Belimumab With Rituximab for Primary Membranous Nephropathy (REBOOT)
Membranous Nephropathy, Nephrotic Syndrome
About this trial
This is an interventional treatment trial for Membranous Nephropathy focused on measuring Primary Membranous Nephropathy, nephrotic syndrome, Pharmacokinetics (PK) Analysis, Double-Blind (Masked), Placebo-Controlled Clinical Trial, Co-administered belimumab and rituximab
Eligibility Criteria
Inclusion Criteria:
Subjects must meet all of the following criteria to be eligible for this study-
Diagnosis of one of the following:
Primary membranous nephropathy (MN):
- Confirmed by kidney biopsy obtained in the past 5 years, or
- If relapsing following a complete remission or partial remission, confirmed with a kidney biopsy obtained in the past 7 years
- Nephrotic syndrome, and a contraindication to kidney biopsy (e.g., anti-coagulation, solitary kidney, body habitus that increases the risk of biopsy, or other contraindication in the opinion of the investigator).
- Serum anti-PLA2R positive;
- Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m^2 while on maximally tolerated renin-angiotensin system (RAS) blockade;
Proteinuria:
- ≥4 and < 8 g/day that has been present for ≥ 3 months while on while on maximally tolerated RAS blockade, or
- ≥8 g/day while on maximally tolerated RAS blockade.
Blood pressure while on maximally tolerated RAS blockade:
- Systolic blood pressure ≤ 140 mmHg, and
- Diastolic blood pressure ≤ 90 mmHg
Exclusion Criteria:
Subjects meeting any of the following criteria will not be eligible for this study-
- Secondary cause of membranous nephropathy (MN) (e.g., systemic lupus erythematosus (SLE), drug, infection, malignancy) suggested by review of the subject's medical history and/or clinical presentation;
- Rituximab use within the previous 12 months;
Rituximab use > 12 months ago:
- With an undetectable CD19 B cell count, or
- Did not result in a complete remission (CR) or partial remission (PR) with rituximab treatment alone (e.g., without other immunosuppressive or immunomodulatory therapy).
- Use of anti-B cell therapy other than rituximab within the previous 12 months (or 5 half-lives, whichever is greater);
- Cyclophosphamide use within the past 3 months;
- Use of other immunosuppressive medications, such as cyclosporine or tacrolimus, within the past 30 days;
- Use of systemic corticosteroids within the past 30 days;
- Use of any biologic investigational agent, defined as any drug not approved for sale in the country it is used, in the previous 12 months;
- Use of any non-biologic investigational agent in the past 30 days (or 5 half-lives, which ever is greater);
- Poorly controlled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 9.0%
Patients with diabetic glomerulopathy on renal biopsy that is:
- Greater than Class I diabetic glomerulopathy, or
- Class I diabetic glomerulopathy with a history of poor diabetic control (e.g., HbA1c ≥ 9.0%) since time of biopsy;
- Unstable kidney function defined as > 15% decrease in the Estimated Glomerular Filtration Rate (eGFR) during the previous 3 months;
- Decrease in proteinuria by 50% or more during the previous 12 months;
- White blood cell (WBC) count < 3.0 x 10^3/µl;
- Absolute neutrophil count < 1.5 x 10^3/µl;
- Moderately severe anemia (hemoglobin <9mg/dL);
- History of primary immunodeficiency;
- Serum immunoglobulin A (IgA) < 10 mg/dL;
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = ≥2 times the upper limit of normal (ULN);
- Positive human immunodeficiency virus (HIV) serology;
- Positive hepatitis C virus (HCV) serology, unless treated with anti-viral therapy with achievement of a sustained virologic response (undetectable viral load 24 weeks after cessation of therapy);
- Evidence of current or prior infection with hepatitis B, as indicated by a positive HBsAg, positive HBcAb, or positive HBsAb serology without history of vaccination;
Positive QuantiFERON - tuberculosis (TB) Gold test results,
--Note: Tuberculin Purified Protein Derivative (PPD) test may be substituted for QuantiFERON - TB Gold test.
- History of lung disease with FVC < 70% predicted, DLCO < 70% predicted, or requiring supplemental oxygen;
History of malignant neoplasm within the last 5 years,
--Exception: basal cell or squamous cell carcinoma of the skin treated with local resection only, or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years.
