DMARDs for Rheumatoid Arthritis

Overseen By Aimee B Schreiner, MS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Nebraska

Must be taking: Dmards

Disqualifiers: Pregnancy, Breastfeeding, No contraception, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 8

Duration: 16 weeks

400 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to identify factors that predict how well individuals with rheumatoid arthritis (RA) respond to treatment with disease-modifying antirheumatic drugs (DMARDs). Participants will receive one of several DMARD treatments, such as methotrexate, abatacept, or adalimumab. The study will also examine levels of superoxide radicals, molecules linked to inflammation, to determine if they change with treatment. This trial suits those diagnosed with RA who have experienced symptoms like joint swelling and morning stiffness for at least six weeks and are beginning a new DMARD medication. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to the development of potentially groundbreaking treatments.

Will I have to stop taking my current medications?

If you are already taking DMARDs, you must be on a stable dose for at least 6 weeks before starting the trial. If you are taking glucocorticoids, you need to be on a stable dose for at least 2 weeks.

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

Research shows that many drugs studied for rheumatoid arthritis (RA) have available safety data. Here’s a look at some of them:

1. **Abatacept**: Studies indicate abatacept is generally safe and well-tolerated in people with RA. Side effects are similar to those seen with a placebo, meaning it doesn't cause more issues than a dummy treatment.

2. **Adalimumab**: Long-term studies suggest adalimumab is generally safe for RA patients, but there is a higher risk of serious infections, which may require hospital care.

3. **Azathioprine**: About 15% of patients in earlier studies stopped using azathioprine due to side effects like stomach problems and changes in blood counts. These need monitoring during treatment.

4. **Baricitinib**: Research shows baricitinib is safe for long-term use in RA patients, with an average use of 4.6 years in studies. However, it requires careful monitoring for side effects.

5. **Certolizumab**: Certolizumab has a good safety record, but serious side effects, including infections like tuberculosis, can occur. Long-term data suggests it is safe when used correctly.

6. **Etanercept**: Etanercept is generally well-tolerated and has a strong safety profile, supported by ten years of safety data for treating moderate to severe RA.

7. **Golimumab**: Five-year safety data show golimumab is mostly safe but carries risks like serious infections, which are more common in RA patients on this medication.

8. **Hydroxychloroquine**: This drug is often used safely for RA, but it can cause blood disorders, which need monitoring.

9. **Infliximab**: Infliximab is FDA-approved for RA and has a known safety profile, though it can lead to serious infections.

10. **Leflunomide**: Generally safe, leflunomide is effective for RA, but serious side effects, like liver damage, have been reported.

11. **Methotrexate**: Known for being well-tolerated, methotrexate is the standard for RA treatment. Side effects can include nausea and mouth ulcers.

12. **Minocycline**: Studies show minocycline is beneficial and relatively safe, though rare lupus-like reactions can occur.

13. **Rituximab**: While effective, rituximab can cause serious infusion reactions, especially with the first dose.

14. **Sarilumab**: Sarilumab has a safety record similar to other RA drugs, with infections being the most common serious side effect.

15. **Sulfasalazine**: This drug is almost as effective as methotrexate but can be less tolerated due to stomach issues.

16. **Tofacitinib**: Tofacitinib is effective but carries some risks, including heart issues and cancer, in certain patients.

These drugs have been studied for safety, but each person may react differently. Always discuss potential risks and benefits with a healthcare provider before starting any new treatment. ^{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 a variety of mechanisms and targets beyond the current options. While traditional treatments often include methotrexate and biological agents like adalimumab, this trial explores a broader spectrum of drugs such as abatacept, which modulates immune cell activity, and tofacitinib, a JAK inhibitor targeting cellular signaling pathways directly. These approaches may provide more tailored and potentially effective options for patients who haven't responded to standard therapies. Additionally, treatments like rituximab, which targets B cells, and baricitinib, another JAK inhibitor, offer alternatives that could minimize side effects or improve outcomes for specific patient groups. This diversity in mechanisms and targets is what makes these treatments particularly promising.

