Belimumab + Rituximab for Kidney Disease

(REBOOT Trial)

Recruiting in Palo Alto (17 mi)

+25 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: RAS blockers

Must not be taking: Cyclophosphamide, Cyclosporine, Tacrolimus, Corticosteroids

Disqualifiers: Secondary MN, Poor diabetes control, HIV, others

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The primary objective of this study is to evaluate the effectiveness of belimumab and intravenous rituximab co-administration at inducing a complete or partial remission (CR or PR) compared to rituximab alone in participants with primary membranous nephropathy. 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 has been tested in other autoimmune diseases, including lupus nephritis and Sjögren's syndrome.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must not have used rituximab in the past 12 months, cyclophosphamide in the past 3 months, or other immunosuppressive medications like cyclosporine or tacrolimus in the past 30 days. Additionally, you should not have used systemic corticosteroids in the past 30 days.

What data supports the effectiveness of the drug combination Belimumab and Rituximab for kidney disease?

Research shows that Belimumab can improve kidney outcomes in lupus nephritis, a type of kidney disease, by increasing the chances of a complete kidney response and reducing the likelihood of no response. Rituximab is also used in treating lupus nephritis, suggesting that the combination may be effective for kidney disease. ^{1 2 3 4 5}

How is the drug combination of Belimumab and Rituximab unique for treating kidney disease?

The combination of Belimumab and Rituximab is unique because it targets B cells, which play a role in kidney diseases like nephrotic syndrome. Rituximab is already used for various kidney conditions, and Belimumab adds another layer by modulating B cells, potentially offering a more comprehensive approach to treatment. ^{6 7 8 9 10}

Research Team

Patrick Nachman

Principal Investigator

University of Minnesota, Department of Medicine, Division of Renal Diseases and Hypertension

Iñaki Sanz

Principal Investigator

Emory University, Department of Medicine, Division of Rheumatology

Eligibility Criteria

Adults aged 18-75 with primary membranous nephropathy, confirmed by kidney biopsy within the last 5-7 years, and experiencing significant protein loss in urine despite treatment. Participants must have a stable kidney function and blood pressure under control. They should be vaccinated against COVID-19 as per CDC guidelines. Pregnant or breastfeeding women, recent recipients of certain immunosuppressants or live vaccines, and those with various health complications are excluded.

Inclusion Criteria

My blood test is positive for anti-PLA2R antibodies.

I have had protein in my urine between 4 and 8 g/day for the last 3 months despite treatment.

My blood pressure is 140 or lower with my current medication.

Exclusion Criteria

My condition might have a specific cause based on my medical history.

You have a positive QuantiFERON - TB Gold test.

You have a positive HIV test.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Open-label Phase (Part A)

Participants receive belimumab weekly and rituximab at weeks 4 and 6, followed by safety assessments

52 weeks

Weekly visits for belimumab administration, additional visits at weeks 4 and 6 for rituximab

Randomized Phase (Part B)

Participants are randomized to receive belimumab and rituximab or placebo and rituximab, with assessments at week 30

52 weeks

Weekly visits for belimumab or placebo administration, additional visits at weeks 4 and 6 for rituximab

Follow-up

Participants are monitored for safety and effectiveness after treatment, with primary endpoint assessment at week 104

104 weeks

Periodic visits for assessment

Treatment Details

Interventions

• Belimumab (Monoclonal Antibodies)
• Rituximab (Monoclonal Antibodies)

Trial Overview The trial is testing if belimumab combined with rituximab can induce complete remission in primary membranous nephropathy more effectively than rituximab alone. Belimumab may reduce new B cells that cause immune attacks on kidneys; neither drug is currently FDA-approved for this condition.

Participant Groups

Group I: Part B: Belimumab and Rituximab Experimental Treatment 2 Interventions

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

Group II: Part A: Low Proteinuria Group - Belimumab and Rituximab Experimental Treatment 2 Interventions

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).

Group III: Part A :High Proteinuria Group - Belimumab and Rituximab Experimental Treatment 2 Interventions

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).

Group IV: Part B: Placebo and Rituximab Placebo Group 2 Interventions

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

Belimumab is already approved in United States, European Union, Canada, Japan for the following indications:

🇺🇸 Approved in United States as Benlysta for:

• Systemic lupus erythematosus (SLE)

🇪🇺 Approved in European Union as Benlysta for:

• Systemic lupus erythematosus (SLE)

🇨🇦 Approved in Canada as Benlysta for:

• Systemic lupus erythematosus (SLE)

🇯🇵 Approved in Japan as Benlysta for:

• Systemic lupus erythematosus (SLE)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Toronto, Sunnybrook Health Sciences Centre: Nephrology Toronto, Canada

University of Toronto, University Health Network: Nephrology Toronto, Canada

Mayo Clinic Rochester: Department of Nephrology and Hypertension Rochester, MN

The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center:Division of Nephrology and Hypertension Torrance, CA

More Trial Locations

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3361

Patients Recruited

5,516,000+

PPD DEVELOPMENT, LP

Industry Sponsor

Trials

167

Patients Recruited

38,000+

Immune Tolerance Network (ITN)

Collaborator

Trials

68

Patients Recruited

7,900+

GlaxoSmithKline

Industry Sponsor

Trials

4834

Patients Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

PPD

Industry Sponsor

Trials

162

Patients Recruited

36,600+

Rho Federal Systems Division, Inc.

