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.
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.
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.
Condition | Membranous Nephropathy, Nephrotic Syndrome |
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Treatment | Rituximab, belimumab, Placebo for Belimumab |
Clinical Study Identifier | NCT03949855 |
Sponsor | National Institute of Allergy and Infectious Diseases (NIAID) |
Last Modified on | 13 October 2022 |
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