Rituximab + Cyclosporine for Glomerulonephritis

Recruiting at 2 trial locations

Overseen By Meryl A Waldman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must be taking: Blood pressure medications

Must not be taking: Immunosuppressants, Experimental drugs

Disqualifiers: Low GFR, HIV, HCV, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 6 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: * Membranous nephropathy is associated with damage to the walls of the glomeruli, the small blood vessels in the kidneys that filter waste products from the blood. This damage causes leakage of blood proteins into the urine and is associated with low blood protein levels, high blood cholesterol values, and swelling of the legs. These problems can decrease or go away without treatment in about 25 percent of patients, but if they persist, some patients may experience impaired (or loss of) kidney function, blood vessel and heart disease, and a risk of forming blood clots in veins. * Kidney biopsies that show that antibodies have been deposited along the glomeruli suggest that specialized cells of the immune system, called B and T cells, are causing damage to the kidneys through their increased activity. To suppress the action of B and T cells and to decrease the harmful deposits in the kidneys, drug treatments are required. * Patients with membranous nephropathy are often treated with immunosuppressive drugs such as cyclosporine or cytoxan plus steroids that attempt to reduce or suppress the activity of the immune system, decrease antibody production, and reduce antibody deposits in the kidney. However, not everyone responds to these medications and the kidney disease can return in some patients when the drugs are stopped. Also, there are side effects associated with long term usage of these medications. Rituximab, a different immunosuppressant, has also been used for this purpose. Although cyclosporine and Rituximab have been used separately, they have not been tried in combination as a possible treatment for membranous nephropathy. Objectives: - To determine the safety and effectiveness of combining rituximab and cyclosporine to treat membranous nephropathy. Eligibility: - Individuals 18 years of age and older who have been diagnosed with membranous nephropathy based on a kidney biopsy done within the preceding 24 months, and who have had excess levels of protein in the urine for at least 6 months based on urine and blood tests. Design: * Potential participants will be screened with an initial clinic evaluation and full medical history. * Before the treatment, there will be a run-in period that will last up to 2 months. During this time, participants will be placed on a blood pressure lowering medication and will not take any other immunosuppressant medications. * Participants will visit the NIH clinical center for a baseline evaluation, four intravenous infusions of rituximab, and also at 1- to 6-month intervals throughout the study. * Active treatment period will involve a 6-month course of cyclosporine and a total of four doses of rituximab. Participants will take cyclosporine tablets twice daily, and have two infusions of rituximab given 2 weeks apart, After 6 months, the cyclosporine dose will slowly be decreased over several weeks and then completely discontinued. Participants will then receive another course (two doses 2 weeks apart) of rituximab, depending on results of blood work. * Participants will have frequent blood and urine tests performed to monitor the results of treatment and reduce the chance of side effects.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any immunosuppressant medications before starting the trial. There is a run-in period of up to 2 months where you will only take a blood pressure lowering medication.

What data supports the effectiveness of the drug combination Rituximab and Cyclosporine for treating glomerulonephritis?

Rituximab has shown effectiveness in treating certain kidney conditions like lupus nephritis and membranous nephropathy, with some patients achieving remission. However, its effectiveness for primary glomerulonephritis is limited and controversial, with mixed results in case reports. ^{1 2 3 4 5}

How is the drug combination of Rituximab and Cyclosporine unique for treating glomerulonephritis?

The combination of Rituximab and Cyclosporine for glomerulonephritis is unique because Rituximab targets CD20 lymphocytes, which are part of the immune system, and is used as a nonstandard therapy for those not eligible for routine treatments. This approach is different from standard treatments and may offer an alternative for patients with limited options. ^{1 2 4 6 7}

Research Team

Meryl A Waldman, M.D.

Principal Investigator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Eligibility Criteria

Adults over 18 with membranous nephropathy confirmed by kidney biopsy within the last 24 months, and persistent proteinuria despite treatment. Participants must be able to take oral medication, adhere to a specific regimen, and use effective contraception if of reproductive potential. Exclusions include HIV/HCV positivity, recent cancer (except skin), severe liver disease, certain blood disorders, diabetes, low kidney function, recent immunosuppressants or rituximab use.

Inclusion Criteria

Ability to understand and willingness to sign a written informed consent document

I have high levels of protein in my urine despite taking angiotensin antagonist for 2 months or I cannot tolerate it.

My blood pressure has been 140/90 or lower on most checks while on medication for 1-2 months.

Exclusion Criteria

I have diabetes.

I have used cyclosporine or tacrolimus for over 6 months or had a bad reaction to them.

My kidney function is low, with a GFR under 40, while on specific blood pressure meds.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Run-in Period

Participants are placed on a blood pressure lowering medication and will not take any other immunosuppressant medications

Up to 8 weeks

1 visit (in-person)

Treatment

Participants receive a 6-month course of cyclosporine and four doses of rituximab, with cyclosporine dose tapered and discontinued after 6 months

6 months

Multiple visits at 1- to 6-month intervals

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

Frequent blood and urine tests

Treatment Details

Interventions

• Cyclosporine
• Rituximab

Trial Overview The trial is testing the combination of Rituximab infusions and oral Cyclosporine in treating membranous nephropathy. It involves an initial evaluation followed by a run-in period without other immunosuppressants. Treatment includes four doses of Rituximab and six months of Cyclosporine therapy with follow-up visits for monitoring through frequent blood and urine tests.

