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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
43
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
University of Alabama, Birmingham
Birmingham, Alabama, United States
UCLA Medical Center: Division of Rheumatology
Los Angeles, California, United States
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.
Time frame: Week 0 to Week 96
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.
Time frame: 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).
Time frame: Week 24, Week 48 and Week 96
Percentage of Participants With a Complete Response at Week 24, Week 48, and Week 96
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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
University of California, San Francisco
San Francisco, California, United States
University of Colorado Denver: School of Medicine: Division of Rheumatology
Aurora, Colorado, United States
Colorado Kidney Care
Denver, Colorado, United States
Emory University School of Medicine
Atlanta, Georgia, United States
Washington University in St. Louis
St Louis, Missouri, United States
Feinstein Institute, North Shore Hospital
Manhasset, New York, United States
New York University, Langone Medical Center
New York, New York, United States
Weill Cornell Medical College: Hospital for Special Surgery -
New York, New York, United States
...and 5 more locations
The percentage of participants who achieved a complete response, defined as meeting all of the following criteria: 1. Urine protein-to-creatinine ratio (UPCR) \< 0.5, based on a 24-hour collection; 2. 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 3. Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions.
Time frame: 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: 1. \>50% improvement in the urine protein-to-creatinine ratio (UPCR) from study entry, based on a 24-hour collection; 2. 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 3. Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions.
Time frame: 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: 1. Urine protein-to-creatinine ratio (UPCR) \< 0.5, based on a 24-hour collection; 2. 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 3. Prednisone dose tapered to 10 mg/day and adherence to prednisone dosing provisions.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Week 96