Prednisone Taper for Rheumatoid Arthritis

(SMART-RA Trial)

Recruiting at 1 trial location

Overseen By Beth Wallace, MD MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must be taking: Prednisone, DMARDs

Disqualifiers: Pregnancy, Schizophrenia, Psychosis, others

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

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

200 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that you continue using your current RA treatment regimen, including prednisone and another approved medication, without changes for at least 90 days before joining.

What data supports the effectiveness of the drug prednisone for rheumatoid arthritis?

In the SEMIRA trial, 65% of patients with rheumatoid arthritis who had low disease activity on stable biologic therapy were able to successfully taper glucocorticoids like prednisone, suggesting that tapering can be effective for maintaining disease control. ^{1 2 3 4 5}

Is prednisone tapering safe for humans?

Prednisone, a type of glucocorticoid, is generally safe for short-term use in humans, but long-term use can lead to side effects like cardiovascular issues. Tapering the dose is recommended to minimize these risks, although there is limited data on the safety of low-dose therapy. ^{3 6 7 8 9}

How does the drug prednisone taper differ from other treatments for rheumatoid arthritis?

Prednisone tapering is unique because it involves gradually reducing the dose of the oral steroid prednisone, which can help manage rheumatoid arthritis symptoms while minimizing long-term side effects. This approach is different from other treatments that may involve continuous use of medications or biologics without dose reduction. ^{1 3 8 10 11}

What is the purpose of this trial?

The purpose of this clinical trial is to better understand how people with rheumatoid arthritis (RA) respond to gradual dose reduction, or "tapering", of steroid medications like prednisone. Some people with RA have symptoms when steroid dose is reduced, while others don't. This trial will look at different patient characteristics, including levels of inflammation in the body, differences in the way the brain processes sensory information, and certain hormone levels, to help researchers better understand why different people have these different responses to steroid tapering. The hypotheses include: * Greater or equal to ( ) 30% of participants in each arm will develop taper intolerance (either subjective, objective, or both) during the study period * Greater or equal to 60% of participants will reduce Glucocorticoid dose by at least 5 Milligrams per day during the study period

Research Team

Beth Wallace, MD MSc

Principal Investigator

VA Ann Arbor Healthcare System, Ann Arbor, MI

Eligibility Criteria

This trial is for adults with rheumatoid arthritis who are currently on a stable RA treatment regimen including oral prednisone and another approved DMARD, without changes in the last 90 days. They must be able to take oral medication, read and speak English, provide consent, and commit to the study duration. Pregnant individuals or those with high RA activity or recent other steroid use are excluded.

Inclusion Criteria

Stated willingness to comply with all study procedures and availability for the duration of the study

I can take pills and will follow the study's treatment plan.

I have been diagnosed with rheumatoid arthritis by a doctor.

Exclusion Criteria

Treatment with another investigational drug or intervention within 90 days

Pregnancy

I have been diagnosed with adrenal insufficiency.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

15-day Taper Treatment

Participants undergo a 15-day tapering strategy for prednisone over 30 days

4 weeks

Remote participation or clinic visits as needed

150-day Taper Treatment

Participants undergo a 150-day tapering strategy for prednisone over 180 days

26 weeks

Remote participation or clinic visits as needed

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Oral prednisone

Trial Overview The trial is testing how reducing doses of prednisone over either 15 days or 150 days affects people with rheumatoid arthritis. It aims to understand why some patients experience symptoms when their steroid dose is lowered by examining inflammation levels, sensory processing in the brain, and hormone levels.

Participant Groups

Group I: 150-day taper prednisone Experimental Treatment 1 Intervention

This will be for 180 days. Participants who are not eligible for the 15-day strategy, but are eligible for the 150-day strategy, will be enrolled in the 150-day strategy.

Group II: 15-day taper prednisone Experimental Treatment 1 Intervention

This will be for 30 days. Participants will be allocated to the 15-day strategy preferentially until enrollment goals have been met; once completing the 15-day strategy, many participants will also be eligible to complete the 150-day strategy, and may subsequently enroll in it if they wish. Participants that are not eligible for the 15-day strategy, but are eligible for the 150-day strategy, will be enrolled in the 150-day strategy.

