Non-TNFi Biologics vs Targeted Synthetic DMARDs for Rheumatoid Arthritis

(RA-PROPR Trial)

Recruiting at 48 trial locations

Overseen By Kevin W Byram, 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

Trial Summary

What is the purpose of this trial?

This trial is testing advanced medications for RA patients who haven't responded to standard treatments. It compares biologic drugs that target immune proteins and synthetic drugs that block harmful molecules in immune cells. The goal is to see which treatment improves patients' quality of life and daily functioning better. Biologic therapies have notably improved the treatment of RA, making disease remission a realistic goal.

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.

What data supports the effectiveness of the drugs used in the clinical trial for rheumatoid arthritis?

Research shows that tocilizumab and TNF inhibitors are effective for rheumatoid arthritis, especially after other treatments have been tried. Tocilizumab, in particular, has been compared favorably to TNF inhibitors in certain cases, suggesting it can be a strong option for patients who have not responded to other biologic drugs. ^{1 2 3 4 5}

What safety data exists for Non-TNFi Biologics and Targeted Synthetic DMARDs in humans?

TNF inhibitors do not show an increased risk of cancer and have a lower risk of blood clots compared to conventional DMARDs. Tocilizumab, an interleukin-6 inhibitor, may increase the risk of intestinal perforations. Janus kinase inhibitors, like tofacitinib, can increase the risk of shingles. Rituximab is effective but not usually a first choice due to safety concerns. ^{1 5 6 7 8}

How do non-TNFi biologics and targeted synthetic DMARDs for rheumatoid arthritis differ from other drugs?

Non-TNFi biologics and targeted synthetic DMARDs offer alternative mechanisms of action compared to traditional TNF inhibitors, targeting specific pathways in the immune system. This can be beneficial for patients who do not respond well to TNF inhibitors, providing more personalized treatment options. ^{1 4 5 9 10}

Research Team

Jasvinder Singh, MD

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. England 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. [2015]

2. England 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. [2022]

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

Indirect comparison of biological treatments in refractory rheumatoid arthritis. [2018]

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

Treatment Persistence and Healthcare Costs Among Patients with Rheumatoid Arthritis After a Change in Targeted Therapy. [2022]

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

Proposal for a new nomenclature of disease-modifying antirheumatic drugs. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

[Risk profile of disease-modifying antirheumatic drugs: an update from the RABBIT register]. [2021]

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

Pharmacotherapy options in rheumatoid arthritis. [2022]

8. United States 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. [2022]

9. Canada 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. [2021]

10. England 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. [2022]