Rituximab and Belimumab for Lupus Nephritis

Study Overview
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Brief Summary
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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.

Detailed Description
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Lupus nephritis is a severe form of systemic lupus erythematosus (SLE) with active disease in the kidneys. SLE is a complex disease in which the body's own immune system attacks some of the body parts: the skin, the joints, the kidneys, the nervous system, the heart, the lungs and the blood. The cause of SLE is not known. Treatment for SLE usually involves drugs that are designed to block the immune system attacks. When SLE affects the kidneys (nephritis), stronger immune suppressing treatment is usually needed. The drugs used in treatment of lupus nephritis often do not cure the disease and can cause serious side effects, including lowering the immune system too much. When the immune system is too low, a person is at a higher risk of getting infections. Therefore, research into new treatments with fewer serious side effects is needed for lupus nephritis.

Official Title
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Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis (ITN055AI)

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Biological: Rituximab
* Drug: Cyclophosphamide
* Drug: Prednisone
* Drug: Methylprednisolone
* Drug: Diphenhydramine
* Drug: Acetaminophen
* Biological: Rituximab
* Drug: Cyclophosphamide
* Drug: Prednisone
* Drug: Methylprednisolone
* Drug: Diphenhydramine
* Drug: Acetaminophen
* Biological: Belimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology (ACR) criteria. Positive antinuclear antibody (ANA) or positive anti-ds DNA test results at visit -1 or any time within 14 days before visit -1. 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. Urine protein-to-creatinine ratio (UPCR) >1 at study entry based on a 24-hour collection. Ability to provide informed consent. Exclusion Criteria: New onset lupus nephritis, defined as lupus nephritis for which the participant has not yet been treated with either mycophenolate mofetil or cyclophosphamide. Neutropenia (absolute neutrophil count <1500/mm^3). Thrombocytopenia (platelets <50,000/mm^3). Moderately severe anemia (Hgb < mg/dL). Moderately severe hypogammaglobulinemia (IgG <450 mg/dL) or Immunoglobulin A (IgA) <10mg/dL. Positive QuantiFERON -Tuberculosis (TB) Gold test results. Pulmonary fibrotic changes on chest radiograph consistent with prior healed tuberculosis. Active bacterial, viral, fungal, or opportunistic infections. Evidence of infection with human immunodeficiency virus (HIV), hepatitis B (as assessed by HBsAg and anti-HBc) or hepatitis C. Hospitalization for treatment of infections, or parenteral (IV or IM) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within the past 60 days. 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. History of significant infection or recurrent infection that, in the investigator's opinion, places the participant at risk by participating in this study. Receipt of a live-attenuated vaccine within 3 months of study enrollment. End-stage renal disease (eGFR <20 mL/min/1.73m^2). 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. History of transplantation. History of primary immunodeficiency. Pregnancy. Breastfeeding. 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). Use of cyclophosphamide within the past 6 months. 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. Intravenous immunoglobulin (IVIG), plasmapheresis, or leukopheresis within the past 90 days. Use of investigational biologic agent within the past 12 months. Prior treatment with rituximab, belimumab, atacicept, or other biologic B cell therapy. Liver function test [aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase] results that are >=2 times the upper limit of normal. 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). Comorbidities requiring corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the previous 12 months. Current substance abuse or history of substance abuse within the past year. History of severe allergic or anaphylactic reactions to chimeric or fully human monoclonal antibodies. History of anaphylactic reaction to parenteral administration of contrast agents. Lack of peripheral venous access. History of severe depression or severe psychiatric condition. 