Pegloticase + Methotrexate for Gout

Not currently recruiting at 139 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Amgen

Must be taking: Methotrexate

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Chronic infections, Transplant history, Hepatitis, HIV, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness and safety of a gout treatment called pegloticase, administered with methotrexate. The study compares two dosing schedules to determine which is more effective for individuals with difficult-to-control gout that hasn't improved with other treatments. Participants should have ongoing gout symptoms and must have unsuccessfully tried xanthine oxidase inhibitors. As a Phase 4 trial, this research aims to understand how the already FDA-approved treatment benefits more patients.

Do I have to stop taking my current medications for this trial?

You will need to stop taking any oral urate-lowering therapy (ULT) for at least 7 days before starting methotrexate and continue not taking it during the trial. The protocol does not specify other medications, but you should discuss your current medications with the trial team.

Will I have to stop taking my current medications?

You will need to stop taking any oral uric acid-lowering therapy (ULT) for at least 7 days before starting methotrexate and continue not taking it during the trial. The protocol does not specify other medications, so it's best to discuss with the trial team.

What is the safety track record for these treatments?

Research has shown that the combination of pegloticase and methotrexate is generally well-tolerated. Studies reported common side effects such as gout flares, joint pain, nausea, and tiredness, affecting 5% or more of patients. Importantly, methotrexate reduced the body's reaction against pegloticase, enhancing the treatment's effectiveness and tolerability over time. No new safety issues emerged during a six-month period. Overall, the treatment appears promising for individuals with hard-to-treat gout. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the combination of Pegloticase and Methotrexate for treating gout because it offers a new approach to improving the effectiveness of Pegloticase. Pegloticase, typically used alone, breaks down uric acid but often faces challenges with the immune system reducing its effectiveness over time. By adding Methotrexate, an immunosuppressant, this treatment aims to reduce the body's immune response, potentially allowing Pegloticase to work more effectively and for a longer period. This combination could provide a more durable solution compared to standard treatments like allopurinol or febuxostat, which primarily work by reducing uric acid production.

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

This trial will evaluate two different dosing schedules of pegloticase combined with methotrexate for treating gout. Research has shown that combining pegloticase with methotrexate improves outcomes for people with uncontrolled gout. In one study, 71% of participants responded well to this combination, compared to 38.5% who used pegloticase alone, meaning more people reached their target uric acid levels. Additionally, there was a 23% improvement in eliminating gout tophi, the painful lumps from uric acid buildup. Another study found that more than half of the patients saw their tophi disappear with this treatment. These findings suggest that this combination effectively manages gout symptoms and lowers uric acid levels. ^{3 6 7 8 9}

Who Is on the Research Team?

MD

Principal Investigator

Amgen

Are You a Good Fit for This Trial?

Adults over 18 with uncontrolled refractory gout, who have high uric acid levels and haven't responded to standard treatments. Participants must stop any oral gout medications before starting the trial and use contraception if necessary. Women of childbearing potential need negative pregnancy tests.

Inclusion Criteria

I have gout that's not managed well, with high uric acid and symptoms despite medication.

Women of childbearing potential must have negative serum/urine pregnancy tests during screening and Week -4

I agree to use contraception during the trial as I am not vasectomized.

Exclusion Criteria

I have a history of hepatitis B or C.

I do not have uncontrolled heart issues or high blood pressure.

I have abnormal blood counts or a recent cancer history, but no bone infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double-blind Treatment

Participants receive pegloticase with methotrexate, either every 2 weeks or every 4 weeks, to evaluate non-inferiority in efficacy and safety

24 weeks

Open-label Extension

Participants receive pegloticase every 4 weeks with methotrexate in an open-label setting

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pegloticase

Trial Overview The study is testing whether giving Pegloticase every four weeks with Methotrexate (MTX) is as effective as every two weeks for reducing uric acid in gout patients. The first half is blinded, then all get the four-week treatment for another six months.

How Is the Trial Designed?

Group I: Pegloticase + Methotrexate Q4W Experimental Treatment 2 Interventions

16 mg pegloticase will be administered intravenously every 4 weeks for 24 weeks during double blind treatment and 24 weeks during open label.