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

Approved in United States as Deltasone for:

• Rheumatoid arthritis
• Lupus
• Vasculitis
• Osteoarthritis
• Psoriatic arthritis

Approved in European Union as Prednisone for:

• Rheumatoid arthritis
• Lupus
• Vasculitis
• Osteoarthritis
• Psoriatic arthritis

Approved in Canada as Prednisone for:

• Rheumatoid arthritis
• Lupus
• Vasculitis
• Osteoarthritis
• Psoriatic arthritis

Approved in Japan as Prednisone for:

• Rheumatoid arthritis
• Lupus
• Vasculitis
• Osteoarthritis
• Psoriatic arthritis

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

Findings from Research

The review emphasizes the importance of tapering biologic therapies in rheumatoid arthritis (RA) after achieving remission, as current guidelines suggest, to reduce adverse effects and costs associated with long-term immunosuppressive therapy.

It provides practical recommendations based on recent clinical trials, focusing on outcomes like flare rates and disease control, and suggests using musculoskeletal ultrasound to identify patients who may successfully taper their biologic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice. Lenert, A., Lenert, P.[2018]

In a real-world study of 95 patients with rheumatoid arthritis using biologic therapies, 54% successfully tapered their glucocorticoid use, and 33% completely discontinued prednisone within 6 months.

Factors such as positive rheumatoid factor, higher inflammation markers, and a shorter time to achieve low disease activity were linked to a higher likelihood of successful glucocorticoid tapering.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lowering Expectations: Glucocorticoid Tapering Among Veterans With Rheumatoid Arthritis Achieving Low Disease Activity on Stable Biologic Therapy. Wallace, BI., England, BR., Baker, JF., et al.[2023]

In the SEMIRA trial involving 259 patients with rheumatoid arthritis, continuing low-dose glucocorticoids (5 mg/day) for 24 weeks resulted in better disease control compared to tapering the dose, with a significant difference in disease activity scores (DAS28-ESR) favoring the continued treatment group.

Despite the benefits of continuing glucocorticoids, about two-thirds of patients were able to taper their glucocorticoid dose safely, indicating that tapering may be feasible for some patients without significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Burmester, GR., Buttgereit, F., Bernasconi, C., et al.[2020]

In a study of 332 rheumatoid arthritis patients, 42.1% were able to successfully taper their biological disease-modifying antirheumatic drugs (bDMARDs) after achieving low disease activity or remission, indicating that dose reduction is feasible in daily practice.

Patients who tapered their bDMARDs were more likely to be on a combination therapy with methotrexate, and the most commonly tapered medications were adalimumab, etanercept, and rituximab, which also led to significant cost savings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tapering of biological antirheumatic drugs in rheumatoid arthritis patients is achievable and cost-effective in daily clinical practice: data from the Brussels UCLouvain RA Cohort. Dierckx, S., Sokolova, T., Lauwerys, BR., et al.[2021]

In a study of 437 rheumatoid arthritis patients over 2.5 years, individual tapering of DMARDs did not significantly increase the risk of disease flare-ups or loss of remission compared to those who continued their full dosage.

Patients who tapered their medication experienced a significant reduction in drug costs (by 1017€), while those who did not taper saw an increase in costs (by 1151€), suggesting that tapering can be both safe and economically beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-individual tapering of DMARDs in rheumatoid arthritis patients in a real-world setting. Birkner, B., Rech, J., Edelmann, E., et al.[2023]

Glucocorticoids are effective in managing rheumatoid arthritis due to their strong anti-inflammatory and immunomodulatory properties, but concerns about potential adverse effects limit their use, especially at higher doses and longer durations.

Current evidence on the safety of low-dose glucocorticoid therapy in rheumatoid arthritis is limited, highlighting the need for more quality studies, while new formulations like modified-release prednisone are being developed to enhance their therapeutic benefits and reduce risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Balancing the benefits and risks of low-dose glucocorticoid in rheumatoid arthritis. Santiago, T., Jacobs, JW., Saag, KG., et al.[2017]

In a study of 1009 patients with rheumatoid arthritis (RA) receiving intravenous abatacept, 72.7% were prescribed glucocorticoids at the start, with a median dose of 7.5 mg/day.

