Pegloticase + Methotrexate for Gout

Recruiting at 115 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

262 Participants Needed

Trial Summary

What is the purpose of this trial?

The study consists of 24-week double-blind trial to evaluate the non-inferiority of the efficacy and safety of pegloticase Q4W with MTX versus pegloticase Q2W with MTX, followed by a 24-week open-label extension of pegloticase Q4W with MTX, in participants with uncontrolled refractory gout. The main objective of the study is to evaluate the effect of pegloticase 16 mg administered Q4W with MTX versus pegloticase 8 mg administered Q2W with MTX, on the response rate during Month 6, as measured by the sustained normalization of sUA to \< 6 mg/dL for at least 80% of the time.

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 data supports the idea that Pegloticase + Methotrexate for Gout is an effective drug?

The available research shows that combining Pegloticase with Methotrexate improves the effectiveness of the treatment for gout. One study found that adding Methotrexate helps more patients respond to Pegloticase, increasing the response rate from 42% when Pegloticase is used alone. This combination helps prevent the body from developing antibodies that can make Pegloticase less effective. Another study confirmed these findings, showing that the combination is effective in patients with uncontrolled gout. This suggests that Pegloticase with Methotrexate is a more reliable option compared to using Pegloticase by itself. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Pegloticase combined with Methotrexate for treating gout?

Research shows that adding methotrexate to pegloticase can improve the drug's effectiveness for treating gout by reducing the development of antibodies that can make pegloticase less effective. This combination has been shown to increase the response rate compared to using pegloticase alone. ^{1 2 3 4 5}

What safety data is available for Pegloticase and Methotrexate treatment for gout?

Pegloticase, used for chronic refractory gout, has shown efficacy in reducing serum uric acid and improving joint function, but it is associated with a higher risk of adverse events, including infusion-related reactions and gout flares. Combining Pegloticase with Methotrexate may improve response durability by reducing antidrug antibody development. Clinical trials and studies, such as the MIRROR study, are exploring the safety and efficacy of this combination. However, infusion reactions remain a significant concern, and anti-inflammatory strategies may be needed to mitigate these effects. ^{2 3 4 6 7}

Is the combination of Pegloticase and Methotrexate safe for treating gout?

Pegloticase, used for treating severe gout, has been associated with a higher risk of adverse events, including infusion-related reactions and gout flares. Combining it with Methotrexate is being studied to improve treatment response, but safety data is still being explored. ^{2 3 4 6 7}

Is the drug Pegloticase a promising treatment for gout?

Yes, Pegloticase is a promising drug for treating gout, especially when used with methotrexate. This combination significantly improves the response rate, helping more patients benefit from the treatment. ^{2 4 5 8 9}

How is the drug Pegloticase + Methotrexate unique for treating gout?

The combination of Pegloticase with Methotrexate is unique because it improves the response rate in patients with refractory gout by reducing the development of antidrug antibodies, which often limit the effectiveness of Pegloticase alone. ^{2 4 5 8 9}

Research Team

MD

Principal Investigator

Amgen

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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]

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]

References

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

Pegloticase failure and a possible solution: Immunosuppression to prevent intolerance and inefficacy in patients with gout. [2018]

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

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

3. Canada pubmed.ncbi.nlm.nih.gov

Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). [2022]

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

New advances in the treatment of gout: review of pegloticase. [2021]

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

Effect of Leflunomide on Pegloticase Response Rate in Patients with Uncontrolled Gout: A Retrospective Study. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

Evaluation of the efficacy and safety of pegloticase for the treatment of chronic refractory gout through meta-analysis. [2023]

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

Infusion-related reactions with pegloticase, a recombinant uricase for the treatment of chronic gout refractory to conventional therapy. [2018]

8. England 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. [2022]

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

The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review. [2021]