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

This trial will compare various treatments for rheumatoid arthritis (RA), each in separate treatment arms. Research has shown that methotrexate, which participants in one arm may receive, is a top treatment for RA, with about 59.4% of patients experiencing success and 33% reaching remission. Abatacept, another treatment option, has increased remission rates from 46.1% to 55.2% over two years. Adalimumab, also being tested, remains effective long-term, especially when combined with methotrexate. Azathioprine benefits joint activity, though results may take weeks. Baricitinib works well for up to 6.5 years, maintaining low disease activity and achieving remission. Certolizumab reduces RA symptoms effectively, with a high response rate in some patients. Etanercept helps patients reach remission and improve joint health. Golimumab improves symptoms and physical function, with strong results in certain groups. Hydroxychloroquine slows disease progression and boosts methotrexate's effects. Infliximab reduces symptoms and prevents joint damage. Leflunomide decreases joint pain and swelling. Minocycline is safe and moderately effective for joint conditions. Rituximab significantly reduces symptoms and slows joint damage, especially after other treatments fail. Sarilumab quickly and lastingly improves RA symptoms. Sulfasalazine helps control joint disease activity. Tofacitinib significantly reduces disease activity and remains effective over time. Each of these treatments has a proven track record of improving symptoms and quality of life for RA patients. ^{6 7 8 9 10}

Who Is on the Research Team?

James R O'Dell, MD

Principal Investigator

University of Nebraska

Are You a Good Fit for This Trial?

This trial is for adults diagnosed with Rheumatoid Arthritis (RA) who meet specific criteria like morning stiffness, joint swelling, and positive RA factors. They must be starting a new DMARD medication and have stable doses of any other DMARDs or low-dose glucocorticoids. Pregnant individuals or those not using contraception are excluded.

Inclusion Criteria

Able to adhere to study visit schedule: enrollment, 8 wks & 16 wks (+/- 2 wks)

I have been on a stable dose of my current medication for at least 6 weeks.

I was diagnosed with rheumatoid arthritis after turning 19.

Exclusion Criteria

Pregnant or breastfeeding women

I am not willing to use contraception.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive DMARD therapy for rheumatoid arthritis, with potential dose adjustments by the investigator

16 weeks

Visits at baseline, week 8, and week 16

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Abatacept
• Adalimumab
• Azathioprine
• Baricitinib
• Certolizumab
• Etanercept
• Golimumab
• Hydroxychloroquine
• Infliximab
• Leflunomide
• Methotrexate
• Minocycline
• Rituximab
• Sarilumab
• Sulfasalazine
• Tofacitinib

Trial Overview The study tests how well different Disease-Modifying Antirheumatic Drugs (DMARDs) work for treating RA over 16 weeks. It aims to find predictors of treatment response by adjusting dosages as needed and monitoring the generation of inflammation-related radicals in the blood.

How Is the Trial Designed?

Group I: Methotrexate Therapy Active Control 1 Intervention

Participants will receive methotrexate therapy for rheumatoid arthritis (RA) treatment.

Group II: Abatacept Therapy Active Control 1 Intervention

Participants will receive abatacept therapy for rheumatoid arthritis (RA) treatment.

Group III: Adalimumab Therapy Active Control 1 Intervention

Participants will receive adalimumab therapy for rheumatoid arthritis (RA) treatment.

Group IV: Azathioprine Therapy Active Control 1 Intervention

Participants will receive azathioprine therapy for rheumatoid arthritis (RA) treatment.

Group V: Barcitinib Therapy Active Control 1 Intervention

Participants will receive barcitinib therapy for rheumatoid arthritis (RA) treatment.

Group VI: Certolizumab Therapy Active Control 1 Intervention

Participants will receive certolizumab therapy for rheumatoid arthritis (RA) treatment.

Group VII: Etanercept Therapy Active Control 1 Intervention

Participants will receive etanercept therapy for rheumatoid arthritis (RA) treatment.

Group VIII: Golimumab Therapy Active Control 1 Intervention

Participants will receive golimumab therapy for rheumatoid arthritis (RA) treatment.

