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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining rituximab and cyclosporine (an immunosuppressant) is safe and effective for treating membranous nephropathy, a kidney condition that causes protein leakage into the urine. The trial will assess whether this combination can reduce kidney damage by calming the immune system. Suitable candidates for this trial have been diagnosed with membranous nephropathy through a kidney biopsy in the last two years and have experienced high protein levels in their urine for at least six months. Participants will receive both medications and undergo regular check-ups to monitor their health and the treatment's effects. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant medical advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using rituximab and cyclosporine together can be effective and generally safe for treating membranous nephropathy, a kidney condition. Past studies have shown that this combination significantly reduces protein in the urine, with many patients experiencing a decrease or disappearance of symptoms within a year.

While this treatment appears promising, side effects can occur. Some patients experienced relapses, with symptoms returning after improvement. However, many patients still achieved either full or partial improvement, indicating that most handle the treatment well.

As this is a Phase 2 trial, researchers are closely monitoring the treatment's safety. Phase 2 trials primarily assess the treatment's effectiveness while also observing patient responses. Prospective participants should discuss any concerns with the trial team to understand the possible risks and benefits. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for glomerulonephritis focus on managing symptoms and slowing disease progression with drugs like corticosteroids or standard immunosuppressants. But this new treatment, combining rituximab and cyclosporine, offers a unique approach. Rituximab targets B-cells, which are part of the immune system that can contribute to kidney damage in glomerulonephritis. Meanwhile, cyclosporine helps reduce immune system activity more broadly. The combination of these two drugs could provide a more effective way to control the immune response and protect the kidneys, sparking excitement among researchers for its potential to offer better outcomes for patients.

What evidence suggests that the combination of rituximab and cyclosporine could be an effective treatment for membranous nephropathy?

Research has shown that using rituximab and cyclosporine together, as studied in this trial, can effectively treat membranous nephropathy. One study found that 92% of patients experienced partial or complete symptom improvement within 9 months, and 54% achieved complete symptom relief after 12 months. Previous studies have also found that rituximab alone works as well as cyclosporine in easing symptoms. Combining these two drugs might lead to even better results, such as lowering protein levels in urine, an important indicator of the disease. Although some patients might experience a return of symptoms, these findings suggest a promising treatment option. ^{1 2 4 6 7}

Who Is on the Research Team?

Meryl A Waldman, M.D.

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5138549/

Membranous Nephropathy: Pilot Study of a Novel Regimen ... Combined complete or partial remission was achieved in 92% of patients by 9 months; 54% achieved complete remission at 12 months. Two patients relapsed during ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2468024916300080

Pilot Study of a Novel Regimen Combining Cyclosporine ... Combined complete or partial remission was achieved in 92% of patients by 9 months; 54% achieved complete remission at 12 months. Two patients relapsed during ...

3. academic.oup.com academic.oup.com/ndt/article/39/12/2058/7646078

Rituximab or cyclosporine A for the treatment of membranous ... The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00977977

Rituximab Plus Cyclosporine in Idiopathic Membranous ... The combination of Rituximab and cyclosporine may achieve greater reductions in proteinuria, increase the number of remissions (especially complete) of the ...

5. ajkd.org ajkd.org/article/S0272-6386(21)00690-9/fulltext

Combination of Rituximab, Low-Dose Cyclophosphamide, ... After 1 year, the median UPCR fell from 8.4 (IQR, 5.0-10.7) to 0.3 (IQR, 0.2-0.8) g/g (P < 0.001). No patient relapsed throughout the duration ...

6. mdpi.com mdpi.com/2227-9059/13/9/2157

The Use of Rituximab in Glomerulonephritis At 12 months, rituximab was shown to be non-inferior compared with cyclosporine in inducing remission (60% vs. 52%). However, at 24 months, one ...

7. link.springer.com link.springer.com/article/10.1007/s10157-023-02431-0

Rituximab in combination with cyclosporine and steroid ... The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions ...