Febuxostat for treating chronic gout

Jean H Tayar; Maria Angeles Lopez‐Olivo; Maria E Suarez‐Almazor

doi:10.1002/14651858.CD008653.pub2

. 2012 Nov 14;2012(11):CD008653. doi: 10.1002/14651858.CD008653.pub2

Febuxostat for treating chronic gout

Jean H Tayar ¹, Maria Angeles Lopez‐Olivo ^1,^✉, Maria E Suarez‐Almazor ¹

Editor: Cochrane Musculoskeletal Group

PMCID: PMC4058893 NIHMSID: NIHMS562079 PMID: 23152264

Abstract

Background

Gout is the most common inflammatory arthritis in men over 40 years and has an increasing prevalence among postmenopausal women. Lowering serum uric acid levels remains one of the primary goals in the treatment of chronic gout. In clinical trials, febuxostat has been shown to be effective in lowering serum uric acid levels to < 6.0 mg/dL.

Objectives

To evaluate the benefits and harms of febuxostat for chronic gout.

Search methods

We searched The Cochrane Library, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from inception to July 2011. The ClinicalTrials.gov website was searched for references to trials of febuxostat. Our search did not include any restrictions.

Selection criteria

Two authors independently reviewed the search results and disagreements were resolved by discussion. We included any controlled clinical trial or open label trial (OLT) using febuxostat at any dose.

Data collection and analysis

Data and risk of bias were independently extracted by two authors and summarised in a meta‐analysis. Continuous data were expressed as mean difference and dichotomous data as risk ratio (RR).

Main results

Four randomised trials and two OLTs with 3978 patients were included. Risk of bias differed by outcome, ranging from low to high risk of bias. Included studies failed to report on five to six of the nine outcome measures recommended by OMERACT. Patients taking febuxostat 120 mg and 240 mg reported more frequent gout flares than in the placebo group at 4 to 28 weeks (RR 1.7; 95% CI 1.3 to 2.3, and RR 2.6; 95% CI 1.8 to 3.7 respectively). No statistically significant differences were observed at 40 mg and 80 mg. Compared to placebo, patients on febuxostat 40 mg were 40.1 times more likely to achieve serum uric acid levels < 6.0 mg/dL at 4 weeks (95% CI 2.5 to 639), with an absolute treatment benefit of 56% (95% CI 37% to 71%). For febuxostat 80 mg and 120 mg, patients were 68.9 and 80.7 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit compared to placebo (95% CI 13.8 to 343.9, 95% CI 16.0 to 405.5), respectively; with an absolute treatment benefit of 75% and 87% (95% CI 68 to 80% and 81 to 91%), respectively. Total discontinuation rates were significantly higher in the febuxostat 80 mg group compared to placebo (RR 1.4; 95% CI 1.0 to 2.0, absolute risk increase 11%; 95% CI 3 to 19%). No other differences were observed.

When comparing allopurinol to febuxostat at 24 to 52 weeks, the number of gout flares was not significantly different between the two groups, except for febuxostat 240 mg (RR 2.3; 95% CI 1.7 to 3.0). Patients on febuxostat 40 mg showed no statistically significant differences in benefits or harms. Patients on febuxostat 80 mg and 120 mg were 1.8 and 2.2 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit (95% CI 1.6 to 2.2, 95% CI 1.9 to 2.5) with an absolute treatment benefit of 29% and 44% (95% CI 25% to 33%, 95% CI 38% to 50%), respectively, at 24 to 52 weeks. Total discontinuation rates were higher for febuxostat 80 mg and 120 mg compared to allopurinol (RR 1.5; 95% CI 1.2 to 1.8, absolute risk increase 11%; 95% CI 6% to 16%; and RR 2.6; 95% CI 2.0 to 3.3, absolute risk increase 20%; 95% CI 3% to 14%, respectively). Discontinuations due to adverse events were similar across groups. Total adverse events were lower for febuxostat 80 mg and 120 mg compared with allopurinol (RR 0.93; 95% CI 0.87 to 0.99, absolute risk increase 6%; 95% CI 0.7% to 11%; and RR 0.90; 95% CI 0.84 to 0.96, absolute risk increase 8%; 95% CI 3% to 13%, respectively). No other relevant differences were noted.

After 3 years of follow‐up there were no statistically significant differences regarding effectiveness and harms between febuxostat 80 mg or 120 mg and allopurinol groups (adverse event rate per 100 patient‐years 227, 216, and 246, respectively).

Authors' conclusions

Although the incidence of gout flares requiring treatment may be increased in patients taking febuxostat compared to placebo or allopurinol during early treatment, no such increase in gout flares was observed in the long‐term follow‐up study when compared to allopurinol. Febuxostat at any dose was shown to be beneficial in achieving serum uric acid levels < 6.0 mg/dL and reducing serum uric acid levels in the period from baseline to final visit when compared to placebo and to allopurinol. However, the grade of evidence ranged from low to high, which indicates that further research is needed.

Plain language summary

Febuxostat for treating chronic gout

This summary of a Cochrane review represents what we know from research about the effect of febuxostat for treating chronic gout.

From six studies including 3978 people with chronic gout, the review shows that,

In people with chronic gout:

‐ febuxostat probably reduces uric acid levels;

‐ febuxostat probably increases the incidence of gout flares during early treatment (while getting the uric acid levels down). The normalization of serum uric acid leads to mobilization of urate from tissue deposits, which in turn may increase the number of attacks;

‐ febuxostat probably shows similar benefits as allopurinol after three years of use.

We do not have information about febuxostat effects on joint imaging, musculoskeletal function, pain, overall assessment, and quality of life. Also, we do not have precise information about side effects and complications. This is particularly true for rare but serious side effects. Possible side effects may include liver enzyme elevations, high blood pressure and diarrhoea. Rare complications may include certain cardiovascular events (chest pain, coronary artery disease, myocardial infarction, or atrial fibrillation).

What is chronic gout and what is febuxostat?

Uric acid is a product normally present in the blood as a result of the breakdown of certain products called 'purines'. Gout is a disease caused by high uric acid levels in the blood leading to crystal formation in the joints, most commonly joints of the lower limbs such as the big toe, heels, ankles and knees. Gout usually presents as acute attacks causing joint swelling and pain, but also can lead to chronic arthritis. While there is no cure for the disease, treatment can prevent recurrent gout attacks and improve its chronic form.

Research shows that keeping uric acid levels below 6.0 mg/dL can reduce gout attacks over time. However, in the first months of therapy, there could be an increased number of gout attacks, due to the nature of the treatment.

Febuxostat is a new drug that can help lower uric acid levels in the blood in adults with gout.

Best estimate of what happens to people with chronic gout who take febuxostat:

Febuxostat was proven effective in lowering uric acid to less than 6.0 mg/dL.

