Belimumab + Rituximab for Systemic Sclerosis

Overseen By Liza Morales

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Hospital for Special Surgery, New York

Must be taking: Mycophenolate Mofetil

Must not be taking: Anti-fibrotics, Corticosteroids, Biologics, others

Disqualifiers: Severe lung disease, HIV, Hepatitis, 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: Unknown

Duration: 48 weeks

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 two medications, Belimumab (an immunosuppressive drug) and Rituximab (a monoclonal antibody), with a stable dose of Mycophenolate Mofetil (MMF), can improve skin fibrosis (thickening and hardening of skin) in individuals with early diffuse cutaneous systemic sclerosis (dcSSc). Participants will receive either the combination treatment or a placebo while continuing their MMF. The goal is to assess whether the combination treatment is more effective than the placebo in reducing skin problems caused by dcSSc. Individuals diagnosed with dcSSc for less than 3 years and experiencing significant skin symptoms might be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires participants to stay on Mycophenolate Mofetil (MMF) throughout the study. If you are taking other medications, especially anti-fibrotic agents or certain biologics, you may need to stop them before joining the trial. The protocol does not specify for all medications, so it's best to discuss your current medications with the study team.

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

Research is testing the safety of combining Belimumab and Rituximab to treat systemic sclerosis, a condition that hardens and tightens the skin. Previous studies showed that Rituximab alone reduced skin thickening and scarring. Patients using Rituximab also required fewer steroids, which can have serious side effects.

Earlier studies found that the combination of Belimumab and Rituximab was generally well-tolerated, with most patients not experiencing unexpected or severe side effects. This suggests it might be safe for individuals with early diffuse cutaneous systemic sclerosis (dcSSc).

However, this treatment is still under investigation. While early results are promising, more research is needed to confirm its safety and effectiveness. Those considering joining a trial should discuss the potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatment for systemic sclerosis, which often includes medications like immunosuppressants and steroids, the combination of Belimumab and Rituximab offers a unique approach by targeting specific parts of the immune system. Belimumab is a monoclonal antibody that inhibits B-cell activating factor, potentially reducing the abnormal immune response seen in systemic sclerosis. Rituximab, another monoclonal antibody, targets CD20 on B-cells, helping to deplete these cells that may be contributing to the disease. Researchers are excited because this dual-target strategy could offer a more precise way to manage the condition, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for systemic sclerosis?

Research has shown that using Belimumab and Rituximab together may help treat systemic sclerosis (SSc). In this trial, one group of participants will receive the combination therapy of Belimumab and Rituximab alongside MMF. One study found that patients who received this combination therapy experienced a 70% reduction in an important disease marker compared to those who took a placebo. Another study found that patients taking Belimumab had better skin health, as indicated by improved skin scores, compared to those on a placebo. These findings suggest that the combination of Belimumab and Rituximab might improve symptoms in people with systemic sclerosis. ^{1 2 3 5 6}

Who Is on the Research Team?

Robert Spiera, MD

Principal Investigator

Hospital for Special Surgery, New York

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with early diffuse cutaneous systemic sclerosis (dcSSc), diagnosed within the last 3 years, and a modified Rodnan Skin Score over 14. Participants must not have used certain drugs like Belimumab or Rituximab before, be free from severe infections or lung disease, and agree to use effective contraception.

Inclusion Criteria

I have been diagnosed with diffuse cutaneous systemic sclerosis.

My first non-Raynaud's symptom appeared less than 3 years ago.

Your skin score is higher than 14.

Exclusion Criteria

I do not have any health conditions that would make it unsafe for me to take a new drug.

My condition has been diagnosed for over 3 years.

I haven't taken any anti-fibrotic drugs like colchicine or tyrosine kinase inhibitors in the last month.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Belimumab and Rituximab or placebo, with background Mycophenolate Mofetil for 48 weeks

48 weeks

Weekly subcutaneous injections and two infusions two weeks apart

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Belimumab
• MMF
• Placebo Infusion
• Placebo Subcutaneous Injection
• Rituximab

Trial Overview The study tests if combining Belimumab and Rituximab improves skin fibrosis in dcSSc patients compared to placebo. All participants will continue their Mycophenolate Mofetil (MMF) treatment. The active drugs or placebos are given via subcutaneous injections and intravenous infusions over a year.

How Is the Trial Designed?

Group I: MMF + Rituximab + Belimumab Experimental Treatment 3 Interventions

Two infusions of 1000 mg of Rituximab, two weeks apart, weekly subcutaneous injections of 200 mg of Belimumab, and background MMF, 1000 -1500 mg twice daily for 48 weeks.

Group II: MMF + Placebo + Placebo Placebo Group 3 Interventions

Two placebo infusions of normal saline, two weeks apart, weekly saline placebo subcutaneous injections, and background MMF, 1000 -1500 mg twice daily for 48 weeks.

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?

Hospital for Special Surgery, New York

Lead Sponsor

Trials

257

Recruited

61,800+

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

Published Research Related to This Trial

In a 52-week pilot study involving 20 patients with early diffuse cutaneous systemic sclerosis (dcSSc), treatment with belimumab alongside mycophenolate mofetil (MMF) showed a greater median decrease in skin thickness (MRSS) compared to placebo, although this difference was not statistically significant.

Both treatment groups experienced significant improvements in MRSS, and belimumab treatment was associated with a notable reduction in profibrotic gene expression, suggesting its potential mechanism of action in reducing fibrosis in dcSSc.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. Gordon, JK., Martyanov, V., Franks, JM., et al.[2023]

Rituximab treatment in 15 patients with systemic sclerosis led to a significant decrease in CD4+IL4+ T cells in both skin and peripheral blood, indicating a potential mechanism for its effects on skin fibrosis and lung function.

