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Rheumatology Advance Access published online on July 24, 2007
Rheumatology, doi:10.1093/rheumatology/kem178
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Assessment of outcome in clinical trials of gout—a review of current measures

W. J. Taylor1, H. R. Schumacher, Jr2, J. A. Singh3,4, R. Grainger5 and N. Dalbeth6

1Rehabilitation Teaching and Research Unit, Department of Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand, 2Division of Rheumatology, University of Pennsylvania School of Medicine and Veterans Affairs Medical Center, Philadelphia, PA, 3Rheumatology Section, Medicine Service and Center for Epidemiological and Clinical Research, Center for Chronic Disease Outcomes Research at the VA Medical Center, 4Division of Rheumatology, Department of Medicine, University of Minnesota, Minneapolis, MN, USA, 5Malaghan Institute of Medical Research, Wellington and 6Department of Medicine, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand.

Correspondence to: Dr William J. Taylor, Department of Medicine, Wellington School of Medicine and Health Sciences, University of Otago, PO Box 7343, Wellington 6242, New Zealand. E-mail: will.taylor{at}otago.ac.nz


   Abstract
Top
 Abstract
Introduction
 What are appropriate study...
 What has been measured...
 How to measure the...
 Response criteria
 Conclusion
 References
 
There has been renewed interest in the treatment of gout with recent reported intervention studies of new agents such as etoricoxib, febuxostat and pegylated-uricase. However, these studies have highlighted the relative paucity of validated outcome measures with which to judge efficacy. This review outlines the published information regarding which endpoints have been measured in randomized clinical trials, what should be measured, what tools or instruments are available for this and the technical properties of such instruments. It highlights recent work that validates measures of tophi, radiographic damage and patient-reported outcomes. The absence of a valid definition of gout-flare or how flare reduction defines response is problematic; this forms the basis for a current ACR-EULAR sponsored project.


   Introduction
Top
 Abstract
 Introduction
What are appropriate study...
 What has been measured...
 How to measure the...
 Response criteria
 Conclusion
 References
 
Gout is a common disease characterized by acute self-limiting attacks of arthritis, sometimes progressing to a chronic arthropathy, due to intra-articular urate crystal deposition. Other manifestations of gout may include tophi, joint damage or destruction, or renal disease. It may be associated with the metabolic syndrome with an increased risk of cardiovascular disease.

There has been renewed interest in the treatment of gout with recent reported intervention studies of new agents including etoricoxib, febuxostat and pegylated-uricase. However, these studies have highlighted the relative paucity of validated outcome measures with which to judge efficacy. This review outlines the published information regarding which endpoints have been measured in randomized clinical trials (RCTs), what should be measured, what tools or instruments are available for this and the technical properties of such instruments.

Although it is true that validated outcome measures may be useful in observational clinical studies, or even in routine clinical practice, there are different demands of measures in these different contexts. In particular, use of standardized measures for individual patient care (as opposed to group-level data in clinical research) demands a much greater standard of reliability: interpretation of significant change in an individual is more challenging than interpretation of significant change within or between groups. We have, therefore, chosen to focus this review upon the context of clinical trials in which groups of patients are allocated to different drugs or treatment strategies.


   What are appropriate study outcomes in gout intervention trials?
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 Abstract
 Introduction
 What are appropriate study...
What has been measured...
 How to measure the...
 Response criteria
 Conclusion
 References
 
Domains of measurement refer to the broad concepts that are being measured, rather than the particular method by which the concept is being measured. For example, the domain of physical functioning may be measured using a variety of self-report questionnaires or observed performance on standardized tasks. Selection of appropriate domains of measurement for many rheumatic diseases has been successfully accomplished through the OMERACT (Outcome Measures In Rheumatology Clinical Trials) consensus process [1]. Gout has been discussed at OMERACT 7 [2] and OMERACT 8 [3], and a preliminary list of relevant domains has been developed by a Special Interest Group (Table 1). A formal consensus exercise using the Delphi technique to determine the extent of agreement with these domains is planned.