In short‐term studies (one year or less), when febuxostat was compared with placebo (a sham or fake medication):

‐ 6 patients out of 100 had more gout attacks taking febuxostat 80 mg (6% absolute increase in attacks);

‐ 75 more patients out of 100 taking febuxostat 80 mg reached their goal of uric acid level below 6.0 mg/dL (75% absolute benefit).

When febuxostat was compared with allopurinol, another medicine often used to lower uric acid:

‐ 2 patients out of 100 had more gout attacks taking febuxostat 80 mg (2% absolute increase in attacks);

‐ 29 more patients out of 100 on febuxostat 80 mg reached an acid level below 6.0 mg/dL (29% absolute benefit).

In studies of more than three years:

febuxostat at any dose had the same effect as allopurinol in reaching a uric acid level of less than 6.0 mg/dL, and there was no observed increase in gout attacks.

Summary of findings

Background

Description of the condition

Gout is the most common inflammatory arthritis in men over 40 years and has an increasing prevalence among postmenopausal women (Chohan 2009). It results from the deposition of monosodium uric acid crystals in and around the joints and soft tissues (Schlesinger 2004). It has been recognized that the formation of such crystals requires the presence of hyperuricaemia, defined as a serum uric acid concentration (serum uric acid levels) above its solubility limit (6.8 mg/dL) supersaturating the body fluids (Schumacher 2005). The disease can evolve from an asymptomatic stage of hyperuricaemia to recurrent gout attacks with inter‐critical periods and subsequently chronic gouty arthritis. Formation of tophi and progression to chronic destructive arthritis can result from persistent monosodium uric acid crystal deposition that is left untreated. Furthermore, hyperuricaemia can be associated with renal damage secondary to interstitial monosodium uric acid crystal deposition and the formation of kidney stones (Schlesinger 2004).

Description of the intervention

Lowering serum uric acid levels below saturating levels, at a target < 6.0 mg/dL, remains one of the major goals in the treatment of chronic gout to reduce or reverse clinical events (Zhang 2006). The pharmacological methods currently employed for that purpose are i) reduction of uric acid production by use of the xanthine oxidase inhibitors; ii) enhancement of urinary uric acid excretion with uricosuric agents; and iii) promotion of the catabolism of uric acid with the pegylated recombinant uricase (pegloticase) (Anderson 2010). Among the xanthine oxidase inhibitors, allopurinol, a purine analogue has been the main drug available for decades. However, allopurinol’s side effects, although rare, can be serious (hypersensitivity syndrome) and are more common in patients with renal dysfunction (Arellano 1993; Dalbeth 2007).

Febuxostat, a novel non‐purine analogue xanthine oxidase inhibitor, at daily dosages of 40 mg to 240 mg has been shown in studies to be at least as good as allopurinol (dose ≤ 300 mg/day) in lowering serum uric acid levels to < 6.0 mg/dL, and may require fewer dose adjustments in patients with mild to moderate renal dysfunction (Bruce 2006; Edwards 2009). Approved doses in the US are 40 mg and 80 mg daily, and in Europe 80 mg and 120 mg.

How the intervention might work

The reversibility of monosodium uric acid crystal deposition by reducing the serum uric acid levels below saturation level has been recognized for years, making the reduction and maintenance of serum uric acid levels below 6.0 mg/dL a goal in managing chronic gout (Pascual 2007). Allopurinol has been the gold standard therapy for the past 40 years. However, there are patients who are refractory to allopurinol or with impaired renal function who may benefit from the newer alternative, febuxostat. The newer inhibitor of xanthine oxidase was approved for use in many countries in 2009. Individual studies found that it could be at least as effective as allopurinol. Furthermore, there were no reports of hypersensitivity reactions in patients on febuxostat, and it has been shown to be safe when used in patients with mild to moderate renal dysfunction (Becker 2010). A potential benefit with its uses could also be in allopurinol refractory patients.

Why it is important to do this review

The goal of this review was to systematically review the current data on febuxostat's benefit and harms in treating chronic gout (Bruce 2006; Stevenson 2011). Patients, clinicians and policy‐makers need to keep abreast with the current literature in terms of benefit and harms of febuxostat.

To our knowledge there are only two systematic reviews to date on febuxostat for the treatment of chronic gout. This is the first systematic review of the literature with a meta‐analysis of randomised controlled trials and it differs from other reviews in that it includes summary data on open label trials.

Objectives

To evaluate the benefits and harms of febuxostat alone or combined with non‐steroidal antiinflammatory drugs or colchicine, or both, in comparison to allopurinol or placebo for the treatment of chronic gout.

Methods

Criteria for considering studies for this review

Types of studies

Any randomised controlled trial (RCT), controlled clinical trial, or open label trial (OLT) comparing febuxostat (alone or combined with non‐steroidal antiinflammatory drugs or colchicine, or both) in patients with gout with any control or placebo, with a minimum duration of three months.

Types of participants

Patients at least 16 years of age meeting the preliminary American College of Rheumatology (ACR) criteria for acute arthritis of primary gout (Wallace 1977) or given a diagnosis of gout as described by the authors.

Types of interventions

The following comparisons were eligible for inclusion: febuxostat alone or in combination with colchicine or non‐steroidal antiinflammatory drugs (NSAIDs) or lifestyle changes versus placebo or any control alone or in combination with colchicine, NSAIDs or lifestyle changes. Any dosages were included.

Types of outcome measures

We used the primary outcome measures for response to gout treatment that were proposed by the American College of Rheumatology outcome measures for gout clinical trials and OMERACT 9 gout report (OMERACT 9).

Major outcomes

Benefit as assessed by the OMERACT 9 outcome domains for studies of acute and chronic gout (OMERACT 9).

1) Gout flares: we extracted data on frequency of recurrent attacks in all ways reported.

2) Serum urate: change in serum uric acid levels, and per cent change in serum uric acid levels from baseline at final visit. Evidence suggests that lowering serum uric acid levels to < 6.0 mg/dL increases crystal disappearance from synovial fluid (Edwards 1981; Li‐Yu 2001).

3) Harms as assessed by the incidence of patients with adverse events (total and serious adverse events, liver function test abnormalities, skin reactions, cardiovascular events, hypertension, and diarrhoea) and the withdrawal rates (total withdrawals, withdrawals due to adverse events, withdrawals due to gout flares, withdrawals due to lack of efficacy, withdrawals due to other reasons).

Minor outcomes

The following secondary outcomes were also considered when reported.

Tophus burden as measured by size measurement of individual tophus (regression of tophi), including disappearance of tophi and velocity of tophus regression.
Health‐related quality of life as assessed by measures: Short Form‐36 (SF‐36), Gout Assessment Questionnaire (GAQ), and the Gout Impact Scale (GIS).
Pain: on Likert scales as well as the visual analog scale (VAS), numeric rating scale (NRS), or qualitative scales.
Musculoskeletal function: function as assessed by activities of daily living scales including composite outcomes such as the Health Assessment Questionnaire (HAQ) or other activities of daily living scales (ADLs), and work productivity.
Patient global and physician global assessment.
Joint imaging: joint damage as assessed by the van der Heijde‐Sharp radiographic score modified for gout.

