Efficacy of Belimumab and Rituximab Compared to Rituximab Alone for the Treatment of Primary Membranous Nephropathy (ITN080AI) (REBOOT)

  • STATUS
    Recruiting
  • End date
    Oct 13, 2026
  • participants needed
    124
  • sponsor
    National Institute of Allergy and Infectious Diseases (NIAID)
Updated on 13 October 2022
cancer
remission
rituximab
monoclonal antibodies
monoclonal antibody
glomerular filtration rate
angiotensin
nephropathy
sjogren's syndrome
arthritis
proteinuria
lupus
autoimmune diseases
mammogram
systemic lupus erythematosus
kidney biopsy
nephrotic syndrome

Summary

The primary objective of this study is to evaluate the effectiveness of belimumab and intravenous rituximab co-administration at inducing a complete remission (CR) compared to rituximab alone in participants with PM.

Background

Primary membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in adults. MN affects individuals of all ages and races. The peak incidence of MN is in the fifth decade of life.

Primary MN is recognized to be an autoimmune disease, a disease where the body's own immune system causes damage to kidneys. This damage can cause the loss of too much protein in the urine.

Drugs used to treat MN aim to reduce the attack by one's own immune system on the kidneys by blocking inflammation and reducing the immune system's function. These drugs can have serious side effects and often do not cure the disease. There is a need for new treatments for MN that are better at improving the disease while reducing fewer treatment associated side effects.

In this study, researchers will evaluate if treatment with a combination of two different drugs, belimumab and rituximab, is effective at blocking the immune attacks on the kidney compared to rituximab alone. Rituximab works by decreasing a type of immune cell, called B cells. B cells are known to have a role in MN. Once these cells are removed, disease may become less active or even inactive. However, after stopping treatment, the body will make new B cells which may cause disease to become active again.

Belimumab works by decreasing the new B cells produced by the body and, may even change the type of new B cells subsequently produced. Belimumab is approved by the US Food and Drug Administration (FDA) to treat systemic lupus erythematosus (also referred to as lupus or SLE). Rituximab is approved by the FDA to treat some types of cancer, rheumatoid arthritis, and vasculitis. Neither rituximab nor belimumab is approved by the FDA to treat MN. Treatment with a combination of belimumab and rituximab has not been studied in individuals with MN, but it is currently being tested in other autoimmune diseases, including lupus nephritis and Sjögren's syndrome.

Description

This trial is a two-part study (Part A and Part B) of adults with primary membranous nephropathy (MN), ages 18-75 inclusive. The study will be conducted at multiple sites in the United States and Canada.

Part A: Open-label Phase

Part A is an open-label, pharmacokinetics (PK) phase to compare belimumab exposure between participants who have "low" proteinuria (≥ 4 to < 8 g/day) and "high" proteinuria (≥ 8 g/day) at the Screening Visit, Visit-1.

Part A will enroll 20 individuals with primary MN: 10 individuals with low proteinuria and 10 individuals with high proteinuria. All Part A participants will receive 200 mg subcutaneous belimumab weekly for 52 doses (weeks 0-51), unless a dose increase is warranted by the PK analysis. Trough serum belimumab levels will be obtained weekly following the first 4 doses of belimumab. Participants will receive rituximab 1000 mg intravenously (IV) at weeks 4 and 6.

All participants will be followed after the 52 week treatment period on no study medication until week 156.

Belimumab serum trough levels will be analyzed after all participants receive the first 4 belimumab doses to compare belimumab exposure between the low and high proteinuria groups. Belimumab serum trough levels will also be analyzed to determine if a different proteinuria level (instead of 8 g/day) warrants increased belimumab dosing and should be used to define "high" proteinuria.

Dose determinations for participants with high proteinuria in Parts A and B will be made by an adjudication committee.

The study participation phase is 156 weeks (3 years), which includes a treatment phase of 52 weeks and a post-treatment observation phase of 104 weeks.

Part B: Randomized Phase

Part B is a prospective, randomized, phase II, double-blind, placebo-controlled, multicenter clinical trial in adults with primary MN. Part B will commence after the analysis of the PK data in Part A.

A total of 104 participants will be randomized in a 1:1 fashion into two treatment arms.

Randomization will be stratified by low and high proteinuria as determined by the identified threshold in Part A.

Participants in both arms will receive rituximab 1000 mg IV at weeks 4 and 6. Participants randomized to the experimental arm will receive subcutaneous belimumab 200 mg weekly for 52 doses (weeks 0-51), unless the results from Part A indicate that participants with high proteinuria should receive belimumab 400 mg weekly. If the participant's proteinuria subsequently decreases to below the high proteinuria threshold, the belimumab dose will be decreased to 200 mg weekly for the remainder of the treatment phase.

Participants randomized to the comparator arm will receive subcutaneous belimumab placebo according to the same dose and schedule.

The study participation phase is 156 weeks (3 years), which includes a treatment phase of 52 weeks and a post-treatment observation phase of 104 weeks.

Details
Condition Membranous Nephropathy, Nephrotic Syndrome
Treatment Rituximab, belimumab, Placebo for Belimumab
Clinical Study IdentifierNCT03949855
SponsorNational Institute of Allergy and Infectious Diseases (NIAID)
Last Modified on13 October 2022

Eligibility

Yes No Not Sure

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
Proteinuria
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
Serum anti-PLA2R positive
biopsy, or other contraindication in the opinion of the investigator)
Blood pressure while on maximally tolerated RAS blockade
Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73m^2 while on maximally tolerated renin-angiotensin system (RAS) blockade
≥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
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)
Cyclophosphamide use within the past 3 months
Use of other immunosuppressive medications, such as cyclosporine or tacrolimus, 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)
Use of anti-B cell therapy other than rituximab within the previous 12 months (or 5
Use of systemic corticosteroids within the past 30 days
half-lives, whichever is greater)
Decrease in proteinuria by 50% or more during the previous 12 months
Moderately severe anemia (hemoglobin <9mg/dL)
Patients with diabetic glomerulopathy on renal biopsy that is
History of primary immunodeficiency
Greater than Class I diabetic glomerulopathy, or
Serum immunoglobulin A (IgA) < 10 mg/dL
Poorly controlled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 9.0%
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)
Class I diabetic glomerulopathy with a history of poor diabetic control (e.g., HbA1c ≥ 9.0%) since time of biopsy
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
Unstable kidney function defined as > 15% decrease in the Estimated Glomerular
\--Note: Tuberculin Purified Protein Derivative (PPD) test may be substituted
Filtration Rate (eGFR) during the previous 3 months
for QuantiFERON - TB Gold test
White blood cell (WBC) count < 3.0 x 10^3/µl
History of malignant neoplasm within the last 5 years
Absolute neutrophil count < 1.5 x 10^3/µl
\--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
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = ≥2 times the upper limit of normal (ULN)
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
History of lung disease with FVC < 70% predicted, DLCO < 70% predicted, or requiring supplemental oxygen
parenteral anti-microbial (including anti-bacterial, anti-viral, or anti-fungal agents) use in the past 60 days for infection
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
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
History of anaphylactic reaction to parenteral administration of contrast agents
human or murine proteins or monoclonal antibodies, including
Evidence of current drug or alcohol abuse or dependence, or a history of drug or
alcohol abuse or dependence in the past 12 months
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