovirus, herpes
             simplex virus, herpes zoster, and atypical mycobacteria.

         12. History of significant infection or recurrent infection that, in the investigator's
             opinion, places the participant at risk by participating in this study.

         13. Receipt of a live-attenuated vaccine within 3 months of study enrollment.

         14. End-stage renal disease (eGFR <20 mL/min/1.73m^2).

         15. Concomitant malignancies or a history of malignancy, with the exception of adequately
             treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the
             cervix.

         16. History of transplantation.

         17. History of primary immunodeficiency.

         18. Pregnancy.

         19. Breastfeeding.

         20. Unwillingness to use an FDA-approved form of birth control (including but not limited
             to a diaphragm, an intrauterine device, progesterone implants or injections, oral
             contraceptives, the double-barrier method, or a condom).

         21. Use of cyclophosphamide within the past 6 months.

         22. Use of anti-Tumor Necrosis Factor (TNF) medication, other biologic medications, or
             experimental non- biologic therapeutic agents within the past 90 days, or 5 half-lives
             prior to screening, whichever is greater.

         23. Intravenous immunoglobulin (IVIG), plasmapheresis, or leukopheresis within the past 90
             days.

         24. Use of investigational biologic agent within the past 12 months.

         25. Prior treatment with rituximab, belimumab, atacicept, or other biologic B cell
             therapy.

         26. Liver function test [aspartate aminotransferase (AST), alanine aminotransferase (ALT),
             or alkaline phosphatase] results that are >=2 times the upper limit of normal.

         27. Severe, progressive, or uncontrolled renal, hepatic, hematological,gastrointestinal,
             pulmonary, cardiac, or neurological disease, either related or unrelated to SLE, with
             the exception of active lupus nephritis (or, in the investigator's opinion, any other
             concomitant medical condition that places the participant at risk by participating in
             this study).

         28. Comorbidities requiring corticosteroid therapy, including those which have required
             three or more courses of systemic corticosteroids within the previous 12 months.

         29. Current substance abuse or history of substance abuse within the past year.

         30. History of severe allergic or anaphylactic reactions to chimeric or fully human
             monoclonal antibodies.

         31. History of anaphylactic reaction to parenteral administration of contrast agents.

         32. Lack of peripheral venous access.

         33. History of severe depression or severe psychiatric condition.

         34. History of suicidal thoughts within the past 2 months or suicidal behavior within the
             past 6 months, or a significant suicide risk in the investigator's opinion.

         35. Inability to comply with study and follow-up procedures.