We used the GRADE software to generate the 'Summary of findings' table and reported outcomes include: 1) incidence of gout flares, 2) serum uric acid levels < 6.0 mg/dL at final visit, 3) pain, 4) patient global assessment, 5) health‐related quality of life, 6) total number of patients with serious adverse events, and 7) total number of withdrawals due to adverse events.

Search methods for identification of studies

Electronic searches

The following electronic databases were searched: The Cochrane Library (2011, Issue 6), including the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessments (HTA); MEDLINE (1950 to July 2011); EMBASE (1980 to July 2011); and International Pharmaceutical Abstracts Database (IPAD). The ClinicalTrials.gov website was searched for references to trials of febuxostat.

The search was not limited by language, year of publication or type of publication. The full search strategy in Appendix 1 was developed for MEDLINE and was adapted for the other electronic databases.

Searching other resources

The reference lists from comprehensive reviews and identified clinical trials were also manually searched.

Websites of the following regulatory agencies were searched for reported adverse events using the terms 'gout', 'febuxostat' and 'uloric':

FDA’s MedWatch, www.fda.gov/harms/medwatch/default.htm;   National Guideline Clearing House, www.guideline.gov;   National Institute for Health and Clinical Excellence, www.nice.org.uk/guidance/index.jsp?action=byID&o=11830;   Agency for Healthcare Research and Quality (AHRQ), www.ahrq.gov/;   Health Technology Assessment (HTAi), www.htai.org/;   Turning Research Into Practice (TRIP), www.tripdatabase.com.

Data collection and analysis

EndNote X2 software was used to manage the records retrieved from searches of electronic databases. Results from handsearches were tracked on a Microsoft Excel spreadsheet. A data extraction form was created in Word to capture all the information available for each individual trial.

Selection of studies

Results of the various searches were independently reviewed by two authors (JT, MLO). Titles and abstracts were reviewed and if additional information was required, the full text was obtained. A record of reasons for excluding studies was kept. Disagreements were resolved by discussion. Inter‐rater agreement was calculated using Cohen's kappa.

Data extraction and management

Data were independently extracted from the included trials by two review authors (MLO, JT); then the collected data were entered into RevMan 5.0 using the double‐entry system.

Data included the following.

General study information such as title, authors, contact address, publication source, publication year, country, and study sponsor.
Characteristics of the study: design, study setting, inclusion and exclusion criteria, quality criteria (e.g. randomisation method; allocation procedure; blinding of patients, caregivers and outcome assessors; withdrawals and dropouts, intention‐to‐treat (ITT) analysis).
Characteristics of the study population (age, sex, duration of disease, treatment history, presence of co‐morbidity and peripheral disease, concurrent treatments).
Characteristics of the intervention, such as treatment comparators, dose, method of administration, frequency of administration, duration of treatment, and numbers in each intervention group.
Outcome measures as noted above.
Results for the ITT population (where possible); outcome measures at the end of the controlled phase; and any summary measures with standard deviations, confidence intervals and P values, where given; dropout rate and reasons for withdrawal.

Assessment of risk of bias in included studies

The risk of bias of the included studies was also assessed by two independent review authors. As recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008), the following methodological domains were assessed.

Random sequence generation.
Allocation sequence concealment.
Blinding of participants and personnel.
Blinding of outcome assessors.
Incomplete outcome data.
Selective reporting.
Other bias.

Each of these criteria were explicitly judged using: 'low risk of bias' ,'high risk of bias', or 'unclear' (uncertainty over the potential for bias).

Measures of treatment effect

The results of the studies were analysed using Review Manager 5.1. Data were summarised in a meta‐analysis when they were sufficiently homogeneous, both clinically and statistically. Continuous data were expressed as mean difference (MD) or standardized mean difference (SMD) depending on similarity of scales measuring an outcome. Dichotomous data were expressed as risk ratios (RR) or, in the case of rare events (< 10%), Peto odds ratios (Peto OR) were used.

To establish equivalence between febuxostat and allopurinol we used the Becker et al definition where non‐inferiority is a greater than 10% difference in achieving final serum uric acid levels < 6.0 mg/dL of the lower limit of the 95% confidence interval (CI) (Becker 2010).

Summary of findings tables were completed in order to improve the readability of the review. In addition to the absolute and relative magnitude of effect provided in the summary of findings table, the number needed to treat (NNT) was calculated from the control group event rate (unless the population event rate was known) and the risk ratio using the Visual Rx NNT calculator (Cates 2004). For continuous outcomes, the NNT was calculated using the Wells calculator available at the Cochrane Musculoskeletal Group editorial office. GRADE software was used to provide an overall grading of the quality of the evidence and to provide a comment on our confidence in the results. The possible grades of evidence are: 'high quality', 'moderate quality', 'low quality', 'very low quality'.

Unit of analysis issues

Treatment groups were analysed separately. No comparisons were added by combining all relevant experimental intervention groups of the study into a single group.

Dealing with missing data

We considered two strategies for handling withdrawals and dropouts.   i. Accounting for the numbers: were the numbers of withdrawals and dropouts reported for both groups?   ii. Accommodating withdrawals (ITT analysis, imputation): were the withdrawals and dropouts accounted for in the analysis (for example through ITT analysis using imputation methods) or the last observation carried forward (LOCF) was used.

Assessment of heterogeneity

Heterogeneity of the data was formally tested using the Chi² test with a P value < 0.10 indicating significant heterogeneity. The I² statistic (Higgins 2003) was also assessed. A value greater than 50% may indicate substantial heterogeneity. In the case of substantial heterogeneity, the data were further explored, including subgroup analyses, in an attempt to explain the heterogeneity.

Assessment of reporting biases

A funnel plot was not performed due to the limited number of publications retrieved.

Data synthesis

The fixed‐effect model of meta‐analysis was used to assess all outcomes. However, when significant heterogeneity was found and could not be explained, the random‐effects model was used.

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses were performed to explore possible effect size differences:

intervention (different dosage, duration of treatment), and
characteristics of participants (severity of baseline disease, age, disease duration, renal function).

Sensitivity analysis

We explored effect size differences and the robustness of conclusions by:

effect of study quality that is defined as adequate allocation concealment and outcome assessor blinding, and
effect of imputation of missing data or statistical transformations.

Results

Description of studies

Studies are reported according to the follow‐up duration. Characteristics of included studies are summarised in the tables section.

