DMARDs for Rheumatoid Arthritis

Recruiting in Palo Alto (17 mi)

Overseen by James R O'Dell, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: University of Nebraska

Must be taking: Dmards

Disqualifiers: Pregnancy, Breastfeeding, No contraception, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This is a 16-week, open-label study to identify factors that help predict clinical responses to disease-modifying antirheumatic drugs (DMARD) therapies for rheumatoid arthritis (RA) patients. All patients will receive a starting dose of DMARD medication(s) which may be adjusted by the investigator as needed. If a subject becomes intolerant to a DMARD medication the subject will be withdrawn from the study at the discretion of the investigator. Visits (prior to week 16) where withdrawal is determined to be necessary will be considered end of study. End of study data (week 16) as well as study serum will be collected. (Serum only collected on those subjects who have consented to the addendum Serum and DNA of this study). A portion of the blood collected at baseline, week 8 and week 16 with the addendum portion of the study is for future research and will be utilized attempting to look to detect the generation of superoxide radicals. The radicals have been shown to be associated with inflammation and may correlate with the progression of RA. If this is true, then treatment with RA should decrease the levels of these radicals signaling response to treatment.

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.

What data supports the effectiveness of the drugs used in the DMARDs for Rheumatoid Arthritis trial?

Research shows that drugs like rituximab, abatacept, and tocilizumab are effective for rheumatoid arthritis, especially when other treatments have failed. These drugs work by targeting specific parts of the immune system to reduce inflammation and joint damage. ^{1 2 3 4 5}

Is there safety data for DMARDs like tofacitinib, baricitinib, tocilizumab, rituximab, and abatacept in humans?

Research shows that tofacitinib, baricitinib, tocilizumab, rituximab, and abatacept have been studied for safety in people with rheumatoid arthritis, and they are generally considered safe for human use, although individual responses can vary. ^{1 6 7 8 9}

What makes the DMARDs treatment for rheumatoid arthritis unique?

This treatment is unique because it includes a variety of drugs with different mechanisms of action, such as TNF inhibitors, T-cell co-stimulation modulators, and Janus kinase inhibitors, offering multiple options for patients who may not respond to traditional therapies. It combines both synthetic and biological DMARDs, providing a comprehensive approach to managing rheumatoid arthritis. ^{3 5 10 11 12}

Research Team

James R O'Dell, MD

Principal Investigator

University of Nebraska

Eligibility Criteria

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)

Hgb > 9g/dl

Creatinine <1.6

Exclusion Criteria

Pregnant or breastfeeding women

I am not willing to use contraception.

Trial Timeline

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

Treatment Details

Interventions

• Abatacept (Biological Response Modifier)
• Adalimumab (Biological Response Modifier)
• Azathioprine (Disease-modifying antirheumatic drugs (DMARDs))
• Baricitinib (Disease-modifying antirheumatic drugs (DMARDs))
• Certolizumab (Biological Response Modifier)
• Etanercept (Biological Response Modifier)
• Golimumab (Biological Response Modifier)
• Hydroxychloroquine (Disease-modifying antirheumatic drugs (DMARDs))
• Infliximab (Biological Response Modifier)
• Leflunomide (Disease-modifying antirheumatic drugs (DMARDs))
• Methotrexate (Disease-modifying antirheumatic drugs (DMARDs))
• Minocycline (Disease-modifying antirheumatic drugs (DMARDs))
• Rituximab (Biological Response Modifier)
• Sarilumab (Biological Response Modifier)
• Sulfasalazine (Disease-modifying antirheumatic drugs (DMARDs))
• Tofacitinib (Disease-modifying antirheumatic drugs (DMARDs))

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.

Participant Groups

Group I: Methotrexate Therapy Active Control 1 Intervention

Subjects will receive methotrexate therapy for RA treatment.

Group II: Abatacept Therapy Active Control 1 Intervention

Subjects will receive abatacept therapy for RA treatment.

Group III: Adalimumab Therapy Active Control 1 Intervention

Subjects will receive adalimumab therapy for RA treatment.

Group IV: Azathioprine Therapy Active Control 1 Intervention

Subjects will receive azathioprine therapy for RA treatment.

Group V: Barcitinib Therapy Active Control 1 Intervention

Subjects will receive barcitinib therapy for RA treatment.

Group VI: Certolizumab Therapy Active Control 1 Intervention

Subjects will receive certolizumab therapy for RA treatment.

Group VII: Etanercept Therapy Active Control 1 Intervention

Subjects will receive etanercept therapy for RA treatment.

Group VIII: Golimumab Therapy Active Control 1 Intervention

Subjects will receive golimumab therapy for RA treatment.

Group IX: Hydroxycholoroquine Therapy Active Control 1 Intervention

Subjects will receive hydroxychloroquine therapy for RA treatment.

Group X: Infliximab Therapy Active Control 1 Intervention

Subjects will receive infliximab therapy for RA treatment.

Group XI: Leflunomide Therapy Active Control 1 Intervention

Subjects will receive leflunomide therapy for RA treatment.

Group XII: Minocycline Therapy Active Control 1 Intervention

Subjects will receive minocycline therapy for RA treatment.

Group XIII: Rituximab Therapy Active Control 1 Intervention

Subjects will receive rituximab therapy for RA treatment.

Group XIV: Sarilumab Therapy Active Control 1 Intervention

Subjects will receive sarilumab therapy for RA treatment.

Group XV: Sulfasalazine Therapy Active Control 1 Intervention

Subjects will receive sulfasalazine therapy for RA treatment.

Group XVI: Tofacitinib Therapy Active Control 1 Intervention

Subjects will receive tofacitinib therapy for RA treatment.

Abatacept is already approved in Canada, Japan for the following indications:

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+

Michael Dixon

University of Nebraska

Chief Executive Officer since 2010

PhD in Molecular Biology

Dr. Makker

University of Nebraska

Chief Medical Officer since 2020

MD from University of Nebraska Medical School

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2020]

2. England pubmed.ncbi.nlm.nih.gov

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

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

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

4. New Zealand pubmed.ncbi.nlm.nih.gov

Rituximab is more effective than second anti-TNF therapy in rheumatoid arthritis patients and previous TNFα blocker failure. [2022]

5. France pubmed.ncbi.nlm.nih.gov

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

6. Germany 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. [2021]

7. England 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. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Abatacept vs. Tofacitinib in Rheumatoid Arthritis Patients who are CCP. [2023]

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

Pharmacotherapy options in rheumatoid arthritis. [2022]

11. England pubmed.ncbi.nlm.nih.gov

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

12. Germany pubmed.ncbi.nlm.nih.gov

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