Belimumab + Rituximab for Kidney Disease

(REBOOT Trial)

Recruiting at 25 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 8

58 Participants Needed

Trial Summary

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}

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.

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.

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
• Rituximab

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)

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

PPD DEVELOPMENT, LP

Industry Sponsor

Trials

167

Recruited

38,000+

David Simmons

PPD DEVELOPMENT, LP

Chief Executive Officer since 2012

BSc in Applied Science from Georgia Institute of Technology

Martina Flammer

PPD DEVELOPMENT, LP

Chief Medical Officer since 2024

MD

PPD Development, LP

Industry Sponsor

Immune Tolerance Network (ITN)

Collaborator

Trials

68

Recruited

7,900+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

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)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

PPD

Industry Sponsor

Trials

162

Recruited

36,600+

Dr. Austin Smith

PPD

Chief Medical Officer since 2020

Doctor of Medicine from the Royal College of Surgeons in Ireland

David Simmons

PPD

Chief Executive Officer since 2012

Bachelor’s degree in Applied Mathematics and Industrial Management from Carnegie Mellon University

Rho Federal Systems Division, Inc.

Industry Sponsor

Trials

44

Recruited

15,000+

Findings from Research

In a review of two randomized controlled trials, belimumab significantly improved the odds of achieving a complete renal response in patients with lupus nephritis, showing 1.71 times higher odds compared to the control group.

Belimumab was found to be safe, with no significant increase in treatment-related adverse events compared to standard treatment, indicating it can be effectively used in the maintenance phase for lupus nephritis without raising safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belimumab in Lupus Nephritis: A Systematic Review and Meta-Analysis. Shrestha, S., Budhathoki, P., Adhikari, Y., et al.[2022]

In a study of 17 female patients with lupus nephritis treated with belimumab for a median of 36 months, all patients experienced resolution of arthralgia and skin manifestations, indicating its efficacy in managing these symptoms.

Belimumab treatment led to normalization of proteinuria in three patients and allowed for the reduction or complete withdrawal of corticosteroids in 35% of patients, demonstrating its potential to improve kidney function and reduce reliance on steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belimumab may decrease flare rate and allow glucocorticoid withdrawal in lupus nephritis (including dialysis and transplanted patient). Binda, V., Trezzi, B., Del Papa, N., et al.[2021]

Belimumab is a fully-humanized monoclonal antibody that effectively inhibits B-lymphocyte stimulator, and it has been approved for treating adults with autoantibody-positive systemic lupus erythematosus (SLE), showing a favorable safety profile in phase III trials.

Rituximab, a chimeric anti-CD20 monoclonal antibody, is also used in SLE treatment, and the review discusses its safety and efficacy alongside belimumab, providing insights into their use in both adult and pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted B cell therapies in the treatment of adult and pediatric systemic lupus erythematosus. Hui-Yuen, JS., Nguyen, SC., Askanase, AD.[2017]

In the phase 3 BLISS-LN study involving 448 patients with lupus nephritis, belimumab significantly improved kidney-related outcomes compared to placebo, with a higher percentage of patients achieving primary and complete renal responses, especially in relapsed patients.

The efficacy of belimumab was consistent regardless of whether patients received glucocorticoid pulses during induction therapy, indicating its potential as a reliable treatment option for both newly diagnosed and relapsed lupus nephritis.

NCBI (Pubmed)

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. Anders, HJ., Furie, R., Malvar, A., et al.[2023]

The combination of rituximab and belimumab was found to be safe for patients with refractory lupus nephritis, showing no increase in adverse events compared to those receiving rituximab alone.

While the addition of belimumab did not improve clinical efficacy compared to rituximab and cyclophosphamide alone, it did lead to a greater reduction in certain B cell populations, suggesting a mechanism that enhances the negative selection of autoreactive B cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Atisha-Fregoso, Y., Malkiel, S., Harris, KM., et al.[2022]

Rituximab was used as a rescue therapy in 27 patients with kidney disease, showing a success rate of 48% in improving kidney function and managing conditions like nephrotic syndrome and humoral rejection after transplantation.

While rituximab did not increase the overall risk of complications associated with standard immunosuppression, it was linked to serious but reversible toxic leukoencephalopathy, particularly at higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical evaluation of rituximab rescue in 27 patients with different types of kidney disease. Ganzemueller, J., Hartmann, B., Keller, F., et al.[2017]

In a pilot study involving 10 children with frequently relapsing nephrotic syndrome, belimumab was found to be well tolerated with no infusion reactions, but it did not significantly reduce the number of relapses or the cumulative prednisone dose compared to the 6 months prior to treatment.

The study was terminated early due to the lack of clear benefits from belimumab, suggesting that the inconvenience of monthly intravenous infusions outweighed any potential advantages, while also indicating that memory B cells may still play a pathogenic role in the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belimumab for the treatment of children with frequently relapsing nephrotic syndrome: the BELNEPH study. Vivarelli, M., Colucci, M., Gargiulo, A., et al.[2022]

Rituximab was administered to a 10-year-old patient with end-stage renal failure and immediate recurrence of nephrotic syndrome after a kidney transplant, leading to a partial remission initially.

Despite the initial response to rituximab, the patient later developed severe respiratory failure and ultimately passed away due to respiratory acute lung injury (RALI), highlighting potential severe complications associated with rituximab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal rituximab-associated lung injury syndrome in a patient treated with rituximab for recurrence of post-transplant nephrotic syndrome. Grenda, R., Jarmużek, W., Rubik, J., et al.[2015]

Rituximab was successfully used to treat IgA nephropathy in a patient with recessive dystrophic epidermolysis bullosa, marking a novel application of this treatment.

This case represents the first documented instance in medical literature of using rituximab for this specific condition, highlighting its potential as a therapeutic option.

NCBI (Pubmed)

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. Hunjan, MK., Bardhan, A., Harper, N., et al.[2022]

Rituximab, a monoclonal antibody targeting CD20 on B cells, has shown efficacy in inducing remission and reducing proteinuria in patients with membranous nephropathy, an autoimmune disease causing nephrotic syndrome in adults.

Evidence supports the use of B-cell depletion with rituximab as an effective initial therapy for nephrotic patients with membranous nephropathy, highlighting its potential as a treatment option beyond its original use in lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Rituximab in the Treatment of Membranous Nephropathy. Maharjan, R., Wang, JW., Shrestha, IK.[2021]

References

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

Belimumab in Lupus Nephritis: A Systematic Review and Meta-Analysis. [2022]

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]

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

Targeted B cell therapies in the treatment of adult and pediatric systemic lupus erythematosus. [2017]

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]

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]

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

Critical evaluation of rituximab rescue in 27 patients with different types of kidney disease. [2017]

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

Belimumab for the treatment of children with frequently relapsing nephrotic syndrome: the BELNEPH study. [2022]

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]

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]

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

The Efficacy of Rituximab in the Treatment of Membranous Nephropathy. [2021]