Results of the search

In our electronic search we retrieved a total of 271 citations: 93 from MEDLINE, 135 from EMBASE, 30 from IPAD, and 13 from web links. Searching other resources (described in the Methods paragraph) did not reveal additional records for review. In a first review based on abstracts and titles we excluded 72 citations. Of the remaining 199, 189 were excluded in a second step review mainly because of the type of citation (Figure 1). Of the 10 full texts then retrieved for our third and final review, two were excluded (see Characteristics of excluded studies for details) and a total of six met the inclusion criteria. The percentage of inter‐rater agreement for the study selection was 93% (κ = 0.80). Four RCTs (six publications) were included in our efficacy and harms analysis (Becker 2005a; Becker 2005b; Becker 2010; Schumacher 2008) and two open label trials (OLTs) were included in effectiveness and harms analysis (Becker 2009; Schumacher 2009). We have also included two more tables: Studies awaiting classification and Ongoing studies, which may be useful for future updates of this review.

Diagram of study selection.

* RCT plus abstract (2 publications)

Included studies

Design

There were four randomised, double‐blind, placebo‐controlled trials: Becker 2005b, Becker 2010, Schumacher 2008, Becker 2005a of 4‐week, 26‐week, 28‐week, and 52‐week duration, respectively. From these four RCTs, two were combined (Becker 2005a; Schumacher 2008) and followed over a three‐year period in an OLT (Becker 2009), and one (Becker 2005b) had an OLT of five years (Schumacher 2009). Table 31 shows the characteristics of the two OLTs included in this review. In Becker 2010 patients completing either one of the OLTs were eligible to participate. Randomisation was reported in ratios of 1:1:1:1 for Becker 2005b, 1:1:1 for Becker 2010 and Becker 2005a, and 2:2:1:2:1 for Schumacher 2008. Schumacher 2008 had three febuxostat arms versus allopurinol versus placebo; Becker 2005b had three febuxostat arms versus placebo; and Becker 2010 and Becker 2005a had two febuxostat arms versus allopurinol.

1. Open label trials characteristics.

	Schumacher 2009			Becker 2009
Name	Febuxostat in the treatment of gout: 5‐yr findings of the FOCUS efficacy and harms study			Clinical efficacy and harms of successful long term uric acid lowering with febuxostat or allopurinol in subjects with gout FACT and APEX open label trial
Duration of RCT	28 days			52 weeks and 28 weeks
Duration of open label trial	60 months			40 months
Arms	Febuxostat 40mg	Febuxostat 80mg	Febuxostat 120mg	Febuxostat 80mg	Febuxostat 120mg	Allopurinol
Subjects enrolled in open label trial	8	79	29	606	388	92
Subjects completed open label trial	6	41	11	412	217	35
Primary endpoint	Proportion of subjects that achieved and maintained SUA < 6mg/dL			Proportion of subjects with sUA < 6mg/dL at each visit
Secondary endpoints	Percentage reduction from baseline sUA; Proportion of subjects with sUA < 5mg/dL and 4 mg/dL;Proportion of subjects with flares requiring treatment; resolution of palpable tophi			Percentage reduction from baseline sUA; proportion of subjects with sUA decreasing to < 6mg/dL across treatment changes; reduction in the incidence of flares requiring treatment; percentage reduction in number of tophi; reduction in the size or disappearance of the index tophus

Febuxostat 40 mg/day compared to placebo for chronic gout
Patient or population: patients with chronic gout   Settings: Primary care   Intervention: Febuxostat 40 mg/day   Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Febuxostat 40 mg/day
Incidence of gout flares   Follow‐up: 28 days	368 per 1000	350 per 1000   (191 to 640)	RR 0.95   (0.52 to 1.7)	75   (1 study)	++OO   low^1,2	Not statistically significant.
Serum uric acid <6.0 mg/dL at final visit   Follow‐up: 28 days	27 per 1000⁴	1000 per 1000   (68 to 1000)⁴	RR 40.1   (2.5 to 639.1)	69   (1 study)	++OO   low^1,3	NNT = 2 (95% CI 1 to 3)⁴; ATB = 56% (95% CI 37 to 71%); RRR = 39% (637% to 1.5%)⁴.
Pain	See comment	See comment	See comment	See comment	See comment	Not assessed
Patient global assessment	See comment	See comment	See comment	See comment	See comment	Not assessed
Health Related Quality of Life	See comment	See comment	See comment	See comment	See comment	Not assessed
Serious Adverse Events   Follow‐up: 28 days	26 per 1000⁴	26 per 1000   (0 to 0)⁴	RR 1.0 (0 to 0)⁴	75   (1 study)	+++O   moderate¹	Not statistically significant .
Discontinuations   due to adverse events   Follow‐up: 28 days	26 per 1000	27 per 1000   (2 to 416)	RR 1.0   (0.07 to 15.8)	75   (1 study)	+++O   moderate¹	Not statistically significant.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).     CI: Confidence interval; RR: Risk ratio; NNT: Number needed to treat; ATB: Absolute treatment benefit; RRR: Relative risk reduction; NE: Not estimable.
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.
¹ High risk of bias in 1 item (intention to treat was not performed)   ² Study include relatively few patients and few events and thus has wide confidence intervals around the estimate of the effect   ³ Outcome is a substitute measurement (surrogate endpoint). ⁴ Numbers calculated adding a continuity correction value of 0.5 to each cell of the 2x2 table.

Febuxostat 80 mg/day compared to placebo for chronic gout
Patient or population: patients with chronic gout   Settings: Primary care   Intervention: Febuxostat 80 mg/day   Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Febuxostat 80 mg/day
Incidence of gout flares   Follow‐up: 4‐28 weeks	238 per 1000	314 per 1000   (228 to 431)	RR 1.32   (0.96 to 1.8)	474   (2 studies)	++OO   low^1,2	Not statistically significant.
Serum uric acid <6.0 mg/dL at final visit   Follow‐up: 4‐28 weeks	7 per 1000	482 per 1000   (97 to 1000)	RR 68.9   (13.8 to 343.9)	332   (2 studies)	++OO   low^1,3	NNT = 1 (95% CI 1 to 1); ATB = 75% (95% CI 68 to 80%); RRR = 10,000% (95% CI 71,500 to 13,300%).
Pain	See comment	See comment	See comment	See comment	See comment	Not assessed
Patient global assessment	See comment	See comment	See comment	See comment	See comment	Not assessed
Health Related Quality of Life	See comment	See comment	See comment	See comment	See comment	Not assessed
Serious Adverse Events   Follow‐up: 4‐28 weeks	12 per 1000	32 per 1000⁵   (8 to 125)	RR 2.8   (0.72 to 10.7)	479   (2 studies)	+++O   moderate¹	Not statistically significant.
Discontinuations   due to adverse events   Follow‐up: 4‐28 weeks	35 per 1000	63 per 1000   (26 to 156)	RR 1.8   (0.74 to 4.5)	479   (2 studies)	+++O   moderate	Not statistically significant.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).     CI: Confidence interval; RR: Risk ratio; NNT: Number needed to treat; ATB: Absolute treatment benefit; RRR: Relative risk reduction; NE: Not estimable.
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.
¹ High risk of bias in 1 item (intention to treat was not performed)   ² The Becker 2005b trial includes relatively few patients and few events and thus has wide confidence intervals around the estimate of the effect   ³ Outcome is a substitute measurement (surrogate endpoint).   ⁴ Heterogeneity exists across the studies ⁵ In the placebo group 12 people out of 1000 had Serious Adverse Events over 4 to 28 weeks, compared to 32 (95% CI 8 to 125) out of 1000 for the febuxostat group. The reported serious adverse events were cardiovascular disorders (chest pain, coronary artery disease, myocardial infarction and atrial fibrillation).