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. Inability to comply with study and follow-up procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab/Cyclophosphamide (RC)<br>Prednisone taper to 10 mg/day by week 12 and continue prednisone 10 mg/day to week 96. | Biological: Rituximab<br>* Rituximab 1000mg intravenously (IV) at week 0 and week 2<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Cyclophosphamide (750 mg) intravenously (IV) at week 0 and week 2.<br>* Other names: Cytoxan;Drug: Prednisone<br>* 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<br>* Other names: Deltasone;Drug: Methylprednisolone<br>* Week 0 and Week 2: Solumedrol (100 mg) IV<br>* Other names: Solu-Medrol;Drug: Diphenhydramine<br>* 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.<br>Drug: Acetaminophen<br>* Acetaminophen (650 mg) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.<br>* Other names: Tylenol;|
| Experimental: Rituximab/Cyclophosphamide/Belimumab (RCB)<br>Belimumab (10 mg/kg IV) at weeks 4, 6, 8, and every 4 weeks to week 48. Prednisone taper to 10 mg/day by week 12, and continue prednisone 10 mg/day to week 96. | Biological: Rituximab<br>* Rituximab 1000mg intravenously (IV) at week 0 and week 2.<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Cyclophosphamide (750 mg) intravenously (IV) at week 0 and week 2.<br>* Other names: Cytoxan;Drug: Prednisone<br>* 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<br>* Other names: Deltasone;Drug: Methylprednisolone<br>* Week 0 and Week 2: Solumedrol (100 mg) IV<br>* Other names: Solu-Medrol;Drug: Diphenhydramine<br>* 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.<br>Drug: Acetaminophen<br>* Acetaminophen (650 mg) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.<br>* Other names: Tylenol;Biological: Belimumab<br>* The RCB Group will receive IV belimumab 10mg/kg at weeks 4, 6, 8, and then every 4 weeks through week 48<br>* Other names: Benlysta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With At Least One Grade 3 or Higher Infectious Adverse Event By Week 24, Week 48 and Week 96 | The percentage of participants who experienced at least one Grade 3 or higher treatment-emergent infectious adverse event. The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03:June 14, 2010). Treatment-emergent AEs are those: with an onset date on or after the first dose of study medication, with onset before first dose but that worsened in severity after first dose, and for which the start of the AE in relation to the start of study medication could not be established. AEs were classified by system organ class and preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) version 17.0. Grade 3 or higher AEs were classified infectious based on the study team's review of the MedDRA body systems and preferred terms of the AEs. | Week 0 to Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With B Cell Reconstitution at Week 24, Week 48 and Week 96 | The percentage of participants who achieved B cell reconstitution, defined as a peripheral blood total B cell count ≥ to the baseline count or the lower limit of normal, whichever was lower. Note: B cell depletion was expected to occur in this study between Weeks 0 and 4, after initiation of rituximab and cyclophosphamide. Normal peripheral blood B Cell count: 107 to 698 cells/µL. | Week 24, Week 48 and Week 96 | 
| Percentage of Participants With Grade 4 Hypogammaglobulinemia by Week 24, Week 48, and Week 96 | The percentage of participants who experienced Grade 4 hypogammaglobulinemia, defined as having a serum Immunoglobulin G (IgG) level < 300 mg/dL. Severity of adverse events (AEs) was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03:June 14, 2010). | Week 24, Week 48 and Week 96 | 
| Percentage of Participants With a Complete Response at Week 24, Week 48, and Week 96 | The percentage of participants who achieved a complete response, defined as meeting all of the following criteria: Urine protein-to-creatinine ratio (UPCR) < 0.5, based on a 24-hour collection; Estimated glomerular filtration rate (eGFR) ≥ 120 ml/min/1.73 m^2 calculated by the CKD-EPI formula or, if < 120 ml/min/1.73 m^2, then > 80% of eGFR at entry; and Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions. | Week 24, Week 48 and Week 96 | 
| Percentage of Participants With an Overall Response at Week 24, Week 48, and Week 96 | The percentage of participants who achieved an overall response, defined as meeting all of the following criteria: >50% improvement in the urine protein-to-creatinine ratio (UPCR) from study entry, based on a 24-hour collection; Estimated glomerular filtration rate (eGFR) ≥120 ml/min/1.73 m^2 calculated by the CKD-EPI formula or, if < 120 ml/min/1.73 m^2, then > 80% of eGFR at entry; and Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions. | Week 24, Week 48 and Week 96 | 
