Outcome reporting in randomized trials in gout: A systematic scoping review from the OMERACT gout working group assessing the uptake of the core outcome set.

OBJECTIVE: The selection and reporting of core outcome measures in clinical trials is essential for patients, researchers, and healthcare providers for clinical research to have an impact on healthcare. In this systematic scoping review, we aimed to quantify the extent to which gout clinical trials are collecting and reporting data in accordance with the core outcome domains from Outcome Measures in Rheumatology (OMERACT) published in 2009 applicable for both acute and chronic trials and evaluate the reporting according to the core domains before and after the 2009 OMERACT endorsement. METHODS: We searched multiple databases PubMed, EMBASE, the Cochrane Library including the Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews (CDSR) and www. CLINICALTRIALS: gov for randomized controlled trials (RCTs) allocating people with gout versus an active pharmacological gout treatment or a control comparator (no date limitation). We extracted the data in accordance with the core outcome sets, focusing individually on core outcome domains and the core outcome measurements for acute and chronic trials, respectively. In this study 'Acute trials' reflect studies that describe interventions for short term management of gout flares, and 'chronic trials' describe interventions for long-term urate lowering therapy in the management of gout. RESULTS: From 8,522 records identified in the database search, 134 full text papers were reviewed, and 71 trials were included, of which 36 were acute and 35 were chronic. Only 3 of 36 (8%) acute trials reported all five core domains and none of the 35 included chronic trials reported all 7 core domains. In the acute trials, twenty-seven unique measurement instruments across the 5 core domains were identified. For chronic trials there were 31 unique measurement instruments used across the 7 core domains. Serum urate was reported in 100% of the chronic trials and gout flares in 80%. However, other core domains were reported in <30% of chronic trials. In particular the patient-important domains such as HR-QOL, patient global assessment and activity limitations were rarely reported. A broad variety of different measurement instruments were used to assess each endorsed core domain, a minority of trials used the OMERACT endorsed instruments. For acute trials, the number reporting on all core domains was consistently low and no change was detected before and after the endorsement of the core domains in 2009. None of the included chronic trials reported on all 7 endorsed core domains at any time. CONCLUSION: In this study we found a low adherence with the intended endorsed (i.e., core) outcome domains for acute and chronic gout studies which represents a poor uptake of the global OMERACT efforts for the minimum of what should be measured in clinical trials. In addition, there is a significant variation in how the OMERACT endorsed outcome domains have been measured. This systematic review demonstrates the need for continuous encouragement among gout researchers to adhere to OMERACT core domains as well as further guidance on outcome measurements reporting. REGISTRATION: Prospero: CRD42019151316.

Association between serum urate and flares in people with gout and evidence for surrogate status: a secondary analysis of two randomised controlled trials.

BACKGROUND: Use of serum urate as a treatment target and outcome measure has become controversial in view of the 2017 American College of Physicians guidelines, which advocated a treat-to-symptom rather than a treat-to-target serum urate approach to gout management. The relevance of serum urate as a treatment target measure implies that achievement of target serum urate is causally associated with improvement in patient-important outcomes such as reduction in the number of gout flares. The aim of this study was to assess the causal relationship between achieving target serum urate and the occurrence of gout flares. METHODS: We analysed individual patient-level data from two randomised trials on urate-lowering therapies in people with gout conducted in Nottingham, UK, and New Zealand. We included participants randomly assigned to immediate dose escalation in the New Zealand study and all participants in the Nottingham study (a nurse-led gout care group and a general practitioner-led usual care group). Individuals who on average achieved a serum urate concentration less than 6 mg/dL (0·36 mmol/L) based on data at 6, 9, and 12 months post-baseline were defined as serum urate responders. The primary outcome was the proportion of participants having at least one gout flare, and the secondary outcome was the mean number of flares per participant per month, from 12 to 24 months after baseline, compared between serum urate responders and non-responders. In adjusted logistic regression models, serum urate at baseline, previous flare history (in the year preceding study entry), presence of tophi at baseline, and, for the Nottingham dataset, the original randomisation group, were included as covariates. The Nottingham study was registered with ClinicalTrials.gov, NCT01477346. The New Zealand study was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000845932. FINDINGS: From the combined individual data from both trials, we identified 343 serum urate responders and 245 serum urate non-responders. Significantly fewer serum urate responders had a gout flare than did serum urate non-responders between 12 and 24 months (91 [27%] of 343 vs 156 [64%] of 245; adjusted odds ratio [OR] 0·29 [95% CI 0·17 to 0·51], p<0·0001). The mean number of flares per participant per month between 12 and 24 months was significantly lower in serum urate responders than in serum urate non-responders (adjusted mean difference -1·41 [95% CI -1·77 to -1·04], p<0·0001). This association was independent of the original randomised treatment allocation. INTERPRETATION: Achieving an average serum urate concentration less than 6 mg/dL is associated with an absence of gout flares and a reduction in the number of flares in the subsequent 12 months in people with gout. These results support a treat-to-target serum urate approach in the management of gout. FUNDING: None.