Febuxostat 120 mg/day compared to placebo for chronic gout
Patient or population: patients with chronic cout   Settings: Primary care   Intervention: Febuxostat 120 mg/day   Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Febuxostat 120 mg/day
Incidence of gout flares   Follow‐up: 4‐28 weeks	238 per 1000	407 per 1000   (300 to 552)	RR 1.7   (1.3 to 2.3)	479   (2 studies)	+++O   moderate¹	NNT = 6 (95% CI 4 to 17); ATB = 15% (95% CI 6 to 23); RRR = 61%.
Serum uric acid <6.0 mg/dL at final visit   Follow‐up: 4‐28 weeks	7 per 1000	565 per 1000   (112 to 1000)	RR 80.7   (16.0 to 405.5)	356   (2 studies)	++OO   low^1,2,3	NNT = NE; ATB = 87% (95% CI 81 to 91%); RRR = NE.
Pain	See comment	See comment	See comment	See comment	See comment	Not assessed
Patient global assessment	See comment	See comment	See comment	See comment	See comment	Not assessed
Health Related Quality of Life	See comment	See comment	See comment	See comment	See comment	Not assessed
Serious Adverse events   Follow‐up: 4‐28 weeks	12 per 1000	31 per 1000   (8 to 19)	RR 2.7   (0.70 to 10.2)	479   (2 studies)	+++O   moderate¹	Not statistically significant.
Discontinuations   due to adverse events   Follow‐up: 4‐28 weeks	35 per 1000	58 per 1000   (23 to 142)	RR 1.7   (0.67 to 4.1)	479   (2 studies)	+++O   moderate¹	Not statistically significant.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).     CI: Confidence interval; RR: Risk ratio; NNT: Number needed to treat; ATB: Absolute treatment benefit; RRR: Relative risk reduction; NE: Not estimable.
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.
¹ High risk of bias in 1 item (intention to treat was not performed)   ² Outcome is a substitute measurement (surrogate endpoint).   ³ The Becker 2005b trial includes relatively few patients and few events and thus has wide confidence intervals around the estimate of the effect

Febuxostat 40 mg/day compared to allopurinol for chronic gout
Patient or population: patients with chronic gout   Settings: Primary care   Intervention: Febuxostat 40 mg/day   Comparison: Allopurinol
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Allopurinol	Febuxostat 40 mg/day
Incidence of gout flares   Follow‐up: 24 weeks	41 per 1000	40 per 1000   (23 to 68)	RR 0.97   (0.57 to 1.65)	1324   (1 study)	++++   high	Not statistically significant.
Serum uric acid <6.0 mg/dL at final visit   Follow‐up: 24 weeks	408 per 1000	432 per 1000   (384 to 494)	RR 1.1   (0.94 to 1.2)	1324   (1 study)	+++O   moderate¹	Not statistically significant.
Pain	See comment	See comment	See comment	See comment	See comment	Not assessed
Patient global assessment	See comment	See comment	See comment	See comment	See comment	Not assessed
Health Related Quality of Life	See comment	See comment	See comment	See comment	See comment	Not assessed
Serious Adverse Events   Follow‐up: 24 weeks	41 per 1000	25 per 1000   (14 to 44)	RR 0.61   (0.35 to 1.07)	1513   (1 study)	++++   high	Not statistically significant.
Discontinuations   due to adverse events   Follow‐up: 24 weeks	85 per 1000	104 per 1000   (76 to 143)	RR 1.2   (0.90 to 1.7)	1513   (1 study)	++++   high	Not statistically significant.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).     CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.
¹ Outcome is a substitute measurement (surrogate endpoint).

Febuxostat 80 mg/day compared to allopurinol for chronic gout
Patient or population: patients with chronic gout   Settings: Primary care   Intervention: Febuxostat 80 mg/day   Comparison: Allopurinol
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Allopurinol	Febuxostat 80 mg/day
Incidence of gout flares   Follow‐up: 8, 26, & 52 weeks	204 per 1000	228 per 1000   (200 to 259)	RR 1.1   (0.98 to 1.3)	2325   (3 studies)	++++   high	Not statistically significant.
Serum uric acid <6.0 mg/dL at final visit   Follow‐up: 8, 26, & 52 weeks	398 per 1000	716 per 1000   (617 to 832)	RR 1.8   (1.6 to 2.2)	2193   (3 studies)	++OO   low^1,2	NNT= 3 (95%CI 3 to 5); ATB = 29% (95% CI 25 to 33%); RRR = 73%.
Pain	See comment	See comment	See comment	See comment	See comment	Not assessed
Patient global assessment	See comment	See comment	See comment	See comment	See comment	Not assessed
Health Related Quality of Life	See comment	See comment	See comment	See comment	See comment	Not assessed
Serious Adverse Events   Follow‐up: 24. 28. & 52 weeks	50 per 1000	45 per 1000   (17 to 122)	RR 0.91   (0.34 to 2.4)	1044   (3 studies)	+++O   moderate^1,4	Not statistically significant.
Discontinuations   due to adverse events   Follow‐up: 24. 28. & 52 weeks	50 per 1000	65 per 1000   (39 to 107)	RR 1.3   (0.79 to 2.1)	1044   (3 studies)	+++O   moderate⁴	Not statistically significant.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).     CI: Confidence interval; RR: Risk ratio; NNT: Number needed to treat; ATB: Absolute treatment benefit; RRR: Relative risk reduction; NE: Not estimable.
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.
¹ Heterogeneity exists across the studies   ² Outcome is a substitute measurement (surrogate endpoint).   ³ Pooled estimates are from 2 studies (Schumacher 2008 and Becker 2005a) ⁴ High risk of bias in 1 item (intention to treat was not performed)