Group II: Pegloticase + Methotrexate Q2W Experimental Treatment 2 Interventions

8 mg pegloticase will be administered intravenously every 2 weeks for 24 weeks during double blind treatment and 16 mg pegloticase every 4 weeks for 24 weeks during open label.

Pegloticase is already approved in United States, European Union for the following indications:

Approved in United States as Krystexxa for:

• Chronic gout in adult patients refractory to conventional therapy

Approved in European Union as Krystexxa for:

• Disabling tophaceous gout

Who Is Running the Clinical Trial?

Amgen

Lead Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Horizon Therapeutics Ireland DAC

Lead Sponsor

Trials

21

Recruited

2,500+

Published Research Related to This Trial

In a multicenter, open-label trial involving 14 men with uncontrolled gout, 78.6% of patients achieved target serum uric acid levels (< 6 mg/dL) when treated with pegloticase and methotrexate over 6 months, significantly higher than the 42% response rate previously reported with pegloticase alone.

All patients tolerated methotrexate well, and no new safety concerns were identified, suggesting that the combination treatment is both effective and safe for managing uncontrolled gout.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). Botson, JK., Tesser, JRP., Bennett, R., et al.[2022]

In a 6-month clinical trial, pegloticase significantly reduced serum urate levels and led to the dissolution of tophi in 40% of patients, indicating its potential efficacy for treating treatment-failure gout.

However, 58% of patients did not achieve the target serum urate level, and a significant number experienced infusion reactions and gout flares, suggesting the need for additional anti-inflammatory strategies to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New advances in the treatment of gout: review of pegloticase. Reinders, MK., Jansen, TL.[2021]

In the MIRROR trial, patients with uncontrolled gout treated with a combination of pegloticase and methotrexate showed a significantly higher 12-month responder rate of 79%, compared to 42% for pegloticase alone, indicating enhanced efficacy of the co-therapy.

The combination therapy was well-tolerated over 12 months, with a notable reduction in serum urate levels and a decrease in gout flares over time, suggesting that methotrexate may help reduce the formation of anti-drug antibodies, leading to better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicentre, efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase (MIRROR): 12-month efficacy, safety, immunogenicity, and pharmacokinetic findings during long-term extension of an open-label study. Botson, JK., Tesser, JRP., Bennett, R., et al.[2022]

In a systematic review of 82 cases, the combination of pegloticase with immunomodulators resulted in a high response rate of 82.9% in patients with refractory gout, significantly improving outcomes compared to pegloticase alone, which had a responder rate of only 40%.

Specific immunomodulators showed varying effectiveness, with methotrexate and mycophenolate mofetil yielding the highest response rates of 87.5% and 86.4%, respectively, indicating that these combinations may enhance the efficacy of pegloticase treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review. Keenan, RT., Botson, JK., Masri, KR., et al.[2021]

In a case series of 10 patients with refractory gout, the addition of methotrexate to pegloticase treatment resulted in a 100% response rate, maintaining serum uric acid levels below 6.0 mg/dL without any infusion reactions.

The study suggests that using methotrexate may help improve the durability of the response to pegloticase, potentially addressing the issue of antidrug antibodies that limit treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretreatment and Coadministration With Methotrexate Improved Durability of Pegloticase Response: An Observational, Proof-of-Concept Case Series. Botson, JK., Peterson, J.[2023]

Pegloticase is effective in reducing serum uric acid levels and improving joint function in patients with chronic refractory gout, based on a meta-analysis of available studies.

However, the use of pegloticase is associated with a higher risk of adverse events, suggesting that it may be best suited for patients in good medical condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the efficacy and safety of pegloticase for the treatment of chronic refractory gout through meta-analysis. Fan, T., Wang, Y., Song, T., et al.[2023]

In a case report, a 56-year-old man with severe refractory tophaceous gout successfully maintained treatment with pegloticase and low-dose azathioprine for 98 weeks, showing a 77% decrease in tophi and no infusion reactions.