The study found that while CD4+IL4+ T cells decreased significantly after rituximab treatment compared to standard treatment, other T cell subpopulations (CD4+INFγ+ and CD4+IL17+) did not show significant changes, suggesting a targeted effect of rituximab on specific immune pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell depletion treatment decreases CD4+IL4+ and CD4+CD40L+ T cells in patients with systemic sclerosis. Antonopoulos, I., Daoussis, D., Lalioti, ME., et al.[2021]

The BLISS-BELIEVE study is a 104-week trial involving 200 adults with systemic lupus erythematosus (SLE) that aims to compare the efficacy and safety of belimumab alone versus belimumab combined with rituximab, focusing on disease control and remission rates.

The primary goal is to determine the proportion of patients achieving disease control at week 52, with safety monitored through the incidence of adverse events, highlighting the potential for enhanced treatment outcomes through combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. Teng, YKO., Bruce, IN., Diamond, B., et al.[2020]

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 a study of 24 patients with progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD), rituximab (RTX) significantly improved lung function after one year, with an increase in %pFVC by 8.8% and %pDLCO by 4.6%.

RTX also allowed for a reduction in prednisone dosage, with 25% of patients able to stop taking it altogether, indicating its potential as a safe and effective add-on therapy for patients who did not respond to conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression. Narváez, J., LLuch, J., Molina-Molina, M., et al.[2021]

In an open-label study of 8 patients with diffuse cutaneous systemic sclerosis (dc-SSc), rituximab effectively depleted B-cells and significantly improved skin sclerosis scores after 24 weeks (p<0.001).

Rituximab treatment also led to notable improvements in skin histopathology, including reduced collagen content and myofibroblast numbers, while being well tolerated with only two serious adverse events deemed unrelated to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Smith, V., Van Praet, JT., Vandooren, B., et al.[2022]

In a study involving 364 patients with systemic lupus erythematosus (SLE), long-term treatment with belimumab combined with standard therapy demonstrated a stable or declining incidence of adverse events over 4 years, indicating a favorable safety profile.

The most common side effects were mild, such as arthralgia and upper respiratory infections, and serious infusion reactions were rare, suggesting that belimumab can be safely administered for extended periods in SLE patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Merrill, JT., Ginzler, EM., Wallace, DJ., et al.[2013]

Rituximab therapy significantly improved skin scores and disease severity in 20 patients with diffuse systemic sclerosis over a follow-up period of approximately 48.5 months.

The treatment also helped preserve lung function, with 85.7% of patients showing stable forced vital capacity (FVC) and over 80% maintaining stable lung imaging scores, indicating its potential as a modifying therapy for early diffuse systemic sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Bosello, SL., De Luca, G., Rucco, M., et al.[2016]

Rituximab was found to be safe and well tolerated in a pilot study involving 15 patients with diffuse cutaneous systemic sclerosis (dcSSc), with only minor adverse events reported.

While rituximab effectively depleted B cells in the skin and circulation, it did not significantly improve skin thickness or show clear benefits for other organ involvement, indicating limited efficacy in treating dcSSc.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Lafyatis, R., Kissin, E., York, M., et al.[2022]

Rituximab, a B cell-targeted biologic used for autoimmune diseases, has a low incidence of serious infections, but there is a rare risk of progressive multifocal leucoencephalopathy, occurring in about 5 out of 100,000 patients, with no proven causal link established.

Repeated use of rituximab can lead to hypogammaglobulinaemia, which increases the risk of serious infections, highlighting the need for careful monitoring of patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B Cell Therapies, Approved and Emerging: a Review of Infectious Risk and Prevention During Use. Md Yusof, MY., Vital, EM., Buch, MH.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03844061

Study Details | NCT03844061 | Belimumab and Rituximab ... Determine whether rituximab/belimumab/mmf is more effective than placebo/placebo/mmf, as measured by change in CRISS, which is a composite outcome measure ...

2. hss.edu hss.edu/research/clinical-trials/belimumab-rituximab-diffuse-cutaneous-systemic-sclerosis

A Randomized, Double-Blind, Placebo-Controlled Study of ... The main purpose of this randomized controlled clinical trial is to learn about the safety of the experimental treatment of SSc with the combination of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6590997/

Belimumab for the Treatment of Early Diffuse Systemic ... The MRSS changed by a median of −10 (IQR −13, −9) in the belimumab group and by a median of −3.0 (IQR −15, −1) in the placebo group (P = 0.411) (Figure 1B).

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/61/NCT03844061/Prot_SAP_000.pdf

A Randomized, Double-Blind, Placebo- Controlled study of ... This is a randomized, double-blind, placebo-controlled study to assess efficacy of Rituximab and. Belimumab combination therapy in patients with diffuse ...

5. ajmc.com ajmc.com/view/phase-ii-study-suggest-belimumab-after-rituximab-leads-to-improvement-in-sle

Phase 2 Study Suggests Belimumab After Rituximab Leads ... In patients refractory to conventional therapy, the combination resulted in a 70% reduction in a key biomarker compared with placebo.

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0003496724022829

Outcomes of patients with systemic sclerosis treated with ... The outcomes showed a high efficacy on skin fibrosis, but not on lung. Patients treated with rituximab were 2-fold more likely to stop or decrease steroids.