| Percentage of Participants With a Sustained Complete Response | The percentage of participants who achieved a sustained complete response, defined as a complete response achieved at Week 48 and Week 96. Complete response was defined as meeting all of the following criteria: Urine protein-to-creatinine ratio (UPCR) < 0.5, based on a 24-hour collection; Estimated glomerular filtration rate (eGFR) ≥120 ml/min/1.73 m^2 calculated by the CKD-EPI formula or, if < 120 ml/min/1.73 m^2, then > 80% of eGFR at entry; and Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions. | Week 48, Week 96 | 
| Percentage of Participants With Treatment Failure by Week 24, Week 48, and Week 96 | The percentage of participants who met the criteria for treatment failure, defined by withdrawal from the protocol treatment regimen due to worsening nephritis, infection, or study medication toxicity. | Week 24, Week 48 and Week 96 | 
| Count of Participants: Frequency of Non-renal Flares by Week 24 | Count of participants who experienced non-renal flares, defined as any new A finding in a non-renal organ system in the British Isles Lupus Assessment Group (BILAG) assessment. A BILAG A finding represents a significant increase in, or a new manifestation of, disease activity. | Week 24 | 
| Count of Participants: Frequency of Non-renal Flares by Week 48 | Count of participants who experienced non-renal flares, defined as any new A finding in a non-renal organ system in the British Isles Lupus Assessment Group (BILAG) assessment. A BILAG A finding represents a significant increase in, or a new manifestation of, disease activity. | Week 48 | 
| Count of Participants: Frequency of Non-renal Flares by Week 96 | Count of participants who experienced non-renal flares, defined as any new A finding in a non-renal organ system in the British Isles Lupus Assessment Group (BILAG) assessment. A BILAG A finding represents a significant increase in, or a new manifestation of, disease activity. | Week 96 | 
| Percentage of Participants With an Negative Anti-dsDNA Result at Week 24, Week 48, and Week 96 | The percentage of participants who were anti-double stranded DNA (anti-dsDNA) negative, defined as having anti-dsDNA levels <30 IU/mL. Anti-dsDNA levels are associated with systemic lupus erythematosus disease activity. | Week 24, Week 48 and Week 96 | 
| Percentage of Participants Hypocomplementemic for Complement Component C3 at Week 24, Week 48, and Week 96 | The percentage of participants who were hypocomplementemic for complement component, C3, defined as a C3 level <90 mg/dL. Serum C3 complement is a protein which can be measured in the blood. Low blood levels of C3 are common in those with active lupus. | Week 24, Week 48 and Week 96 | 
| Percentage of Participants Hypocomplementemic for Complement Component C4 at Week 24, Week 48, and Week 96 | The percentage of participants who were hypocomplementemic for complemen component C4, defined as a C4 level <10 mg/dL. Serum C4 complement is a protein which can be measured in the blood. Low blood levels of C4 are common in those with active lupus. | Week 24, Week 48 and Week 96 | 
| Frequency of Specific Adverse Events of Interest By Event by Week 96 | Number of ≥ Grade 2 specific treatment-emergent adverse events (AEs) of interest. Grade 2 or higher AEs were classified according to the listed categories of interest based on the study team's review of the AEs. Treatment-emergent AEs are those: with an onset date on or after the first dose of study medication, with onset before first dose but that worsened in severity after first dose, and for which the start of the AE in relation to the start of study medication could not be established. The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03: June 14, 2010). AEs were classified by system organ class and preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) version 17.0. | Week 96 | 
| Frequency of Specific Adverse Events of Interest By Participant, By Week 96 | Number of participants who experienced ≥Grade 2 specific treatment-emergent adverse events (AEs) of interest. Grade 2 or higher AEs were classified according to the listed categories of interest based on the study team's review of the AEs. Treatment-emergent AEs are those: with an onset date on or after the first dose of study medication, with onset before first dose but that worsened in severity after first dose, and for which the start of the AE in relation to the start of study medication could not be established. The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03: June 14, 2010). AEs were classified by system organ class and preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) version 17.0. | Week 96 |