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  		TABLE 1. Proposed core domains for intervention studies in gout [2]

 
It is important to note that there are two particular contexts in which gout treatment studies may be conducted. Treatment of acute attacks with the aim of reducing the severity and/or the duration of the attack requires different endpoints than treatment of chronic gout, which might aim to reduce the frequency of flares, prevent joint damage or work disability (for example). The different focus requires different priorities for measurement and possibly different assessment tools.

A critical function of the OMERACT process has been to provide a forum through which credible consensus can be reached, since the selection of appropriate domains of measurement depends upon the purpose of the study and the nature of the disease, rather than the measurement properties of any particular instrument. Thus, selection of domains is not generally guided by quantitative data analysis, but is more judgement-based requiring expert knowledge of the disease, the intervention under consideration and the purpose of that intervention.


   What has been measured in previous intervention studies?
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 Abstract
 Introduction
 What are appropriate study...
 What has been measured...
How to measure the...
 Response criteria
 Conclusion
 References
 
There are relatively few RCTs of gout, particularly in chronic gout. Furthermore, published studies of chronic gout have been of short duration (no longer than 12 months), which is insufficient to determine important outcomes such as radiographic damage and work disability. A number of recent studies of newer agents have been presented as meeting abstracts and not yet fully published. The outcome measures used in these studies are summarized in Tables 2 and 3.


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  		TABLE 2. Randomized controlled trials of treatment for acute gout

 

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  		TABLE 3. Randomized controlled trials of treatment for chronic gout

 
Acute gout studies
The outcomes for intervention studies that aim to treat acute attacks of gout have been: pain intensity in the index joint, patient's global assessment of response to treatment, physician's global assessment of response to treatment, physician's assessment of study joint tenderness, swelling and erythema and a total inflammatory score of the joint.

Global assessment of response entails a comparison of current state with a previous state (judged retrospectively). There are some measurement difficulties with using a retrospective assessment of change to determine response to therapy. In particular, there are issues of recall bias and the extent to which current state determine patients’ or physicians’ perception of change [4]. For example, it is possible that a patient with high disease activity at final assessment will respond differently than a person with low disease activity even though their condition changed by the same absolute or relative amount compared with baseline. The literature on using retrospective assessment of change to determine minimum important differences of continuous variables measured at baseline and follow-up shows that patients are unduly influenced by their current health state when they make transition ratings (that is, global assessments of change) [5].

The technical properties of the 5-point Likert scale for pain assessment in two trials of etoricoxib for acute gout has been presented at a Special Interest Group meeting at OMERACT 8 by Naomi Schlesinger [3]. This analysis demonstrated construct validity (expected correlation with other clinical indicators of disease activity), large effect sizes (within-group change) and discrimination between groups defined by global assessment of response or discontinuation of treatment due to lack of efficacy. Discrimination between treatment groups has not been demonstrated probably since these trials included an active comparator.

Chronic gout studies
It is immediately clear that several domains of measurement thought to be relevant have not been measured or reported. Joint damage from gout has been largely ignored, possibly because there has been no formalized method of scoring radiographic damage in gout. Patient-reported outcomes (PRO) are of major importance for treatment trials, yet to date in published studies these have been limited mainly to self-reported pain levels or patient global assessment of response to treatment. There are no published studies that document other outcomes such as physical disability, health-related quality of life or work disability (although abstracts on these topics have been presented at recent meetings).

The frequency of flare of gouty arthritis is a common endpoint in studies of chronic gout. However, the operational definition of flare has not yet been properly validated and has been ad hoc in reported studies. All RCT studies appear to rely upon individual clinician-investigators to identify when a flare has occurred or as a flare that requires treatment, without explicit criteria or descriptions of features that constitute a flare [6, 7]. The extent to which episodes of musculoskeletal pain reported as flare by these studies actually correspond to true flares is not clear. Other non-randomized or observational studies have also left flare undefined [8–10] but some have used definitions such as: joint symptoms that led to emergency room or urgent outpatient clinic evaluation [11]; office/emergency room visit with gout and/or joint pain administration code(s) and at least one typical gout treatment within 7 days of the visit [12].