After 24 months on abatacept, 40.7% of patients were able to reduce their glucocorticoid dose, indicating that abatacept may help in tapering glucocorticoid therapy safely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decreased use of glucocorticoids in biological-experienced patients with rheumatoid arthritis who initiated intravenous abatacept: results from the 2-year ACTION study. Alten, R., Nüßlein, H., Galeazzi, M., et al.[2018]

Oral prednisone significantly reduces disease activity in 60% of patients with rheumatoid arthritis (RA) within the first 12 weeks of treatment, based on a study of 40 patients over 18 weeks.

However, after tapering the dose, 58% of responders experienced a rebound deterioration in their condition, suggesting that this tapering strategy may not be advisable for bridge therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral steroids as bridge therapy in rheumatoid arthritis patients starting with parenteral gold. A randomized double-blind placebo-controlled trial. van Gestel, AM., Laan, RF., Haagsma, CJ., et al.[2019]

A systematic review and meta-analysis of 13 controlled trials involving 2280 patient-years found no significant increase in the risk of serious infections or severe adverse events (SAEs) when tapering targeted therapies (bDMARDs or JAK inhibitors) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity.

The study indicated that tapering these therapies did not lead to a higher risk of malignancies, cardiovascular adverse events, or deaths compared to continuing the usual care, suggesting that tapering may be a safe option for patients in stable conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and adverse events of special interest in patients with rheumatoid arthritis or spondyloarthritis: a systematic analysis of the literature and meta-analysis. Vinson, D., Molet-Benhamou, L., Degboé, Y., et al.[2023]

In a study of 36 rheumatoid arthritis patients over 2 years, the use of oral glucocorticoids (GC) was successfully reduced from 100% to 13.9% without worsening disease status, indicating a safe tapering strategy.

The Clinical Disease Activity Index remission rate improved from 25.0% to 38.9%, suggesting that patients maintained or even enhanced disease control while reducing GC use, with only two serious adverse events reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tapering and discontinuation of oral glucocorticoids without deterioration of disease status in patients with rheumatoid arthritis under a stable treatment. Hirata, S., Kohno, H., Watanabe, H., et al.[2022]

In a study of 508 rheumatoid arthritis patients, tapering glucocorticoids to doses of 0-2.5 mg/day significantly increased the risk of disease flare-ups, with adjusted odds ratios of 1.45 and 1.37, respectively.

Tapering glucocorticoids to doses greater than 2.5 mg/day did not show a significant increase in flare risk, suggesting that maintaining a dose above this threshold may be safer for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tapering glucocorticoids and risk of flare in rheumatoid arthritis on biological disease-modifying antirheumatic drugs (bDMARDs). Adami, G., Fassio, A., Rossini, M., et al.[2023]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice. [2018]

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

Lowering Expectations: Glucocorticoid Tapering Among Veterans With Rheumatoid Arthritis Achieving Low Disease Activity on Stable Biologic Therapy. [2023]

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

Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Tapering of biological antirheumatic drugs in rheumatoid arthritis patients is achievable and cost-effective in daily clinical practice: data from the Brussels UCLouvain RA Cohort. [2021]

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

Patient-individual tapering of DMARDs in rheumatoid arthritis patients in a real-world setting. [2023]

6. Portugal pubmed.ncbi.nlm.nih.gov

Balancing the benefits and risks of low-dose glucocorticoid in rheumatoid arthritis. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Decreased use of glucocorticoids in biological-experienced patients with rheumatoid arthritis who initiated intravenous abatacept: results from the 2-year ACTION study. [2018]

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

Oral steroids as bridge therapy in rheumatoid arthritis patients starting with parenteral gold. A randomized double-blind placebo-controlled trial. [2019]

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

Impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and adverse events of special interest in patients with rheumatoid arthritis or spondyloarthritis: a systematic analysis of the literature and meta-analysis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Tapering and discontinuation of oral glucocorticoids without deterioration of disease status in patients with rheumatoid arthritis under a stable treatment. [2022]

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

Tapering glucocorticoids and risk of flare in rheumatoid arthritis on biological disease-modifying antirheumatic drugs (bDMARDs). [2023]