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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the best way to manage gout, a type of arthritis that causes painful joint flares. Researchers are comparing two treatment plans: one focuses on controlling symptoms with medications like naproxen and prednisone, while the other targets reducing uric acid levels in the blood using allopurinol, a medication specifically for lowering uric acid. Individuals with gout who have experienced at least one flare in the past year and have elevated uric acid levels (6.0 mg/dL or higher) might be a good fit for this study. The goal is to determine which approach leads to better outcomes for gout and overall health. As a Phase 4 trial, this study involves treatments that are already FDA-approved and proven effective, aiming to understand how they benefit more patients.

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 is the safety track record for these treatments?

Research has shown that allopurinol is generally safe for treating gout. A large study found that using allopurinol for over six months was well tolerated, with no new safety concerns. Another study found that allopurinol had a lower risk of death compared to febuxostat, another gout medication, highlighting its relative safety.

For colchicine, used to prevent gout flare-ups, studies indicate it is well tolerated in low doses. Some people may experience mild side effects like diarrhea, but these are uncommon. Colchicine can also help reduce the risk of heart problems in gout patients starting urate-lowering treatment.

Overall, both allopurinol and colchicine are considered safe options for managing gout, with well-documented safety records. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it explores two different strategies for managing gout: "Treat-to-Target" and "Symptom Management." Unlike traditional approaches that often focus solely on alleviating symptoms, the Treat-to-Target strategy aims for a specific serum urate level using allopurinol, potentially offering a more precise and proactive way to prevent gout attacks. This could lead to better long-term control of the disease. On the other hand, the Symptom Management strategy provides anti-inflammatory treatments to address immediate flare-ups, offering flexibility for patients who may not respond well to standard preventive measures. By comparing these two approaches, researchers hope to find out which method offers the most effective balance of symptom relief and long-term disease management.

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

Research has shown that allopurinol effectively manages gout by lowering uric acid levels in the blood, which is linked to the condition. Studies have demonstrated that allopurinol helps most patients reach their uric acid goals and control gout flare-ups. One study found that 69% of participants achieved their target uric acid levels, and it was effective even for those with chronic kidney disease.

In this trial, participants in the Treat-to-Target-Serum Urate (TTT-SU) group will receive allopurinol to help achieve target uric acid levels. Meanwhile, participants in the treat-to-avoid-symptoms (TTASx) group will receive anti-inflammatory treatments like naproxen, colchicine, and prednisone, which are known to help manage gout attacks. For example, colchicine effectively prevents flare-ups when starting uric acid-lowering treatments like allopurinol. These treatments work together to manage the symptoms and underlying causes of gout. ^{6 7 8 9 10}

Who Is on the Research Team?

Hyon K Choi, MD, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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)

I can swallow pills.

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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 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]

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]

Citations

1. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2100028

Comparative Effectiveness of Allopurinol and Febuxostat in ... Allopurinol and febuxostat achieved serum urate goals in patients with gout; allopurinol was noninferior to febuxostat in controlling flares.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38906504/

Subgroup Analysis of the STOP Gout Trial Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04875702?cond=gout&page=3&rank=24

Treat-to-Target Serum Urate Versus Treat-to-Avoid ... The TRUST study is a randomized, controlled multicenter study to evaluate the management of gout by comparing two commonly used treatment strategies for ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0003496724198184

A randomised controlled trial of the efficacy and safety of ... We have shown that DE of allopurinol is effective in people with gout, including in those with CKD, with 69% achieving target SU at final visit and 59% ...

5. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK356145/

Results - Management of Gout - NCBI Bookshelf - NIH Allopurinol has a greater than 40 year history of use, and high level evidence of its harms in treatment of patients with gout and other conditions has been ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26190562/

An open-label, 6-month study of allopurinol safety in gout This large multicenter study found that the allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months.

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa1710895

Cardiovascular Safety of Febuxostat or Allopurinol in ... All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center ...

8. jrheum.org jrheum.org/content/51/6/556

What Is Allopurinol Failure and What Should We Do About It? In this review, we provide a framework for assessing allopurinol failure, which includes failure of allopurinol to control serum urate concentrations.

9. ajkd.org ajkd.org/article/S0272-6386(24)00835-7/fulltext

Subgroup Analysis of the STOP Gout Trial Conclusions. Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a ...

10. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34013998/

Cardiovascular safety of febuxostat compared to ... The cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout remains equivocal. Febuxostat had a better safety outcome compared ...