Intervention studies for acute gout have had to define flare in terms of entry criteria for the study, rather than as an outcome. The definitions used in these studies have included: meeting the 1977 American College of Rheumatology (ACR) criteria for acute gouty arthritis [13], a symptom score of ≥5 (composite of pain, tenderness, swelling) and pain ≥2 (0–4 Likert scale) [14, 15]; meeting 1977 ACR criteria, inflammatory score ≥5 (composite of functional impairment, tenderness, swelling of the index joint) and pain rated at least moderate [16]. It can be seen that such definitions have the potential to conflate presence of flare with the severity of the flare. While this is appropriate for studies of acute gout, it is probably better to be able to separate out flare presence from flare severity when using flare as an indicator of outcome in studies of chronic gout.

Whether flare frequency is a sufficiently responsive or discriminating trial endpoint for intervention studies is not entirely clear. The reported RCTs of febuxostat have not shown significant differences in flare frequency over 28 days in comparison with placebo [7] or over 1 year in comparison with allopurinol [6]. It is possible that detection of a flare reduction effect from sUA-lowering therapies requires a longer period of observation following the flare-inducing period associated with this kind of treatment. This view is supported by an open label extension study of the 28-day febuxostat study, in which subjects remained on one of three doses of febuxostat for 4 yrs. Flare frequency fell to <1/yr after the first year of stable dosage [17]. In an RCT of colchicine for acute gout prophylaxis during initiation of allopurinol, at least one flare occurred in 33% of treated patients over 6 months compared with 77% of placebo patients (P = 0.008) [18]. The average rate of gout flare was reduced from 2.48/yr to 0.5 over 6 months in the to colchicine group, compared with 2.09/yr increasing to nearly 3 over 6 months in the control group. Thus, it does appear that flare frequency can discriminate between groups treated with colchicine or placebo, but not urate-lowering therapies at this time.

The identification of minimally important difference (MID) is also relevant, when considering flare frequency as a primary study endpoint. There are no data on the reduction in flare frequency that patients or physicians would consider a meaningful reduction. It is also unclear whether patients or physicians would consider flare reduction to a particular threshold level (e.g. <1/yr) in the same way as flare reduction in proportionate terms (e.g. a 20% reduction in flare frequency).

An ACR-EULAR sponsored project is currently underway that aims to validate a case-definition of flare that will then be tested within a randomized clinical trial setting and to address some of these deficiencies.


   How to measure the domains of importance?
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 How to measure the...
Response criteria
 Conclusion
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OMERACT has also been very influential in confirming a framework necessary for robust measurement tools [1]. The OMERACT filter demands that all measurement methods should show truth, discrimination and feasibility [19]. The ‘truth’ aspect refers to traditional concepts of validity that aims to answer the question of whether the instrument is really measuring what it purports to be measuring: face (does it look right?), content (does it cover the relative issues adequately?), construct (does it relate to other measures of similar or different concepts in predicted ways?), predictive (do scores predict future status in expected ways?) and criterion (does it correspond closely with a ‘gold standard’ measure of the concept?). The ‘discrimination’ issue refers to the question of whether the measure changes when it is supposed to change (for example, change sensitivity or responsiveness) and not change when it is not supposed to change (for example, observer reliability or test–retest reliability). In addition to within-group change, an appropriate measure has to be able to discriminate between groups that ought to be different. This is very important in a clinical trial context since measures that change to the same extent in response to placebo and effective treatment will be unable to detect a treatment effect. Feasibility refers to the practical and logistical difficulty in applying the measure in the clinical trial, and is indicated mainly by the monetary cost and respondent burden of the particular instrument or measure.