- Absence of individualized, age-appropriate cancer screening;
- Women of child-bearing potential who are pregnant, nursing, or unwilling to be sexually inactive or use FDA-approved contraception until study week 104;
Acute or chronic infection, including:
- current use of suppressive therapy for chronic infection,
- hospitalization for treatment of infection in the past 60 days, or
- parenteral anti-microbial (including anti-bacterial, anti-viral, or anti-fungal agents) use in the past 60 days for infection.
History of anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies, including:
- rituximab, or
- belimumab.
Evidence of serious suicide risk, including:
- any history of suicidal behavior in the last 6 months,
- any suicidal ideation in the last 2 months, or
- who, in the investigator's judgment, pose a significant suicide risk.
- Evidence of current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence in the past 12 months;
- Vaccination with a live vaccine within the past 30 days;
- Other diseases or conditions which, in the opinion of the investigator, would put the subject at risk or confound the results of the study; or
- Inability to comply with study and follow-up procedures.
Sites / Locations
- University of Alabama at Birmingham School of Medicine: Division of Nephrology
- University of California San Francisco
- Stanford University School of Medicine: Division of Nephrology
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center:Division of Nephrology and Hypertension
- Mayo Clinic Jacksonville: Department of Nephrology and Hypertension
- University of Miami Miller School of Medicine, Div of Nephrology
- National Institutes of Health Clinical Center
- Boston Medical Center: Renal Medicine
- University of Minnesota Health Clinical Research Unit
- Mayo Clinic Rochester: Department of Nephrology and Hypertension
- Washington University in St. Louis
- University of Nebraska
- Columbia University Medical Center: Division of Nephrology
- University of North Carolina School of Medicine: Division of Nephrology and Hypertension, Kidney Center
- Ohio State University Wexner Medical Center: Division of Nephrology
- University of Pennsylvania: Department of Medicine: Renal-Electrolyte and Hypertension Division
- Vanderbilt University Medical Center: Division of Nephrology and Hypertension
- Providence Medical Research Center, Providence Health Care: Nephrology
- The University of British Columbia: Division of Nephrology
- University of Toronto, Sunnybrook Health Sciences Centre: Nephrology
- University of Toronto, University Health Network: Nephrology
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Experimental
Experimental
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Part A: Low Proteinuria Group - Belimumab and Rituximab
Part A :High Proteinuria Group - Belimumab and Rituximab
Part B: Low Proteinuria Group - Belimumab and Rituximab
Part B: Low Proteinuria Group - Placebo and Rituximab
Part B :High Proteinuria Group - Belimumab and Rituximab
Part A :High Proteinuria Group - Placebo and Rituximab
Open-label pharmacokinetics (PK) phase. Participants with low proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6. Low proteinuria classification: The excretion of ≥4 to <8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).
Open-label pharmacokinetics (PK) phase. Participants with high proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6. High proteinuria classification: The excretion of ≥8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).
Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive subcutaneous belimumab 400 mg (two 200 mg injections) once weekly from weeks 0-3, and then 200 mg once weekly from weeks 4-51. Participants will receive rituximab infusions at Weeks 4 and 6. At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two out of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36): Anti-PLA2R level is ≥ 25% of baseline Proteinuria is ≥ 50% of baseline Serum albumin is < 2.8 g/dL
Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive subcutaneous belimumab placebo 400 mg (two 200 mg injections) once weekly from weeks 0-3, and then 200 mg once weekly from weeks 4-51. Participants will receive rituximab infusions at Weeks 4 and 6. At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two out of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36): Anti-PLA2R level is ≥ 25% of baseline Proteinuria is ≥ 50% of baseline Serum albumin is < 2.8 g/dL
Participants in the high proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive subcutaneous belimumab 400 mg (two 200 mg injections) once weekly from weeks 0-3, and then 200 mg once weekly from weeks 4-51. Participants will receive rituximab infusions at Weeks 4 and 6. At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two out of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36): Anti-PLA2R level is ≥ 25% of baseline Proteinuria is ≥ 50% of baseline Serum albumin is < 2.8 g/dL
Participants in the high proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive belimumab placebo weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.