Non-TNFi Biologics vs Targeted Synthetic DMARDs for Rheumatoid Arthritis

(RA-PROPR Trial)

Recruiting at 48 trial locations

Overseen By Kent C Kwoh, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Alabama at Birmingham

Must be taking: TNFi-biologic

Must not be taking: Leflunomide, Sulfasalazine

Disqualifiers: HIV, Heart failure, Hepatitis, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

924 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks the best treatment for individuals with rheumatoid arthritis (RA) who continue to experience symptoms despite using TNFi-biologics. Researchers are comparing two treatments: non-TNFi biologics (such as rituximab or tocilizumab) and targeted synthetic DMARDs (like tofacitinib or baricitinib). The aim is to determine which treatment improves daily living and overall well-being more effectively. Ideal candidates for this trial are those with active, disabling RA who have not found success with TNFi biologics. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

You may need to stop certain medications before joining the trial. If you are taking leflunomide, sulfasalazine, cyclosporine, or azathioprine, you must stop them at least 2 months before starting the study. However, you can continue taking conventional synthetic DMARDs like methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide if you've been on a stable dose for at least 4 weeks before the study.

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

Research has shown that the treatments in this trial have generally been well-tolerated in past studies. Non-TNFi biologics, such as rituximab and tocilizumab, have not been linked to a higher risk of major heart problems compared to other treatments. Studies also indicate that these biologics do not increase the risk of serious side effects for people with rheumatoid arthritis.

For targeted synthetic DMARDs, such as tofacitinib and upadacitinib, research supports their overall safety. However, some studies found a higher risk of certain issues, like heart problems and cancer, with JAK inhibitors (a type of DMARD). Despite this, many patients find their safety profiles acceptable.

Both treatment options have been used in other situations, providing a wealth of safety information. Prospective trial participants should consult with a healthcare provider to understand how these findings might relate to their health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for rheumatoid arthritis because they offer new options beyond the standard TNFi biologics. The non-TNFi-biologics, like rituximab and tocilizumab, work by targeting different molecules involved in inflammation, potentially providing relief for patients who haven't responded to other treatments. Meanwhile, targeted synthetic DMARDs, such as tofacitinib and upadacitinib, offer an oral alternative that can specifically inhibit certain pathways in the immune system, making them a convenient and potentially effective option. These treatments expand the toolkit for managing rheumatoid arthritis, providing hope for better outcomes and more personalized approaches.

What evidence suggests that this trial's treatments could be effective for rheumatoid arthritis?

This trial will compare the effectiveness of non-TNFi biologics and targeted synthetic DMARDs for individuals with rheumatoid arthritis (RA) who haven't found relief with previous treatments. Studies have shown that switching to non-TNFi biologics, such as rituximab, abatacept, and tocilizumab, can reduce symptoms in patients who did not respond well to other drugs. Similarly, switching to targeted synthetic DMARDs, such as upadacitinib, baricitinib, and tofacitinib, has shown promise. Research indicates that these medications can improve joint health and quality of life over time. Both newer biologic drugs and targeted synthetic medications offer good options for those still struggling with RA symptoms. ^{6 7 8 9 10}

Who Is on the Research Team?

Jasvinder Singh, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for patients with active, disabling rheumatoid arthritis who have not improved after using a TNFi-biologic for at least 3 months or stopped due to side effects. They must be on stable doses of certain other medications if used and have access to the study drugs through insurance or assistance programs. People with recent steroid injections, sensitivity to all drug options in the trial, certain infections, untreated hepatitis B/C, pregnant/nursing women, HIV history, multiple prior biologics use or specific heart conditions cannot join.

Inclusion Criteria

I have severe, active rheumatoid arthritis not improved by TNFi treatment or stopped due to side effects.

I have been on a stable dose of my rheumatoid arthritis medication for at least 4 weeks.

My insurance covers at least one drug from each treatment option.

Exclusion Criteria

I haven't had any steroid injections in the last month.

I have not received a live vaccine in the last 90 days.