Febuxostat 120 mg/day compared to allopurinol for chronic gout
Patient or population: patients with chronic gout   Settings: Primary care   Intervention: Febuxostat 120 mg/day   Comparison: Allopurinol
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect   (95% CI)	No of Participants   (studies)	Quality of the evidence   (GRADE)	Comments
	Assumed risk	Corresponding risk
	Allopurinol	Febuxostat 120 mg/day
Incidence of gout flares   Follow‐up: 28 & 52 weeks	420 per 1000	542 per 1000   (365 to 802)	RR 1.3   (0.87 to 1.9)	986   (2 studies)	++++   high	Not statistically significant.
Serum uric acid <6.0 mg/dL at final visit   Follow‐up: 28 & 52 weeks	384 per 1000	829 per 1000   (733 to 941)	RR 2.2   (1.9 to 2.5)	880   (2 studies)	+++O   moderate¹	NNT= 3 (95%CI 2 to 3); ARR = 44% (95% CI 38 to 50%); RRR = NE.
Pain	See comment	See comment	See comment	See comment	See comment	Not assessed
Patient global assessment	See comment	See comment	See comment	See comment	See comment	Not assessed
Health Related Quality of Life	See comment	See comment	See comment	See comment	See comment	Not assessed
Serious Adverse Events   Follow‐up: 28 & 52 weeks	50 per 1000	58 per 1000   (35 to 96)	RR 1.2   (0.70 to 1.93)	1041   (3 studies)	++++   high	Not statistically significant.
Discontinuations due to adverse events   Follow‐up: 28 & 52 weeks	50 per 1000	78 per 1000   (24 to 251)	RR 1.6   (0.49 to 5.0)	1041   (3 studies)	++++   high	Not statistically significant.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).     CI: Confidence interval; RR: Risk ratio; NNT: Number needed to treat; ARR: Absolute risk reduction; ARI: Absolute risk increase; RRR: Relative risk reduction; RRI: Relative risk increase; NE: Not estimable.
GRADE Working Group grades of evidence   High quality: Further research is very unlikely to change our confidence in the estimate of effect.   Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.   Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.   Very low quality: We are very uncertain about the estimate.
¹ Outcome is a substitute measurement (surrogate endpoint).

		1year n/N (%)	2year n/N (%)	3year n/N (%)	4year n/N (%)	5year n/N (%)
Schumacher 2009	Febuxostat 40 mg	4/7 (57)	5/8 (63)	4/ 6 (67)	5/ 6 (83)	6/6 (100)
	Febuxostat 80 mg	47/55 (85)	37/49 (76)	38/ 45 (84)	36/39 (92)	38/41 (93)
	Febuxostat 120 mg	12/18 (67)	12/13 (92)	12/13 (92)	11/13 (85)	10/11 (91)
Becker 2009	Febuxostat 80 mg	375/422 (89)	325/364 (89)	109/120 (91)	‐	‐
	Febuxostat 120 mg	145/168 (86)	123/141 (87)	43/47 (92)	‐	‐
	Allopurinol 300 mg	37/45 (82)	33/42 (79)	9/10 (90)	‐	‐

		AEs Rate per 100 patient‐year
Schumacher 2009	Febuxostat 40 mg	274
	Febuxostat 80 mg	385
	Febuxostat 120 mg	259
Becker 2009	Febuxostat 80 mg	227
	Febuxostat 120 mg	216
	Allopurinol 300 mg	245