Group IX: Hydroxycholoroquine Therapy Active Control 1 Intervention

Participants will receive hydroxychloroquine therapy for rheumatoid arthritis (RA) treatment.

Group X: Infliximab Therapy Active Control 1 Intervention

Participants will receive infliximab therapy for rheumatoid arthritis (RA) treatment.

Group XI: Leflunomide Therapy Active Control 1 Intervention

Participants will receive leflunomide therapy for rheumatoid arthritis (RA) treatment.

Group XII: Minocycline Therapy Active Control 1 Intervention

Participants will receive minocycline therapy for rheumatoid arthritis (RA) treatment.

Group XIII: Rituximab Therapy Active Control 1 Intervention

Participants will receive rituximab therapy for rheumatoid arthritis (RA) treatment.

Group XIV: Sarilumab Therapy Active Control 1 Intervention

Participants will receive sarilumab therapy for rheumatoid arthritis (RA) treatment.

Group XV: Sulfasalazine Therapy Active Control 1 Intervention

Participants will receive sulfasalazine therapy for rheumatoid arthritis (RA) treatment.

Group XVI: Tofacitinib Therapy Active Control 1 Intervention

Participants will receive tofacitinib therapy for rheumatoid arthritis (RA) treatment.

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

Approved in European Union as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in United States as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in Canada as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Approved in Japan as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Who Is Running the Clinical Trial?

University of Nebraska

Lead Sponsor

Trials

563

Recruited

1,147,000+

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 showed significant improvement in joint symptoms for 10 out of 15 patients with systemic sclerosis (SSc) after 5 months, indicating its effectiveness for treating refractory polyarthritis.

Abatacept also improved joint parameters in patients after 11 months, but it did not show any benefit for muscle symptoms in SSc-myopathy, suggesting that while both treatments are safe, their efficacy may vary depending on the specific symptoms being treated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Elhai, M., Meunier, M., Matucci-Cerinic, M., et al.[2022]

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]

Conventional disease-modifying antirheumatic drugs (DMARDs), like injectable gold, still show significant efficacy in treating rheumatoid arthritis (RA), with improvements in disease activity and X-ray progression comparable to modern biologics.

Despite the introduction of biologics, conventional DMARDs should be considered first-line treatments due to their effectiveness and lower cost, as they have demonstrated similar clinical benefits in trials, suggesting they are not outdated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Have traditional DMARDs had their day? Effectiveness of parenteral gold compared to biologic agents. Rau, R.[2018]

In a study of 3162 adults with rheumatoid arthritis, rituximab and tocilizumab showed significantly longer durations of survival without treatment failure compared to abatacept, with average durations of 19.8 months and 19.1 months respectively, versus 15.6 months for abatacept.

No significant differences were found in safety outcomes, such as serious infections or cardiovascular events, indicating that while rituximab and tocilizumab may be more effective, they do not pose additional safety risks compared to abatacept.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study. Gottenberg, JE., Morel, J., Perrodeau, E., et al.[2020]

In a study of 582 patients with rheumatoid arthritis who were positive for anti-cyclic citrullinated peptide (CCP+), abatacept and tofacitinib showed no significant difference in reducing disease activity after 6 months, indicating similar efficacy for both treatments.

Patients who had not previously used biologic therapies showed a slightly greater improvement in disease activity with abatacept compared to tofacitinib, but this difference was not statistically significant, suggesting that both medications are viable options for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Abatacept vs. Tofacitinib in Rheumatoid Arthritis Patients who are CCP. Harrold, LR., Wittstock, K., Kelly, S., et al.[2023]

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 196 rheumatoid arthritis patients who had previously failed TNFα blocker therapy, rituximab treatment resulted in a significantly greater reduction in disease activity compared to a second TNFα blocker, with a mean decrease in Disease Activity Score-28 of -1.64 versus -1.19.

Rituximab also led to a higher percentage of patients achieving a good response according to European League Against Rheumatism criteria (30% vs 15%) and fewer nonresponders (22% vs 35%), suggesting it may be a more effective option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab is more effective than second anti-TNF therapy in rheumatoid arthritis patients and previous TNFα blocker failure. Kekow, J., Mueller-Ladner, U., Schulze-Koops, H.[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]

Tocilizumab is an effective treatment option for rheumatoid arthritis in patients who have not responded to other therapies, but it is not more effective than rituximab in cases of multiple treatment failures, based on clinical evaluations of four placebo-controlled trials.