I have latent TB and haven't started treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants switch to either a non-TNFi biologic or a targeted synthetic DMARD for treatment of active RA

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• non-TNFi-biologic class
• targeted synthetic DMARD class
• TNFi-biologic class
• tsDMARD class

Trial Overview The RA-PRO PRAGMATIC TRIAL is testing whether switching to a non-TNFi biologic (like rituximab) or a targeted synthetic DMARD (like tofacitinib) is more effective for those whose rheumatoid arthritis remains active despite previous treatment with TNFi-biologics. The study aims to provide solid evidence on which option might work better by comparing patient outcomes.

How Is the Trial Designed?

Group I: targeted synthetic DMARD class Active Control 1 Intervention

Switching to a targeted synthetic DMARD (choice from targeted synthetic DMARDs; currently available are tofacitinib, baricitinib, upadacitinib) in people with active RA despite current treatment

Group II: non-TNFi-biologic class Active Control 1 Intervention

Switching to a non-TNFi-biologic (choice from non-TNFi-biologics; currently available are rituximab, abatacept, tocilizumab, or sarilumab) in people with active RA despite current treatment,

non-TNFi-biologic class is already approved in European Union, United States for the following indications:

Approved in European Union as Rituximab for:

• Rheumatoid arthritis
• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia

Approved in European Union as Abatacept for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Approved in European Union as Tocilizumab for:

• Rheumatoid arthritis
• Systemic juvenile idiopathic arthritis
• Giant cell arteritis

Approved in European Union as Sarilumab for:

• Rheumatoid arthritis

Approved in United States as Rituximab for:

• Rheumatoid arthritis
• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia

Approved in United States as Abatacept for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Approved in United States as Tocilizumab for:

• Rheumatoid arthritis
• Systemic juvenile idiopathic arthritis
• Giant cell arteritis

Approved in United States as Sarilumab for:

• Rheumatoid arthritis

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Published Research Related to This Trial

In a study of 6203 rheumatoid arthritis patients, those who switched from TNF inhibitors to alternative mechanisms of action (MOA) had higher treatment persistence rates (50.3%) compared to those who cycled within TNF inhibitors (45.2%).

Patients cycling between alternative MOA agents also showed improved persistence (51.4%) and significantly lower healthcare costs per persistent patient, suggesting that switching medication classes can be more effective and cost-efficient when initial therapies fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Persistence and Healthcare Costs Among Patients with Rheumatoid Arthritis After a Change in Targeted Therapy. Bonafede, MMK., McMorrow, D., Proudfoot, C., et al.[2022]

Tocilizumab (TCZ) showed significantly longer drug retention compared to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis who had previously used at least one biologic DMARD, with median retention times of 2.31 years for TCZ monotherapy and 1.98 years for TCZ in combination therapy versus 1.37 years for TNFi combination therapy.

Both TCZ monotherapy and combination therapy demonstrated similar efficacy in terms of disease activity reduction compared to TNFi therapies, making TCZ a viable treatment option for patients with inadequate response to prior biologic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of tocilizumab versus TNF inhibitors as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis after the use of at least one biologic disease-modifying antirheumatic drug: analyses from the pan-European TOCERRA register collaboration. Lauper, K., Nordström, DC., Pavelka, K., et al.[2022]

A systematic review of ten clinical trials found that all biological treatments for rheumatoid arthritis, including adalimumab, etanercept, infliximab, abatacept, tocilizumab, golimumab, and certolizumab pegol, were more effective than placebo, indicating their overall efficacy in patients resistant to DMARDs.

Indirect comparisons showed that these biological drugs had similar efficacy based on the ACR50 response criteria, suggesting that their choice should be based on safety and convenience rather than effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect comparison of biological treatments in refractory rheumatoid arthritis. Gallego-Galisteo, M., Villa-Rubio, A., Alegre-del Rey, E., et al.[2018]

Adding a TNF inhibitor (TNFi) to a synthetic DMARD in patients with rheumatoid arthritis (RA) results in higher healthcare costs (€124,942 for TNFi strategy vs. €65,584 for synthetic strategy) but provides significant health benefits, making it cost-effective when considering production losses.

