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.
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.
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.
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.
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.
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.
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.
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.
Prospero: CRD42019151316
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'.
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).
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.
CRD42016026991.
In gout research, serum urate has been widely accepted as the primary endpoint in clinical trials of urate-lowering therapies by both the FDA and EMA for many years. However, for serum urate to be a ...meaningful outcome measure, it should reflect at least one important patient-centered clinical outcome, such as gout flares. The relationship between achieving a pre-specified “target” serum urate and a corresponding improvement in patient-centered outcomes has been difficult to show due to variation in reporting of both serum urate and gout flares in clinical trials; a paradoxical rise in gout flares after starting urate-lowering therapy and a delay after achieving the pre-specified target serum urate before gout flares settle coupled with the relatively short duration of the trials. However, recent evidence from individual-level patient data from two, two-year randomized controlled trials clearly shows that achieving target urate is associated with a subsequent reduction and cessation of gout flares. In this review, we examine the evidence supporting serum urate as a surrogate outcome for gout flares, the methods, and the challenges of showing the validity of surrogacy.
The objective of this pilot study was to assess the impact of a salivary gland ultrasound (SGUS) atlas for scoring parenchymal changes in Sjögren’s syndrome by assessing the reliability of the ...scoring system (0–3), without and with the use of the SGUS atlas. Ten participants with varying experience in SGUS contributed to the reliability exercise. Thirty SGUS images of the submandibular and parotid gland with abnormalities ranging from 0 to 3 were scored using the written definitions of the OMERACT SGUS scoring system and using the SGUS atlas based on the OMERACT scoring system. For intra-reader reliability, two rounds were performed without and with the atlas—in the 2nd round the 30 images were rearranged in random order by a physician not included in the scoring. Inter-reader reliability was also determined in both rounds. Without using the atlas, the SGUS OMERACT scoring system showed fair inter-reader reliability in round 1 (mean kappa 0.36; range 0.06–0.69) and moderate intra-reader reliability (mean kappa 0.55; range 0.28–0.81). With the atlas, inter-reader reliability improved in round 1 to moderate (mean kappa 0.52; range 0.31–0.77) and intra-reader reliability to good (mean kappa 0.69; range 0.46–0.86). Higher intra-reader reliability was noted in participants with previous SGUS experience. The SGUS atlas increased both intra- and inter-reader reliability for scoring gland pathology in participants with varying SGUS experience suggesting a possible future role in clinical practice and trials.
Key Points
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Ultrasonography can detect parenchymal changes in salivary glands in patients with Sjögren’s disease.
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An ultrasound atlas may improve reliability of scoring parenchymal changes in salivary glands.
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