Serum urate as surrogate endpoint for flares in people with gout: A systematic review and meta-regression analysis.

OBJECTIVES: The primary efficacy outcome in trials of urate lowering therapy (ULT) for gout is serum urate (SU). The aim of this study was to examine the strength of the relationship between SU and patient-important outcomes to determine whether SU is an adequate surrogate endpoint for clinical trials. METHODS: Multiple databases through October 2017 were searched. Randomized controlled trials comparing any ULT in people with gout with any control or placebo, ≥three months duration were included. Open label extension (OLE) trial data were included in secondary analyses. Standardized data elements were extracted independently by two reviewers. RESULTS: Ten RCTs and 3 OLE studies were identified. From the RCTs (maximum duration 24 months) meta-regression did not reveal an association between the relative risk of a gout flare and the difference in proportions of individuals with SU < 6mg/dL (P = 0.47; R2 = 8%). In a post hoc analysis, the ratio of the time in months at which the proportion of individuals having a flare was reported/time in months at which the proportion of individuals with SU < 6mg/dL was reported was calculated and studies where the ratio was <2 were excluded. Using the remaining 6 studies there was an association between proportion of individuals achieving SU < 6mg/dL and gout flares (over patient years). Duration of ULT was inversely associated with the proportion of patients experiencing a flare. Study duration and variability in reporting of outcomes limited the analysis. Observational studies supported the trend of fewer flares in those with lower SU. CONCLUSIONS: Based on aggregate clinical trial-level data an association between SU and gout flare could not be confirmed. However, based on observational ecological study design data-including longer duration extension studies-SU < 6mg/dL was associated with reduced gout flares.

Variability in the Reporting of Serum Urate and Flares in Gout Clinical Trials: Need for Minimum Reporting Requirements.

OBJECTIVE: To describe the ways in which serum urate (SU) and gout flares are reported in clinical trials, and to propose minimum reporting requirements. METHODS: This analysis was done as part of a systematic review aiming to validate SU as a biomarker for gout. The ways in which SU and flares were reported were extracted from each study by 2 reviewers. RESULTS: A total of 22 studies (10 randomized controlled trials, 3 open-label extension studies, and 9 observational studies) were identified. There were 3 broad categories of SU reporting: percentage at target SU, mean SU, and change in SU. A median of 2 (range 1-3) categories were reported across all studies. The most common method of reporting SU was percentage at target in 17/22 (77.3%) studies, with all studies reporting a target of SU < 6 mg/dl. There were 12/22 (54.5%) studies reporting mean SU at some time after study entry, with 7 (58.3%) of these reporting at more than just the final study visit. Two ways of reporting gout flares were identified: mean flare rate and percentage of participants with flares. There was variability in time periods over which flares rates were reported. CONCLUSION: There is inconsistent reporting of SU and flares in gout studies. Reporting the percentage of participants who achieve a target SU reflects international treatment guidelines. SU should also be reported as a continuous variable with a relevant central and dispersion estimate. Gout flares should be reported as both percentage of participants and mean flare rates at each timepoint.

Using serum urate as a validated surrogate end point for flares in patients with gout: protocol for a systematic review and meta-regression analysis.

INTRODUCTION: Gout is the most common inflammatory arthritis in men over 40 years of age. Long-term urate-lowering therapy is considered a key strategy for effective gout management. The primary outcome measure for efficacy in clinical trials of urate-lowering therapy is serum urate levels, effectively acting as a surrogate for patient-centred outcomes such as frequency of gout attacks or pain. Yet it is not clearly demonstrated that the strength of the relationship between serum urate and clinically relevant outcomes is sufficiently strong for serum urate to be considered an adequate surrogate. Our objective is to investigate the strength of the relationship between changes in serum urate in randomised controlled trials and changes in clinically relevant outcomes according to the 'Biomarker-Surrogacy Evaluation Schema version 3' (BSES3), documenting the validity of selected instruments by applying the 'OMERACT Filter 2.0'. METHODS AND ANALYSIS: A systematic review described in terms of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines will identify all relevant studies. Standardised data elements will be extracted from each study by 2 independent reviewers and disagreements are resolved by discussion. The data will be analysed by meta-regression of the between-arm differences in the change in serum urate level (independent variable) from baseline to 3 months (or 6 and 12 months if 3-month values are not available) against flare rate, tophus size and number and pain at the final study visit (dependent variables). ETHICS AND DISSEMINATION: This study will not require specific ethics approval since it is based on analysis of published (aggregated) data. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-reviewed publications. TRIAL REGISTRATION NUMBER: CRD42016026991.