The cost per additional quality-adjusted life-year (QALY) gained from TNFi treatment is €61,285 using the EQ-5D measure, indicating a 90% probability of cost-effectiveness at the Norwegian willingness-to-pay threshold of €67,300.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of TNF inhibitors vs synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a Markov model study based on two longitudinal observational studies. Kvamme, MK., Lie, E., Uhlig, T., et al.[2015]

In a study of 7740 rheumatoid arthritis patients, nearly 49% stopped their first-line biologic or targeted synthetic DMARD treatment, with 37% classified as primary failures, primarily due to lack of efficacy.

Among those who switched from first-line tumor necrosis factor inhibitors (TNFi), 43% opted for another TNFi, despite longer persistence observed with second-line treatments like rituximab, which had a median duration of 39 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reasons for Biologic and Targeted Synthetic Disease-modifying Antirheumatic Drug Cessation and Persistence of Second-line Treatment in a Rheumatoid Arthritis Dataset. Youssef, P., Marcal, B., Button, P., et al.[2021]

In a study involving patients with rheumatoid arthritis (RA) from a large US healthcare registry, there were no significant differences in effectiveness between first-line treatments using tumor necrosis factor inhibitors (TNFi) and non-TNFi options after one year.

However, TNFi treatment was associated with a lower incidence of anemia compared to non-TNFi treatments, suggesting a potential safety advantage for TNFi in this regard.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of first-line tumour necrosis factor inhibitor versus non-tumour necrosis factor inhibitor biologics and targeted synthetic agents in patients with rheumatoid arthritis: results from a large US registry study. Pappas, DA., St John, G., Etzel, CJ., et al.[2022]

The emergence of new therapeutics for rheumatoid arthritis, including kinase inhibitors and biosimilars, suggests a need for a revised classification system for disease-modifying antirheumatic drugs (DMARDs).

The proposed nomenclature divides DMARDs into two main categories: biological DMARDs (boDMARDs and bsDMARDs) and synthetic DMARDs (conventional csDMARDs and targeted tsDMARDs), which could enhance clarity in clinical studies and reviews.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Smolen, JS., van der Heijde, D., Machold, KP., et al.[2022]

The German biologics register RABBIT and European data show that TNF inhibitors do not increase the overall risk of cancer and are associated with a lower frequency of venous thromboembolism compared to conventional DMARDs.

Tocilizumab, an interleukin-6 inhibitor, is linked to a higher incidence of lower intestinal tract perforations, while Janus kinase inhibitors raise the risk of herpes zoster, highlighting the need for careful monitoring of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Risk profile of disease-modifying antirheumatic drugs: an update from the RABBIT register]. Albrecht, K., Strangfeld, A.[2021]

Biologic agents are recommended for rheumatoid arthritis patients who do not respond well to traditional DMARDs, with anti-TNF agents being the most commonly used first-line biologic treatment.

Tocilizumab may be the most effective biologic when used alone, while rituximab is effective but not typically used first due to safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy options in rheumatoid arthritis. Kumar, P., Banik, S.[2022]

Tofacitinib, an oral Janus kinase inhibitor, shows comparable efficacy and tolerability to biological DMARDs in treating moderate-to-severe rheumatoid arthritis, based on a systematic review of 45 randomized clinical trials.

Both the 5 mg and 10 mg doses of tofacitinib, whether used alone or in combination with DMARDs, had similar rates of discontinuation due to adverse events compared to other treatment options, indicating it is a safe alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib versus Biologic Treatments in Moderate-to-Severe Rheumatoid Arthritis Patients Who Have Had an Inadequate Response to Nonbiologic DMARDs: Systematic Literature Review and Network Meta-Analysis. Bergrath, E., Gerber, RA., Gruben, D., et al.[2022]

Citations

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Compared efficacy of rituximab, abatacept, and tocilizumab in ... Our aim was to compare the efficacy of rituximab, tocilizumab, and abatacept in individuals with rheumatoid arthritis (RA) refractory to treatments with MTX or ...

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FRI0082 EFFECTIVENESS OF TNF INHIBITORS VS. NON- ... Objectives: To characterize patients switching for medical reasons after failure of a non-TNFi used as 1st bDMARD, and to assess the effectiveness of rituximab ...

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Comparative safety of biologic and targeted synthetic disease ... In this large nationwide study, rituximab and IL-6i users had numerically higher, but not statistically significant, MACE risk.

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