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of gout flares	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 28 days	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.52, 1.74]
2 Serum uric acid <6.0 mg/dL at final visit	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 28 days	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	40.11 [2.52, 639.08]
3 Change in serum uric acid concentration from baseline at final visit	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1 28 days	1	69	Mean Difference (IV, Fixed, 95% CI)	‐5.23 [‐5.78, ‐4.69]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of gout flares	2	474	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.96, 1.81]
1.1 28 days	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.67, 2.00]
1.2 8 weeks	1	396	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.94, 2.04]
2 Serum uric acid <6.0 mg/dL at final visit	2	332	Risk Ratio (M‐H, Fixed, 95% CI)	68.86 [13.79, 343.94]
2.1 28 days	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	54.0 [3.42, 852.00]
2.2 28 weeks	1	260	Risk Ratio (M‐H, Fixed, 95% CI)	75.02 [10.65, 528.34]
3 Change in serum uric acid concentration from baseline at final visit	2	332	Mean Difference (IV, Random, 95% CI)	‐4.96 [‐6.23, ‐3.68]
3.1 28 days	1	72	Mean Difference (IV, Random, 95% CI)	‐5.63 [‐6.24, ‐5.03]
3.2 28 weeks	1	260	Mean Difference (IV, Random, 95% CI)	‐4.33 [‐4.65, ‐4.02]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of gout flares	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [1.26, 2.32]
1.1 28 days	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	1.5 [0.91, 2.49]
1.2 8 weeks	1	403	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [1.23, 2.60]
2 Serum uric acid <6.0 mg/dL at final visit	2	356	Risk Ratio (M‐H, Fixed, 95% CI)	80.65 [16.04, 405.52]
2.1 28 days	1	69	Risk Ratio (M‐H, Fixed, 95% CI)	66.86 [4.26, 1050.04]
2.2 28 weeks	1	287	Risk Ratio (M‐H, Fixed, 95% CI)	85.84 [12.20, 603.82]
3 Change in serum uric acid concentration from baseline at final visit	2	472	Mean Difference (IV, Random, 95% CI)	‐5.31 [‐5.68, ‐4.94]
3.1 28 days	1	69	Mean Difference (IV, Random, 95% CI)	‐5.02 [‐5.60, ‐4.45]
3.2 28 weeks	1	403	Mean Difference (IV, Random, 95% CI)	‐5.44 [‐5.70, ‐5.17]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of gout flares	3	2325	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.98, 1.27]
1.1 8 weeks	1	530	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.91, 1.64]
1.2 24 weeks	1	1333	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.92, 2.37]
1.3 52 weeks	1	462	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.88, 1.15]
2 Serum uric acid <6.0 mg/dL at final visit	3	2193	Risk Ratio (M‐H, Random, 95% CI)	1.80 [1.55, 2.09]
2.1 24‐28 weeks	2	1702	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.49, 1.93]
2.2 52 weeks	1	491	Risk Ratio (M‐H, Random, 95% CI)	2.04 [1.70, 2.45]
3 Change in serum uric acid concentration from baseline at final visit	2	1041	Mean Difference (IV, Random, 95% CI)	‐1.24 [‐1.50, ‐0.99]
3.1 8 weeks	1	535	Mean Difference (IV, Random, 95% CI)	‐1.38 [‐1.59, ‐1.16]
3.2 52 weeks	1	506	Mean Difference (IV, Random, 95% CI)	‐1.12 [‐1.30, ‐0.94]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of gout flares	2	986	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.87, 1.91]
1.1 8 weeks	1	537	Risk Ratio (M‐H, Random, 95% CI)	1.58 [1.21, 2.08]
1.2 52 weeks	1	449	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.96, 1.24]
2 Serum uric acid <6.0 mg/dL at final visit	2	880	Risk Ratio (M‐H, Fixed, 95% CI)	2.16 [1.91, 2.45]
2.1 28 weeks	1	396	Risk Ratio (M‐H, Fixed, 95% CI)	2.12 [1.78, 2.52]
2.2 52 weeks	1	484	Risk Ratio (M‐H, Fixed, 95% CI)	2.19 [1.83, 2.62]
3 Change in serum uric acid concentration from baseline at final visit	2	1038	Mean Difference (IV, Random, 95% CI)	‐1.93 [‐2.19, ‐1.67]
3.1 8 weeks	1	537	Mean Difference (IV, Random, 95% CI)	‐2.07 [‐2.28, ‐1.85]
3.2 52 weeks	1	501	Mean Difference (IV, Random, 95% CI)	‐1.80 [‐1.98, ‐1.62]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 28 days	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.05, 5.42]
2 Adverse event	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 28 days	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.07, 15.82]
3 Gout flare	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 28 days	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.14]
4 Lack of efficacy	1		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
4.1 28 days	1	75	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
5 Other reasons	1		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
5.1 28 days	1	75	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [1.01, 1.97]
1.1 28 days	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.25, 8.06]
1.2 28 weeks	1	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [1.01, 1.98]
2 Adverse event	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.74, 4.46]
2.1 28 days	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.9 [0.18, 20.10]
2.2 28 weeks	1	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [0.69, 4.76]
3 Gout flare	2	479	Risk Ratio (M‐H, Random, 95% CI)	2.22 [0.05, 101.12]
3.1 28 days	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.55]
3.2 28 weeks	1	401	Risk Ratio (M‐H, Random, 95% CI)	13.60 [0.81, 227.06]
4 Lack of efficacy	2	479	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.03, 0.03]
4.1 28 days	1	78	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
4.2 28 weeks	1	401	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.03, 0.03]
5 Other reasons	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.76, 1.75]
5.1 28 days	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	2.85 [0.12, 67.97]
5.2 28 weeks	1	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.72]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.73, 1.48]
1.1 28 days	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.15, 6.74]
1.2 28 weeks	1	403	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.73, 1.49]
2 Adverse event	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [0.67, 4.08]
2.1 28 days	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 21.14]
2.2 28 weeks	1	403	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [0.60, 4.26]
3 Gout flare	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	2.23 [0.40, 12.57]
3.1 28 days	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.93]
3.2 28 weeks	1	403	Risk Ratio (M‐H, Fixed, 95% CI)	6.5 [0.37, 114.53]
4 Lack of efficacy	2	479	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.03, 0.02]
4.1 28 days	1	76	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
4.2 28 weeks	1	403	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.04, 0.02]
5 Other reasons	2	479	Risk Difference (M‐H, Fixed, 95% CI)	‐0.02 [‐0.09, 0.05]
5.1 28 days	1	76	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
5.2 28 weeks	1	403	Risk Difference (M‐H, Fixed, 95% CI)	‐0.02 [‐0.10, 0.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	3	2555	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [1.14, 1.51]
1.1 24‐28 weeks	2	2046	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [1.11, 1.54]
1.2 52 weeks	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [1.01, 1.72]
2 Adverse event	3	2555	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.80, 1.39]
2.1 24‐28 weeks	2	2046	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.72, 1.30]
2.2 52 weeks	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	1.98 [0.86, 4.54]
3 Gout flare	3	2555	Risk Ratio (M‐H, Random, 95% CI)	2.99 [0.70, 12.79]
3.1 24‐28 weeks	2	2046	Risk Ratio (M‐H, Random, 95% CI)	5.79 [1.59, 21.05]
3.2 52 weeks	1	509	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.45, 2.66]
4 Lack of efficacy	3	2555	Risk Ratio (M‐H, Random, 95% CI)	3.08 [0.55, 17.20]
4.1 24‐28 weeks	2	2046	Risk Ratio (M‐H, Random, 95% CI)	3.08 [0.55, 17.20]
4.2 52 weeks	1	509	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Other reasons	3	2555	Risk Ratio (M‐H, Random, 95% CI)	1.34 [1.10, 1.62]
5.1 28 weeks	2	2046	Risk Ratio (M‐H, Random, 95% CI)	1.38 [1.09, 1.75]
5.2 52 weeks	1	509	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.90, 1.74]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.83, 1.09]
1.1 28 days	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.46, 3.83]
1.2 28 weeks	1	401	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.82, 1.07]
2 Serious	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	2.78 [0.72, 10.72]
2.1 28 days	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	2.85 [0.12, 67.97]
2.2 28 weeks	1	401	Risk Ratio (M‐H, Fixed, 95% CI)	2.76 [0.62, 12.28]
3 Liver function test abnormalities	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	2.85 [0.92, 8.82]
3.1 28 days	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	2.85 [0.12, 67.97]
3.2 28 weeks	1	401	Risk Ratio (M‐H, Fixed, 95% CI)	2.84 [0.85, 9.53]
4 Skin reaction	2	479	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.04, 0.04]
4.1 28 days	1	78	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
4.2 28 weeks	1	401	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.05, 0.05]
5 Cardiovascular events (chest pain, coronary artery disease, myocardial infarction, atrial fibrillation)	2		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
5.1 28 days	1	78	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
5.2 28 weeks	1	401	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.01, 0.03]
6 Hypertension	2	479	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.05, 0.03]
6.1 28 days	1	78	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
6.2 28 weeks	1	401	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.06, 0.04]
7 Diarrhea	2	479	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.06, 0.04]
7.1 28 days	1	78	Risk Difference (M‐H, Fixed, 95% CI)	0.02 [‐0.11, 0.15]
7.2 28 weeks	1	401	Risk Difference (M‐H, Fixed, 95% CI)	‐0.02 [‐0.08, 0.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.84, 1.10]
1.1 28 days	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	1.4 [0.49, 4.02]
1.2 28 weeks	1	403	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.82, 1.07]
2 Serious	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	2.68 [0.70, 10.20]
2.1 28 days	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.25, 100.80]
2.2 28 weeks	1	403	Risk Ratio (M‐H, Fixed, 95% CI)	2.24 [0.49, 10.23]
3 Liver function test abnormalities	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [0.56, 5.86]
3.1 28 days	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 71.40]
3.2 28 weeks	1	403	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.46, 5.93]
4 Skin reaction	2	479	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.03, 0.05]
4.1 28 days	1	76	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
4.2 28 weeks	1	403	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.04, 0.06]
5 Cardiovascular events (chest pain, coronary artery disease, myocardial infarction, atrial fibrillation)	2		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
5.1 28 days	1	76	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
5.2 28 weeks	1	403	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.01, 0.03]
6 Hypertension	2		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
6.1 28 days	1	76	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
6.2 28 weeks	1	403	Risk Difference (M‐H, Fixed, 95% CI)	‐0.04 [‐0.08, 0.01]
7 Diarrhea	2		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
7.1 28 days	1	76	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.12, 0.12]
7.2 28 weeks	1	403	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.07, 0.04]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.87, 1.17]
1.1 28 weeks	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.87, 1.17]
2 Serious	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	2.5 [0.49, 12.66]
2.1 28 weeks	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	2.5 [0.49, 12.66]
3 Liver function test abnormalities	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 28 weeks	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.51, 7.83]
4 Skin reaction	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 28 weeks	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.30, 2.48]
5 Cardiovascular events (chest pain, coronary artery disease, myocardial infarction, atrial fibrillation)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 28 weeks	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 15.82]
6 Hypertension	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 28 weeks	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.27, 2.10]
7 Diarrhea	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.1 28 weeks	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.80, 3.33]

PERMALINK

Febuxostat for treating chronic gout

Jean H Tayar

Maria Angeles Lopez‐Olivo

Maria E Suarez‐Almazor

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Major outcomes

Minor outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Design

1. Open label trials characteristics.

Sample sizes

Setting

Participants

Intervention

Outcomes

Funding

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Febuxostat 40 mg/day versus placebo.