Literature review suggests that using immunosuppressive therapies like azathioprine can significantly reduce the development of anti-drug antibodies, which are responsible for treatment failure in patients receiving pegloticase for gout.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegloticase failure and a possible solution: Immunosuppression to prevent intolerance and inefficacy in patients with gout. Berhanu, AA., Krasnokutsky, S., Keenan, RT., et al.[2018]

In a study of 10 patients with uncontrolled gout, co-administering leflunomide with pegloticase resulted in a 70% treatment response rate, significantly improving the effectiveness of pegloticase compared to its monotherapy response rate of 42%.

The study also highlighted that leflunomide is a suitable alternative for patients with renal dysfunction, as it is less restricted than methotrexate, making it a valuable option for managing gout in patients with high comorbidity burdens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Leflunomide on Pegloticase Response Rate in Patients with Uncontrolled Gout: A Retrospective Study. Masri, KR., Padnick-Silver, L., Winterling, K., et al.[2022]

Infusion-related reactions (IRs) occurred in 45% of patients receiving pegloticase, with common symptoms including chest discomfort, flushing, and dyspnea, but most reactions were mild or moderate and resolved with adjustments to the infusion.

Monitoring serum uric acid levels before each infusion can help optimize the safety of pegloticase therapy, as IRs were more frequent in patients with higher uric acid levels, indicating a potential strategy to minimize adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion-related reactions with pegloticase, a recombinant uricase for the treatment of chronic gout refractory to conventional therapy. Baraf, HS., Yood, RA., Ottery, FD., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36099211/

A Randomized, Placebo-Controlled Study of Methotrexate ... MTX cotherapy markedly increased pegloticase response rate over placebo (71.0% versus 38.5%) during month 6 with no new safety signals.

2. acrjournals.onlinelibrary.wiley.com acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr.25361

Real‐World Effectiveness of Pegloticase Associated With Use ... Among patients who lost efficacy with pegloticase, 30.2% continued pegloticase therapy. Understanding why pegloticase was continued in patients ...

3. the-rheumatologist.org the-rheumatologist.org/article/pegloticase-plus-methotrexate-effective-for-uncontrolled-gout/

Pegloticase Plus Methotrexate Effective for Uncontrolled ... Additionally, data showed a 23 percentage-point increase in the complete resolution of at least one tophus at month 12 (P=0.048), with complete ...

4. krystexxahcp.com krystexxahcp.com/rheumatology/efficacy/treating-gout-tophi

Efficacy in Treating Tophi | KRYSTEXXA® (pegloticase) HCP Evaluate Your Gout Patients Using “STOP” · 54% (28/52) of patients receiving KRYSTEXXA with methotrexate experienced tophi resolution vs 31% (9/29) of patients ...

5. arthritis-research.biomedcentral.com arthritis-research.biomedcentral.com/articles/10.1186/s13075-022-02979-4

12-month exploratory outcomes of the MIRROR open-label trial One patient who underwent 52 weeks of pegloticase + methotrexate co-therapy had a 99% reduction in total urate volume. The other patient, who ...

6. krystexxahcp.com krystexxahcp.com/rheumatology/safety/safety-results

Side Effects and Safety | Rheumatology *Adverse reactions occurring in 5% or more of patients in either the KRYSTEXXA with methotrexate or KRYSTEXXA alone study arm during a 12-month period.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9404640/

A multicentre, efficacy and safety study of methotrexate to ... Pegloticase + methotrexate co-therapy was well-tolerated over 12 months, with sustained SU lowering, progressive gout flare reduction, and no ...

8. krystexxahcp.com krystexxahcp.com/rheumatology/safety

Side Effects and Safety | KRYSTEXXA® (pegloticase) HCP The most common adverse reactions (≥5%) are: Co-administration with MTX: Gout flares, arthralgia, COVID-19, nausea, and fatigue. KRYSTEXXA alone: Gout flares, ...

9. acrjournals.onlinelibrary.wiley.com acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42335

A Randomized, Placebo‐Controlled Study of Methotrexate to ... MTX cotherapy markedly increased pegloticase response rate over placebo (71.0% versus 38.5%) during month 6 with no new safety signals. These ...