One aspect of validity or ‘truth’ that is receiving increasing attention in the psychometric literature, but only to a limited extent in rheumatology, concerns the Rasch model of measurement. Proponents of this approach contend that multi-item measures that intend to measure a single concept (be uni-dimensional) need to fit the Rasch model to allow summation of items into a single score to have any sensible meaning [20]. Thus, the Rasch model is held to be fundamental to meaningful and valid measurement. A full discussion of the Rasch model is beyond the scope of this review, but it is relevant to mention that several self-report instruments have been examined with regard to the Rasch model [21–24] and a major project that aims to develop a large item-bank for generally applicable functional scales has been reported in the rheumatology literature [25]. Briefly, the Rasch model proposes a probabilistic relationship between the response that an individual makes on a questionnaire item, on the one hand, and the ‘difficulty’ of the item and ‘ability’ of the person on the other. That is, the probability of any particular response is expressed as a mathematical function of person-ability and item-difficulty. For example, people who are less disabled are expected to endorse functionally more difficulty items whereas more disabled people are not. The mathematical function of these two parameters is what defines the Rasch model.

Much of the useful information required to determine whether a particular measure passes through the OMERACT filter is contained within data from randomized clinical trials and observational cohort studies. The extent to which measures of each domain previously listed pass through the filter based on published data is summarized in Table 4. Some of this information will be further expanded subsequently.


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  		TABLE 4. Summary of the OMERACT filter applied to outcome measures in gout studies

 
Patient-reported outcomes such as health-related quality of life or physical disability have not been reported in published RCTs of chronic gout, yet it is known that the disease has a significant impact upon quality of life and functional status [26]. The Health Assessment Questionnaire Disability Index (HAQ-DI) is a widely used measure of physical disability in studies of rheumatic diseases. A cohort study used the HAQ-DI to assess physical disability in gout and showed that tophi and ischaemic heart disease were independently associated with higher levels of disability [27]. However, there are no published studies that document the validity, reliability or change sensitivity of the HAQ-DI in gout. An unpublished cohort study of gout patients showed that the HAQ-DI shows excellent internal consistency (Cronbach's-{alpha} 0.94) and concurrent validity with observed physical performance and other indicators of physical function (correlation coefficients greater than 0.80) [28].

A comprehensive self-report questionnaire to assess gout impact (GI), gout pain and severity between flares (GPSB), well-being impact (WBI) and productivity has been developed and tested for psychometric properties but has not been evaluated in a published clinical trial setting [29]. Internal consistency (Cronbach's-{alpha} 0.75–0.92) and test–retest reliability (0.68–0.81) were satisfactory for the four scales. Some evidence for construct validity was demonstrated by moderate correlations between GPSB and SF-36 Physical Summary Scale (r = –0.401) and the WBI with SF-36 Mental Summary Scale (r = –0.352). Discriminant validity was supported by significant differences in GI and GPSB scales among subjects with increasing gout severity (MD-rated severity and report of tophi P = 0.001/P = 0.052; P = 0.016/P = 0.026) and patient-reported number of attacks last year (P < 0.001). Differences in scale scores among subjects with increasing typical attack pain level were also observed (P < 0.01).

While radiographic damage has not yet been studied as an outcome in a clinical trial setting, it is important that longer-term studies demonstrate that successful management of chronic gout does lead to true ‘disease modification’ with a reduction in radiographic damage. There are no published studies of a scoring method for radiographic damage in gout, although preliminary data on the validity and observer-reliability of a modified Sharp–van der Heijde scoring system was presented in abstract form and the full publication is in press [30]. It will be important for such a scoring system to show relevant change over time in longitudinal studies, but there is already data that shows the scoring system is able to discriminate between early and late disease, or between tophaceous and non-tophaceous disease. It is relevant to mention that other modalities could also represent joint damage [including physical examination, ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI)], but there are no or insufficient data to report concerning these alternative approaches.

Tophi represent an indicator of total body urate and usually indicate more severe disease, in addition to being an unwanted feature of the disease, per se. Accurate measurement of tophi has been of interest and a number of methods have been investigated including physical measurement [31] or measurement using US, MRI or CT. The main advantage of US over physical measurement is that deeper periarticular tophi can be assessed, even when there are no subcutaneous tophi clinically apparent. The observer reliability of US measurement of an index tophus was good (ICC > 0.8) with the smallest detectable difference being 4 mm for the same observer and 9 mm for different observers. The technique was shown to discriminate between patients whose serum urate (sUA) was well controlled (<6.0 mg/dl) and those whose sUA was not controlled [32].

