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Center for Global Research Data

Serum urate as a biomarker in gout Protocol for individual patient data analysis for OMERACT 2020.

Lead Investigator: Lisa Stamp, University of Otago, Christchurch
Title of Research Proposal: Serum urate as a biomarker in gout Protocol for individual patient data analysis for OMERACT 2020.
Vivli Data Request: 4275
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research: 

Gout is one of the most common causes of arthritis. Gout is caused by a buildup of uric acid in the blood. When the levels are high enough small crystals can form in joints and cause intermittent episodes of extremely painful, red, hot, swollen joints, known as gout flares. Current treatment for gout consists of lowering blood uric acid levels. However, whether this causes a reduction in gout flares has been questioned. The aim of this study is to see if there is a direct relationship between serum urate and gout flares.

Background: Serum urate (SU) is considered a potential biomarker for clinically relevant outcomes in people with gout. SU has been endorsed by the Outcome Measures in Rheumatology (OMERACT) gout working group as a core outcome measure in chronic gout studies (H. Schumacher et al., 2009; H. R. Schumacher et al., 2009; W. Taylor et al., 2008; W. J. Taylor et al., 2008).

The relevance of SU as a primary outcome measure implies that achievement of a target SU is associated with clinically meaningful and patient-important outcomes in gout such as a reduction in the number of gout flares and/or tophus size or number; that is, SU is implicitly considered to be a surrogate endpoint. The direct use of patient-important features as outcome measures in trials is challenging as they are likely to require very large sample sizes and/or long-term follow-up for a benefit to be observed (Morillon et al., 2016).

We have previously, by use of evidence synthesis, explored the strength of the relationship between SU and clinically relevant outcomes, including gout flares. We used meta-regression of all randomised controlled trials (RCTs) to evaluate whether SU should be considered a relevant surrogate endpoint for clinically relevant outcomes in people with gout as defined by the Biomarker-Surrogacy Evaluation Schema (BSES)3 framework (Lassere, 2008). Despite many exploratory “meta-attempts” on the aggregate clinical trial-level data, an association between SU and gout flare could not be confirmed. It was concluded though, that based on observational ecological study design data—including longer duration extension studies—SU < 6 mg/dL was associated with reduced gout flares (Stamp et al., 2018).

The previous synthesis included “ecological studies” where the unit of observation is the population or community; this study design includes lots of caveats but can rightfully be used to explore possible associations between the occurrence of gout flares and the corresponding proportion (in the same population) who have achieved SU target. A limitation to the interpretation of such studies, is the potential logical fallacy in the interpretation of statistical data where inferences about the nature of individuals are deduced from inference for the group to which those individuals belong; i.e., the relationship with patient averages across trials may not be the same as the relationship for patients within trials. This “aggregation or ecological bias” cannot be investigated without individual patient data. As SU did not reach the threshold for a validated surrogate using the BSES3 framework primarily due to the short-term nature of the RCTs included in the meta-analysis, we decided to explore – via statistical modelling – the relationship between various measures of SU (absolute/change values as independent variables) vs. the corresponding occurrence of gout flares (i.e. dependent variable) using individual level patient data from randomised controlled trials.

Requested Studies:
A Phase 3, Randomized, Multicenter, Allopurinol and Placebo-Controlled Study Assessing the Safety and Efficacy of Oral Febuxostat in Subjects With Gout.
Sponsor: Takeda
Study ID: NCT00174915
Sponsor ID: C02-009

A Phase 3, Randomized, Multicenter Study Comparing the Safety and Efficacy of Oral Febuxostat Versus Allopurinol in Subjects With Gout
Sponsor: Takeda
Study ID: NCT00102440
Sponsor ID: C02-010

A Phase 3, Randomized, Multicenter, Double-Blind, Allopurinol-Controlled Study Assessing the Efficacy and Safety of Oral Febuxostat in Subjects With Gout.
Sponsor: Takeda
Study ID: NCT00430248
Sponsor ID: F-GT06-153

Phase II, Open-Label Study, to Assess the Long-Term Safety of Oral TMX-67 in Subjects With Gout
Sponsor: Takeda
Study ID: NCT00174941
Sponsor ID: TMX-01-005

A Phase 3, Randomized, Double Blind, Multicenter, Placebo Controlled Study to Evaluate the Efficacy and Safety of Febuxostat 40 mg XR, 80 mg XR, 40 mg IR and 80 mg IR in Subjects With Gout
Sponsor: Takeda
Study ID: NCT02139046
Sponsor ID: FEB-XR_301

A Phase 2, Randomized, Double Blind, Multicenter, Placebo Controlled Study to Evaluate the Efficacy and Safety of Febuxostat 40 mg XR, 80 mg XR, 40 mg IR and 80 mg IR in Subjects With Gout and Moderate Renal Impairment
Sponsor: Takeda
Study ID: NCT02128490
Sponsor ID: FEB-XR_201

A Multicenter, Randomized, Double-Blind, Phase 2 Study to Evaluate the Effect of Febuxostat Versus Placebo in Joint Damage in Hyperuricemic Subjects With Early Gout
Sponsor: Takeda
Study ID: NCT01078389
Sponsor ID: TMX-67_204

Phase II, Dose-Response, Safety and Efficacy Study of Oral TMX-67 in Subjects With Gout.
Sponsor: Takeda
Study ID: NCT00174967
Sponsor ID: TMX-00-004

Update: This data request was withdrawn on 24 December 2020 by the researcher.