While tocilizumab offers convenience with intravenous administration every four weeks, it carries significant risks of serious infections and other adverse effects, and its long-term safety profile, particularly regarding cancer risk, remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab: new drug. Rheumatoid arthritis: another 'mab', no therapeutic advantage. [2016]

Tofacitinib 10 mg combined with methotrexate (MTX) and baricitinib 4 mg combined with MTX were found to be the most effective treatments for rheumatoid arthritis (RA) patients who did not respond adequately to previous therapies, based on a meta-analysis of 12 randomized controlled trials involving 5883 patients.

Both tofacitinib and baricitinib did not show a significant increase in the risk of serious adverse events compared to other treatments, indicating they are safe options for managing RA in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of tofacitinib and baricitinib in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Bae, SC., Lee, YH.[2021]

In a study involving 1681 patients with rheumatoid arthritis who had inadequate responses to previous treatments, tocilizumab showed rapid and sustained efficacy, with significant improvements in disease activity scores over 24 weeks.

The treatment was generally safe, with a low discontinuation rate of 5.1% due to adverse events, although patients who had recently used TNF inhibitors experienced a higher rate of adverse events compared to those who had never used them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Bykerk, VP., Ostör, AJ., Alvaro-Gracia, J., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3383476/

The Efficacy and Safety of Abatacept in Rheumatoid Arthritis Remission rate increased in patients treated also in year 2 from 46.1% at year 1 to 55.2% of patients at the end of year 2 [Westhovens et al. 2009f].

2. orenciahcp.com orenciahcp.com/efficacy-data.html

Efficacy Data - ORENCIA® (abatacept) In controlled clinical trials, adult RA patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs 43%) ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3012435/

Abatacept: the evidence for its place in the treatment of ... These results confirm that abatacept 2 mg/kg is suboptimal for effective treatment of active RA. Table 5. Response to abatacept or placebo after 1 year in ...

4. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(23)02649-1/fulltext

Abatacept in individuals at high risk of rheumatoid arthritis ... At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the ...

5. arthritis-research.biomedcentral.com arthritis-research.biomedcentral.com/articles/10.1186/s13075-020-2100-y

Abatacept in rheumatoid arthritis: survival on drug, clinical ... The aim of this study was to investigate clinical efficacy and tolerability of abatacept in RA, using a national register.

6. orenciahcp.com orenciahcp.com/safety-data.html

Safety Data | ORENCIA® (abatacept) Concomitant use with a TNF antagonist can increase the risk of infections and serious infections. Hypersensitivity and anaphylaxis have occurred. Serious ...

7. orencia.com orencia.com/about-orencia

ORENCIA® Side Effects & Rheumatoid Arthritis (RA) ... ORENCIA has a well-established safety profile · Adult Rheumatoid Arthritis (RA). ORENCIA is used to reduce signs and symptoms of moderate to severe Rheumatoid ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6858048/

Safety of Abatacept Versus Placebo in Rheumatoid Arthritis Clinical trials have also shown that abatacept is safe and well tolerated, with similar rates of adverse events (AEs) compared with placebo, demonstrating a ...

9. news.bms.com news.bms.com/news/details/2009/Updated-ORENCIA-abatacept-Labeling-Includes-Data-to-Support-Earlier-Use-in-Adult-Patients-with-Moderate-to-Severe-Rheumatoid-Arthritis/default.aspx

Updated ORENCIA® (abatacept) Labeling Includes Data to ... Data have shown that ORENCIA can inhibit radiographic progression of rheumatoid arthritis and improve physical function and health-related ...

10. jrheum.org jrheum.org/content/40/6/787

Safety of Abatacept Administered Intravenously in ... Longterm safety of IV abatacept was consistent with the short-term, with no unexpected events and low incidence rates of serious infections, ...