Industry Sponsor

Trials

44

Patients Recruited

15,000+

References

1. United States pubmed.ncbi.nlm.nih.gov

Belimumab in Lupus Nephritis: A Systematic Review and Meta-Analysis. [2022] Belimumab is a recombinant human IgG-1&#955; monoclonal antibody. It inhibits the B-cell activating factor&#160;(BAFF) and is approved for patients with systemic lupus erythematosus (SLE) older than five years with positive autoantibody. We aimed to evaluate the role of belimumab in the maintenance phase of treatment for lupus nephritis (LN). PubMed, PubMed Central (PMC), Cochrane Library, and Embase were searched using appropriate keywords. The screening of title and abstract was done in Covidence, followed by data extraction of the relevant studies based on inclusion criteria. Review manager (RevMan 5.4) was used for data analysis with random or fixed effects model based on heterogeneities. Two randomized controlled trials were included in the quantitative analysis. There were 1.71 times higher odds of complete renal response in the belimumab group than in the control group (odds ratio (OR), 1.71; 95% confidence interval (CI), 1.12-2.60; I-square (I2) &#8203;&#8203;&#8203;&#8203;= 0%). Similarly, there was 34% lower odds for having no response among the belimumab group (OR, 0.66; 95% CI, 0.45-0.96; I2 = 0%). No significant differences between the two groups were observed for the occurrence of treatment-related adverse events (TRAEs) (OR, 1.07; 95% CI, 0.74-1.56; I2 = 0%), treatment-related serious adverse events (OR, 0.54; 95% CI, 0.15-1.96; I2 = 68%), and treatment-related infections (OR, 0.65; 95% CI, 0.27-1.55; I2 = 21%).Therefore, belimumab and standard treatment were instrumental for beneficial renal response in patients with lupus nephritis and were not associated with increased odds of adverse effect compared with the standard treatment alone.

2. Italy pubmed.ncbi.nlm.nih.gov

Belimumab may decrease flare rate and allow glucocorticoid withdrawal in lupus nephritis (including dialysis and transplanted patient). [2021] Belimumab (Benlysta) is currently approved for the treatment of active Lupus despite standard therapy. Few data are available on the efficacy of this drug in lupus nephritis (LN).

3. England pubmed.ncbi.nlm.nih.gov

Targeted B cell therapies in the treatment of adult and pediatric systemic lupus erythematosus. [2017] Belimumab (Benlysta) is a fully-humanized monoclonal antibody that inhibits B-lymphocyte stimulator (also known as B cell activating factor) and was approved by the U.S. Federal Drug Administration and European Medicines Evaluation Agency for treatment in adults with autoantibody-positive systemic lupus erythematosus (SLE). Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody targeting B lymphocytes. This review discusses the key findings of the phase III trials in adults with SLE and of real-world use of belimumab and rituximab in the care of both adult and pediatric SLE patients. It highlights the safety profile of belimumab and rituximab and gives insight into the consideration of these therapies for specific SLE disease states. It concludes with a discussion of the current clinical trials investigating B cell therapies in specific SLE disease states and a look to the future, with ongoing clinical trials.

4. England pubmed.ncbi.nlm.nih.gov

Effect of belimumab on kidney-related outcomes in patients with lupus nephritis: post hoc subgroup analyses of the phase 3 BLISS-LN trial. [2023] Data on belimumab efficacy in patients with lupus nephritis (LN) according to diagnosis duration or induction therapy are limited. Post hoc analyses of the phase 3, randomized, double-blind BLISS-LN study (GSK BEL114054; NCT01639339) were performed to assess belimumab efficacy on kidney-related outcomes in newly diagnosed and relapsed LN subgroups and according to the use of glucocorticoid (GC) pulses at induction.

5. United States pubmed.ncbi.nlm.nih.gov

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. [2022] To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN).

6. Italy pubmed.ncbi.nlm.nih.gov

Critical evaluation of rituximab rescue in 27 patients with different types of kidney disease. [2017] Rituximab is increasingly being used in the treatment of patients with kidney disease. We evaluated our clinical experience at the Ulm University Hospital.

7. Germany pubmed.ncbi.nlm.nih.gov

Belimumab for the treatment of children with frequently relapsing nephrotic syndrome: the BELNEPH study. [2022] Effectiveness of rituximab in pediatric idiopathic nephrotic syndrome suggests that B cells play a pathogenic role. We tested safety and efficacy of the B-cell-modulating agent belimumab in frequently relapsing nephrotic syndrome (FRNS).

8. Denmark pubmed.ncbi.nlm.nih.gov

Fatal rituximab-associated lung injury syndrome in a patient treated with rituximab for recurrence of post-transplant nephrotic syndrome. [2015] Rituximab (anti-B CD20 ab.) in recently widely used in renal transplantation.

9. England pubmed.ncbi.nlm.nih.gov

Successful use of rituximab, an anti-CD20 monoclonal antibody, to treat IgA nephropathy in a patient with recessive dystrophic epidermolysis bullosa. [2022] We describe the successful use of rituximab for the treatment of IgA nephropathy in a patient with recessive dystrophic epidermolysis bullosa. To our knowledge, this is the first reported case in the literature.

10. Nepal pubmed.ncbi.nlm.nih.gov

The Efficacy of Rituximab in the Treatment of Membranous Nephropathy. [2021] Rituximab is a chimeric monoclonal antibody directed against the CD20 expressed on B cells, originally used to treat lymphoma but is increasingly used for the treatment of autoimmune diseases. Membranous nephropathy is an autoimmune disease resulting from the deposition of IgG and complements components onto the subepithelial layer of the glomerular capillary wall and remains the leading cause of nephrotic syndrome in adults. Several prospective and retrospective studies showed rituximab induces remission and may decrease proteinuria in patients with membranous nephropathy. Considerable evidence supports the use of B-cell depletion as initial therapy in nephrotic patients with membranous nephropathy. This review focuses on the efficacy and safety of rituximab in the treatment of membranous nephropathy. Keywords: Membranous nephropathy; rituximab; treatment.