Treat-to-Target vs Symptom Management for Gout

(TRUST Trial)

Recruiting at 8 trial locations

Overseen By Ana D Fernandes, MA

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Massachusetts General Hospital

Must not be taking: Thiopurines, Febuxostat

Disqualifiers: CKD Stage 3B, Pregnancy, 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

Duration: 3 months

650 Participants Needed

Trial Summary

What is the purpose of this trial?

The TRUST study is a randomized, controlled multicenter study to evaluate the management of gout by comparing two commonly used treatment strategies for gout (TTT vs TTASx) to determine the most beneficial for a patient-centered gout outcomes, as well as relevant cardiovascular-metabolic-renal endpoints.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are taking more than 200 mg of allopurinol per day or any dose of febuxostat, you cannot participate. If you are taking 200 mg or less of allopurinol daily, you may participate if you meet other criteria.

What data supports the effectiveness of the drug Allopurinol for treating gout?

Allopurinol is effective in lowering uric acid levels, which helps prevent gout flares and manage chronic gout. However, adherence to the medication is crucial for optimal outcomes, and switching from brand to generic formulations may affect its effectiveness. ^{1 2 3 4 5}

Is allopurinol safe for humans?

Allopurinol is generally used to treat gout, but it can cause rare and serious allergic reactions, including skin rashes and severe conditions like Stevens-Johnson syndrome. These reactions can be life-threatening, so it's important to monitor for any unusual symptoms when taking this medication. ^{2 3 5 6 7}

How is the drug Allopurinol unique in treating gout?

Allopurinol is unique in treating gout because it uses a 'treat-to-target' strategy, which involves setting specific treatment goals and regularly adjusting the medication to achieve those goals, similar to its use in managing other chronic conditions like rheumatoid arthritis. ^{8 9 10 11 12}

Research Team

Hyon K Choi, MD, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults aged 18-90 with chronic kidney disease stage 3B or worse, at least one gout flare in the past year, and high serum urate levels. They must have had two episodes of renal colic within five years and more than one tophus. Participants need to be able to swallow pills and agree to birth control measures if applicable.

Inclusion Criteria

Have a baseline inter-critical serum urate (SU) ≥ 7.0 mg/dL (at screening or in the 30 days before screening)

Be diagnosed with gout by the 2015 ACR/EULAR criteria, with 8 or more points on the 2015 ACR/EULAR criteria scoring algorithm

I can swallow pills.

Exclusion Criteria

Unlikely to survive 2 years because of comorbidities

My kidney function is low, with an eGFR below 45.

I have more than one visible bump under my skin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the TTT-SU or TTASx treatment strategy for gout management over three months

3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on gout flare frequency and quality of life

2 years

Treatment Details

Interventions

• Allopurinol
• Antiinflammatory Agent for Gout Flare Prophylaxis

Trial Overview The TRUST study compares two gout treatment strategies: Treat-to-Target Serum Urate (TTT) versus Treat-to-Avoid Symptoms (TTASx). It aims to find out which approach is better for patient-centered outcomes and cardiovascular-metabolic-renal health.

Participant Groups

Group I: TTASx Active Control 5 Interventions

Subjects randomized to the treat-to-avoid-symptoms (TTASx) group will receive the same education as the TTT-SU group. In addition, they will receive anti-inflammatory treatments (naproxen, colchicine, and/or prednisone); enough to treat up to six flares over the ensuing three months.

Group II: TTT-SU Active Control 3 Interventions

The participants randomized to the Treat-to-Target-Serum Urate (TTT-SU) group will be counseled about gout, generalized lifestyle and dietary issues and will be provided with a three-month supply of allopurinol as well as a treatment to prophylax against attacks that might occur during the up-titration of urate lowering therapy. Allopurinol dose increases will occur until SU concentrations achieve a target level \< 6.0 mg/dL.

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

Approved in United States as Zyloprim for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

Approved in European Union as Zyloric for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

Approved in Canada as Allopurinol for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

Approved in Japan as Allopurinol for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Collaborator

Trials

508

Recruited

1,090,000+

Findings from Research

In a study of 612 gout patients on allopurinol, medication adherence was found to significantly improve the chances of achieving the serum urate goal of less than 6.0 mg/dL, with an odds ratio of 2.35.

Starting patients on a low dose of allopurinol (100 mg/d or less) can enhance adherence and indirectly support goal attainment, but this approach must be paired with effective dose escalation to be truly beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopurinol Medication Adherence as a Mediator of Optimal Outcomes in Gout Management. Coburn, BW., Bendlin, KA., Sayles, H., et al.[2018]

The management of gout involves three key stages: treating acute attacks, lowering uric acid levels to prevent future flares, and providing prophylaxis against acute attacks, with NSAIDs being the preferred treatment for acute inflammation if started early.

For chronic gout management, xanthine oxidase inhibitors like allopurinol are recommended as first-line treatments, especially for patients with renal issues or those on diuretics, while uricosuric drugs are suitable for patients allergic to allopurinol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of acute and chronic gouty arthritis: present state-of-the-art. Schlesinger, N.[2018]

A 56-year-old man experienced a return of acute gout symptoms after switching from the brand formulation of allopurinol (Zyloric®) to a generic version, indicating a lack of therapeutic effect from the generic.