Several different methods of physical tophus measurement have been described. Perez-Ruiz and colleagues [33] described measurement of the longest diameter of index tophi by calipers in an observational study of benzbromarone and allopurinol. This method demonstrated sensitivity to change in response to therapy. Although CT measurement of tophi is also reliable and feasible, a recent comparison of this method of physical measurement using this method with CT measurement did not show that CT measurement was any more reliable and it correlated very highly with physical measurement (r = 0.91) [34]. This method of physical measurement showed with excellent intra- and inter-observer reliability (ICC 0.996 and 0.985, respectively). Recently, Schumacher and colleagues [31] have described the reliability of measuring tophus ‘area’ by physical measurement of two axes using a tape measure. This method was found to have good intra- and inter-observer reproducibility. This method has also been used in the FOCUS study, with a recent report demonstrating that febuxostat therapy was superior to allopurinol in achieving tophus regression over a 1 year period [17].

Biochemical measurement of sUA levels is another important study endpoint, especially in studies that aim explicitly to control gout by control of sUA levels. This objective clearly makes a lot of sense, since there is a very strong relationship between the risk of gout itself [35] and also flare frequency [9, 12] with sUA levels. Furthermore, the fundamental pathogenesis of gout clearly involves formation of intra-articular urate crystal deposition, so interventions to successfully control chronic gout will usually require a sustained reduction in sUA levels. Serum uric acid measurement is easily available, reliable, shows excellent within-group change sensitivity and discriminates well between groups that have been treated with a urate-lowering agent (febuxostat) and placebo.


   Response criteria
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 Abstract
 Introduction
 What are appropriate study...
 What has been measured...
 How to measure the...
 Response criteria
Conclusion
 References
 
When there are multiple study outcome measures, it is often considered useful to derive a single composite index of response. This is particularly appropriate where the individual measures are measuring somewhat similar aspects of outcome and where there are no strong differences in how patients or physicians value each individual measure [36]. In rheumatology, a dichotomous composite index of response (ACR20) has been most successful in rheumatoid arthritis clinical trials. A dichotomous responder index has the advantage of simple interpretation and translation into ‘number needed to treat’ (NNT), but may lose statistical power compared with a continuous measure of efficacy [37]. A composite responder index has not been reported in clinical trials of gout to date.

A dichotomous response has been commonly reported in respect of normalizing sUA levels to subsaturation point. There are very clear-cut data that document a relationship between flare frequency or tophus regression with subsaturation levels of sUA, but the correspondence is probably not strong enough to obviate the need for more direct measures of patient outcome. For example, 76% of subjects whose sUA was normalized to <6.0 mg/dl showed tophus regression compared with 22% of subjects whose sUA was not normalized [32]. This implies that 55% of subjects would have been misclassified as having regression or no regression of tophus, if sUA control alone was used as a surrogate of tophus regression.

It will be necessary for further consensus work to decide whether a composite index of response is necessary or whether a single measure (such as reduction in flare frequency) is sufficiently important and comprehensive. It will also be helpful for empiric data analysis to determine the collinearity of possible elements of a composite responder index, which will identify redundancy—elements that correlate very highly with each other. Finally, any proposed definition of response will need to be tested in clinical trials of interventions that have been proven to lead to better outcomes. In this way, different candidate definitions of response can be compared on their ability to discriminate between effective and not so effective treatment.


   Conclusion
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 Introduction
 What are appropriate study...
 What has been measured...
 How to measure the...
 Response criteria
 Conclusion
References
 
There is growing consensus regarding the areas of outcome that need to be assessed in gout intervention studies. These include self-reported pain, serum uric acid, flare and tophi. But there are many other areas where the level of consensus is unclear or where the instruments to use are poorly characterized. There are efforts underway to correct this and the next few years should see the identification of a ‘core set’ of measures to be used in gout studies.

Formula

J.A.S. received research grants from TAP and Allergan and honoraria from Abbott.


   References
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 What has been measured...
 How to measure the...
 Response criteria
 Conclusion
 References
 

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Submitted 5 April 2007; Accepted 25 May 2007


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