Serum Urate as a Surrogate Endpoint for Flares in People with Gout: A Systematic Review and Meta-Regression Analysis - European Medical Journal

Serum Urate as a Surrogate Endpoint for Flares in People with Gout: A Systematic Review and Meta-Regression Analysis

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*Melanie Birger Morillon,1-3 Sabrina Mai Nielsen,1 Robin Christensen,1 Lisa K. Stamp4

Ms Nielsen and Dr Morillon have declared no conflicts of interests. Dr Stamp declares speaker fees from Amgen and grants from Ardea Biosciences outside the submitted work. Dr Christensen reports non-financial support from Board membership, grants from consultancy (AbbVie, Amgen, Axellus A/S, Bristol-Myers Squibb, Cambridge Weight Plan, Celgene, Eli Lilly, Hospira, MSD, Norpharma, Novartis, Orkla Health, Pfizer, Roche, Sobi, and Takeda), personal fees from employment (Research Unit for Musculoskeletal Function and Physiotherapy, Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark), non-financial support from expert testimony, grants from /grants pending (Axellus A/S, AbbVie, Cambridge Weight Plan, Janssen, MSD, Mundipharma, Novartis, and Roche), grants from payment for lectures, including service on speakers’ bureaus (Abbott, Amgen, Axellus, Bayer HealthCare Pharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Cambridge Weight Plan, Ipsen, Janssen, Laboratoires Expanscience, MSD, Mundipharma, Norpharma, Novartis, Pfizer, Roche, Rottapharm-Madaus, Sobi, and Wyeth), grants from payment for manuscript preparation (Axellus, Bristol-Myers Squibb, and Cambridge Weight Plan, and Aleris-Hamlet [via Norpharma]), non-financial support from patents (planned, pending, or issued), non-financial support from royalties, grants from payment for development of educational presentations (Bristol-Myers Squibb, MSD, and Pfizer), non-financial support from stock/ stock options, grants from travel/accommodations/ meeting expenses unrelated to activities listed (Abbott, AbbVie, Axellus, Bristol-Myers Squibb, Cambridge Weight Plan, Celgene, Laboratoires Expanscience, Norpharma, Novartis, Pfizer, Roche, Rottapharm-Madaus, and Wyeth), and is involved in many healthcare initiatives and research that could benefit from wide uptake of this publication (including Cochrane, OMERACT, IDEOM, RADS, and the GRADE Working Group). Musculoskeletal Statistics Unit, The Parker Institute is grateful for the financial support received from public and private foundations, companies and private individuals over the years. The Parker Institute is supported by a core grant from the Oak Foundation; the Oak Foundation is a group of philanthropic organisations that, since its establishment in 1983, has given grants to not-for-profit organisations around the world.

EMJ Rheumatol. ;4[1]:68-70. Abstract Review No. AR7.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

The OMERACT (Outcome Measures in Rheumatology) gout group has, for several years, been working towards a model for evaluating a biomarker as surrogate endpoint for clinically relevant outcomes. Surrogate measurements are often used in clinical trials when it is difficult or impractical to use clinically relevant or patient-reported outcomes as endpoints. Substituting a target event with a surrogate measurement (for example a soluble biomarker) allows for the conduction of shorter and smaller trials. To evaluate the usability of a biomarker as a surrogate, Maksymowych et al.1 published a model for evaluating a proposed biomarker for surrogacy in 2009. This was followed by Stamp et al.2 applying the OMERACT model to evaluate whether serum urate (SU) fulfilled the OMERACT biomarker criteria. They concluded that, with the exception of its effects on outcome measures, SU met the criteria.2 The need for analysis of existing data to determine whether a reduction in SU predicts a reduction in gout flares, the number/size of tophi, and patient-reported outcomes, was then the next approach in the process of validating SU as a surrogate endpoint for clinically relevant outcomes in people with gout. With this in mind, we conducted a systematic review and meta-analysis, and part of the results were presented at the European League Against Rheumatism (EULAR) congress, 2017, as an oral presentation. For a detailed description of the background and our methods, we refer you to the published protocol.3

A systematic literature review was undertaken to identify all relevant studies. Randomised controlled trials (RCTs) comparing any urate-lowering therapy in people with gout with any control or placebo for 3 months duration were included. The search resulted in 234 abstracts for screening. Subsequently, 82 trials were scrutinised, of which 9 trials (with 16 comparisons) met our inclusion criteria. A total of 5,696 people with gout were entered into the meta-regression model. The longest RCT included was only 12 months in duration. The pooled odds ratio (OR) suggested a small, but statistically significant, favourable association between the active and comparator urate lowering therapies and flare frequency (OR: 0.83; 95% confidence interval: 0.70–0.99). Substantial heterogeneity was present (between trial variance: 0.07; 0.03–0.30). Meta-regression analysis did not reveal any statistically significant association between the proportion of individuals who achieved target SU and the observed flare rate (p=0.82); the model fit did not improve after inclusion of the covariate into the model (between trial variance: 0.08; 0.03–0.33).

In conclusion, substituting surrogate endpoints (proportion achieving target SU) for the important clinical outcome (gout flares) allows for the conduction of shorter, smaller trials. However, based on aggregate trial-level data (meta-regression), an anticipated association between SU and gout flare could not be confirmed. The heterogenicity of the studies and the difference in clinical outcome data reported, as well as the trial duration, is likely to have influenced the results. It is important to note that the longest trial duration was only 12 months and it is likely that this was too short to observe any reduction in gout flares. Additional analysis using data from long-term open label extensions is currently underway.

Maksymowych WP et al. Reappraisal of OMERACT 8 draft validation criteria for a soluble biomarker reflecting structural damage endpoints in rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis: the OMERACT 9 v2 criteria. J Rheumatol. 2009;36(8):1785-91. Stamp LK et al. Serum urate as a soluble biomarker in chronic gout-evidence that serum urate fulfills the OMERACT validation criteria for soluble biomarkers. Semin Arthritis Rheum. 2011;40(6):483-500. Morillon MB et al. Using serum urate as a validated surrogate end point for flares in patients with gout: protocol for a systematic review and meta-regression analysis. BMJ Open. 2016;6(9):e012026.

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