Upon reverting to the brand formulation, the patient's symptoms improved, suggesting that not all generic medications may provide the same efficacy as their brand-name counterparts, highlighting the need for more data on the effectiveness of generic drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of efficacy during the switch from brand to generic allopurinol. De Vuono, A., Scicchitano, F., Palleria, C., et al.[2013]

In a study of 9,482 patients suspected of having gout, only 18% were compliant with allopurinol therapy throughout a 24-month follow-up period, indicating a significant issue with medication adherence.

Low compliance with allopurinol is concerning because untreated gout can lead to serious complications, highlighting the need for strategies to improve patient adherence to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. Riedel, AA., Nelson, M., Joseph-Ridge, N., et al.[2013]

A systematic review and meta-analysis of four studies found no significant association between allopurinol use and all-cause mortality in patients with gout, suggesting it is safe in this regard (adjusted HR 0.80).

While two studies indicated that allopurinol may have a protective effect against mortality, the overall evidence is limited, highlighting the need for further research to clarify its long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mortality in Patients With Gout Treated With Allopurinol: A Systematic Review and Meta-Analysis. Hay, CA., Prior, JA., Belcher, J., et al.[2022]

A review of 901 cases of allopurinol hypersensitivity (AH) revealed that risk factors such as renal impairment, hypertension, and the presence of the HLA-B*5801 allele are commonly associated with this serious adverse reaction, particularly in Asian populations.

The study found no significant link between higher doses of allopurinol and an increased risk of severe cutaneous reactions, challenging previous assumptions about dosage as a risk factor for AH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. Ramasamy, SN., Korb-Wells, CS., Kannangara, DR., et al.[2022]

In a study of over 1.6 million new allopurinol users, the incidence of hypersensitivity reactions was found to be 4.68 per 1000 new users, with significant risk factors including older age, female sex, and higher initial dosages.

Patients with asymptomatic hyperuricemia and existing renal or cardiovascular diseases faced a significantly increased risk of hypersensitivity reactions and related mortality, highlighting the need for careful prescribing in these high-risk groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopurinol Use and Risk of Fatal Hypersensitivity Reactions: A Nationwide Population-Based Study in Taiwan. Yang, CY., Chen, CH., Deng, ST., et al.[2016]

The implementation of a paper-based form to assess disease activity in rheumatoid arthritis (RA) patients significantly increased documentation from 24% to 44% in the first cycle of a quality improvement initiative.

A second cycle that refined the process led to a remarkable increase, with 85% of RA patients having their disease activity measured over a 27-week period, demonstrating that standardized workflows can enhance clinical practice in managing RA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementation of disease activity measurement for rheumatoid arthritis patients in an academic rheumatology clinic. Bays, A., Wahl, E., Daikh, DI., et al.[2022]

The Treat to Target (T2T) strategy, effective in managing conditions like hypertension and rheumatoid arthritis, faces challenges in axial spondyloarthritis (axSpA) due to a lack of evidence on its impact on clinical outcomes and the absence of a clear treatment target.

Recent studies, including the TICOPA trial for psoriatic arthritis, highlight the need for more randomized clinical trials to establish the efficacy of T2T in axSpA and to define specific treatment goals for better management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treat to Target in Axial Spondyloarthritis: What Are the Issues? Danve, A., Deodhar, A.[2022]

Optimizing current therapies for systemic lupus erythematosus (SLE) could significantly improve patient outcomes, similar to the 'treat-to-target' approach used successfully in rheumatoid arthritis.

The article discusses the challenges in defining treatment targets for SLE due to its complexity and the lack of consensus on measuring disease activity, highlighting the need for strategies to overcome these obstacles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The need to define treatment goals for systemic lupus erythematosus. Franklyn, K., Hoi, A., Nikpour, M., et al.[2022]

Setting clear treatment goals and regularly measuring disease activity in rheumatoid arthritis (RA) can significantly improve patient care.

Specialist nurses play a crucial role in implementing treatment to target in RA, including the establishment of nurse-led clinics that enhance patient engagement and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment to target in rheumatoid arthritis. Duggins, H.[2016]

Integrating the treat-to-target approach in rheumatoid arthritis (RA) care is crucial for improving patient outcomes, but it has not been widely adopted despite its connection to payment incentives.

Recent updates in classification criteria and treatment recommendations for RA highlight the importance of using disease-modifying anti-rheumatic drugs and biologics effectively to prevent joint damage and enhance patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rheumatoid arthritis: recommendations for treat to target. Palmer, D., El Miedany, Y.[2014]

References

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

Allopurinol Medication Adherence as a Mediator of Optimal Outcomes in Gout Management. [2018]

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

Management of acute and chronic gouty arthritis: present state-of-the-art. [2018]

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

Lack of efficacy during the switch from brand to generic allopurinol. [2013]

4. Canada pubmed.ncbi.nlm.nih.gov

Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. [2013]

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

Mortality in Patients With Gout Treated With Allopurinol: A Systematic Review and Meta-Analysis. [2022]

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

Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. [2022]

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

Allopurinol Use and Risk of Fatal Hypersensitivity Reactions: A Nationwide Population-Based Study in Taiwan. [2016]

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

Implementation of disease activity measurement for rheumatoid arthritis patients in an academic rheumatology clinic. [2022]

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

Treat to Target in Axial Spondyloarthritis: What Are the Issues? [2022]

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

The need to define treatment goals for systemic lupus erythematosus. [2022]

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

Treatment to target in rheumatoid arthritis. [2016]

12. England pubmed.ncbi.nlm.nih.gov

Rheumatoid arthritis: recommendations for treat to target. [2014]