Participant Groups

Group I: Combination of Rituximab plus cyclosporine Experimental Treatment 2 Interventions

2 infusions (each 1000 mg) separated by 2 weeks; repeated after 6 months. Daily therapy for 6 months (3-5 mg/kg), then tapered and discontinued.

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

Approved in European Union as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in United States as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Approved in Canada as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in Japan as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Who Is Running the Clinical Trial?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

Findings from Research

In a study of 16 children with steroid-resistant or steroid-dependent nephrotic syndrome, rituximab treatment led to remission in 7 patients, indicating its potential efficacy as a nonstandard immunosuppressive therapy.

The treatment was well-tolerated, with no significant side effects or changes in leukocyte counts observed, suggesting that rituximab could be a safe alternative for patients not responding to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of rituximab treatment in children with primary glomerulonephritis. Zachwieja, J., Silska, M., Ostalska-Nowicka, D., et al.[2015]

Rituximab therapy showed variable efficacy in two male patients with rapidly progressive kidney failure due to primary proliferative glomerulonephritis; one patient improved significantly in kidney function after treatment, while the other did not respond at all.

Both patients experienced severe infections following rituximab therapy, highlighting the potential safety concerns of using this treatment in individuals with pre-existing renal impairment and high-dose corticosteroid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab therapy for primary glomerulonephritis: Report on two cases. Fabrizi, F., Cresseri, D., Fogazzi, GB., et al.[2020]

In a study of 17 patients with refractory lupus nephritis, rituximab treatment led to complete or partial renal remission in 53% of cases after 12 months, indicating its potential efficacy as an alternative treatment.

Rituximab also significantly improved proteinuria levels and allowed for a reduction in steroid dosages, suggesting it may help manage the side effects associated with standard treatments like corticosteroids and cyclophosphamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the effectiveness and safety of rituximab in patients with refractory lupus nephritis: a chart review. Contis, A., Vanquaethem, H., Truchetet, ME., et al.[2022]

A 23-year-old woman with severe granulomatosis with polyangiitis (GPA) and rapidly progressive glomerulonephritis (RPGN) showed significant improvement after receiving a combination therapy of rituximab and plasma exchange (PE), leading to stabilization of her condition over a 5-year follow-up.

The combination treatment effectively halted alveolar hemorrhage and improved kidney function, suggesting that rituximab and PE may be a promising approach for managing severe cases of GPA that do not respond to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent treatment with rituximab and plasma exchange for severe refractory granulomatosis with polyangiitis: A case report. Song, R., Chung, SW., Lee, YA.[2022]

Rituximab successfully induced remission in a young male patient with nephrotic syndrome related to membranous nephropathy, but the patient experienced complications such as delayed serum sickness after the seventh infusion.

Ofatumumab, a fully human anti-CD20 monoclonal antibody, also achieved remission in subsequent relapses of nephrotic syndrome with fewer side effects and at a lower cost compared to rituximab, suggesting it may be a safe and effective alternative for patients who do not respond to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ofatumumab for multirelapsing membranous nephropathy complicated by rituximab-induced serum-sickness. Podestà, MA., Ruggiero, B., Remuzzi, G., et al.[2022]

A single-dose treatment of rituximab in renal transplant recipients with recurrent glomerulonephritis (GN) showed a lower incidence of acute rejection compared to controls, with no increase in infection rates, suggesting a safer profile for this approach.

While the overall efficacy of rituximab was similar to non-rituximab treatments at 36 months, it was particularly effective for patients with recurrent membranous nephropathy, achieving a complete response in 40% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose rituximab for recurrent glomerulonephritis post-renal transplant. Spinner, ML., Bowman, LJ., Horwedel, TA., et al.[2019]

A 56-year-old male with membranoproliferative glomerulonephritis Type I and a history of low-grade B cell lymphoma showed significant improvement after receiving immunochemotherapy with rituximab and bendamustine.

The treatment led to complete remission of nephrotic syndrome, marked improvement in renal function and blood pressure, normalization of urinary sediment, and complete disappearance of proteinuria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remission of a B cell CLL-associated membranoproliferative glomerulonephritis Type I with rituximab and bendamustine. Bartel, C., Obermüller, N., Rummel, MJ., et al.[2019]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Efficacy and safety of rituximab treatment in children with primary glomerulonephritis. [2015]

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

Rituximab therapy for primary glomerulonephritis: Report on two cases. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Analysis of the effectiveness and safety of rituximab in patients with refractory lupus nephritis: a chart review. [2022]

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

Concurrent treatment with rituximab and plasma exchange for severe refractory granulomatosis with polyangiitis: A case report. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Ofatumumab for multirelapsing membranous nephropathy complicated by rituximab-induced serum-sickness. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Single-dose rituximab for recurrent glomerulonephritis post-renal transplant. [2019]

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

Remission of a B cell CLL-associated membranoproliferative glomerulonephritis Type I with rituximab and bendamustine. [2019]