Summary of findings 2. Febuxostat 80 mg/day versus placebo.

Summary of findings 3. Febuxostat 120 mg/day versus placebo.

Summary of findings 4. Febuxostat 40 mg/day versus allopurinol.

Summary of findings 5. Febuxostat 80 mg/day versus allopurinol.

Summary of findings 6. Febuxostat 120 mg/day versus allopurinol.

Efficacy

Febuxostat versus placebo

1. Febuxostat 40 mg versus placebo

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

2. Febuxostat 80 mg versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TOTAL	3	2556	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.89, 0.99]
1.1 24‐28 weeks	2	2047	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.87, 1.00]
1.2 52 weeks	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.87, 1.02]
2 Serious	3	2556	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.55, 1.42]
2.1 24‐28 weeks	2	2047	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.65, 1.65]
2.2 52 weeks	1	509	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.28, 1.18]
3 Liver function test abnormalities	3	2556	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.76, 1.39]
3.1 24‐28 weeks	2	2047	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.77, 1.47]
3.2 52 weeks	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.34, 1.92]
4 Skin reaction	3	2556	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.56, 1.09]
4.1 24‐28 weeks	2	2047	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.58, 1.14]
4.2 52 weeks	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.20]
5 Cardiovascular events (chest pain, coronary artery disease, myocardial infarction, atrial fibrillation)	3	2556	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.02, 0.01]
5.1 24‐28 weeks	2	2047	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.02, 0.01]
5.2 52 weeks	1	509	Risk Difference (M‐H, Fixed, 95% CI)	0.0 [‐0.01, 0.01]
6 Hypertension	3	2556	Risk Ratio (M‐H, Fixed, 95% CI)	4.35 [1.25, 15.09]
6.1 24‐28 weeks	2	2047	Risk Ratio (M‐H, Fixed, 95% CI)	4.35 [1.25, 15.09]
6.2 52 weeks	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Diarrhea	3	2556	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.64, 1.18]
7.1 24‐28 weeks	2	2047	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.62, 1.18]
7.2 52 weeks	1	509	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.38, 2.59]

Methods	Phase 3, randomised, double‐blind, allopurinol‐controlled trial. 52‐week, multicentre study. No of patients randomised = 762. No of patients analysed = 756 (2 withdrew without receiving study drug, 4 excluded because baseline serum uric acid was < 8.0mg/dL).
Participants	Inclusion criteria: preliminary criteria of the ACR for gout and serum uric acid ≥ 8.0 mg/dL. Adults. Exclusion criteria: serum creatinine > 1.5 mg/dL or estimated creatinine clearance rate < 50 ml/min; pregnancy or lactation; use of uric acid‐lowering agents, azathioprine, 6‐mercaptopurine, thiazide diuretics, or medications containing aspirin (> 325 mg/day) or other salicylates; BMI > 50; history of xanthinuria, active liver disease, or hepatic dysfunction; use of prednisone at > 10 mg/day; change in hormone‐replacement therapy or oral‐contraceptive therapy within the previous 3 months; and history of alcohol abuse or alcohol intake of more than 14 drinks/week. Location: Centers in the USA and Canada.
Interventions	Patient randomised to 3 groups 1. Febuxostat 80 mg/day N = 257(256 received ≥1dose)   2. Febuxostat 120 mg/day N = 251   3. Allopurinol 300 mg/day N = 254 (253 received ≥1dose) Two‐weeks washout period before randomisation for subjects already on uric acid‐lowering therapy. Prophylaxis with naproxen (250 mg BID) or colchicine (0.6 mg daily) given to all subjects during the washout period and the first 8 weeks of the trial. Subsequent gout flares treated at the investigators' discretion. Duration: 52 weeks.
Outcomes	Primary efficacy endpoint: ‐ serum uric acid < 6.0 mg/dL at each of the last three monthly measurements. Secondary efficacy endpoints: ‐ proportion of subjects with serum uric acid < 6.0 mg/dL at each visit ‐ percentage reduction from baseline in the serum uric acid concentration at each visit. ‐ percentage reduction from baseline in tophus area. ‐ change in the number of tophi at each visit. ‐ proportion of subjects requiring treatment for gout flares from weeks 9 through 52. Adverse events.
Notes	Source of funding: TAP Pharmaceutical Products, Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated central randomisation schedule with a block size of three was used to assign each subject to one of the three groups.
Allocation concealment (selection bias)	Low risk	Not described, but considered probable due to central randomisation.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No details provided other than stating that this is a double‐blind trial.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Some study participants were not accounted for in the efficacy analysis: 4 subjects excluded because they had sUA < 8mg/dL at baseline and 3 because they did not receive the study treatment.
Selective reporting (reporting bias)	Unclear risk	The study protocol is not available, but the authors did not report on 5 of the 9 outcomes recommended by OMERACT (OMERACT 9).
Other bias	Low risk	Representatives of TAP Pharmaceutical Products collected the data, and statisticians at TAP conducted all statistical analyses.

Methods	Phase 2, randomised, double‐blind, placebo‐controlled, dose‐response trial. 28‐day multicentre study. No of patients randomised = 153. No of patients analysed for efficacy = 140 ( 13 excluded because baseline serum uric acid was collected outside the day ‐2 window). No of patients analysed for harms and gout flares = 153.
Participants	Inclusion criteria: preliminary criteria of the ACR for gout and serum uric acid ≥ 8.0 mg/dL. Exclusion criteria: serum creatinine > 1.5 mg/dL or estimated creatinine clearance (eCLcr) < 50 ml/min; pregnancy or lactation; use of uric acid‐lowering agents, azathioprine, 6‐mercaptopurine, or medications containing aspirin (> 325 mg/day) or other salicylates; BMI > 50; history of xanthinuria, active liver disease, or hepatic dysfunction; use of prednisone at > 10 mg/day; change in thiazide or steroid therapy (within 1 month of study) or hormone‐replacement therapy or oral‐contraceptive therapy (within 3 months of study); and history of alcohol abuse or alcohol intake of ≥ 14 drinks/week. Location: centres in the USA.
Interventions	Patient randomised to 4 groups: 1. Febuxostat 40 mg/day N = 37 2. Febuxostat 80 mg/day N = 40 3. Febuxostat 120 mg/day N = 38 4.Placebo N = 38 Two‐weeks washout period before randomisation for subjects already on uric acid‐lowering therapy. Prophylaxis with colchicine (0.6 mg BID) given to all subjects during the washout period and the first 2 weeks of the trial. Subsequent gout flares treated at the investigators' discretion.
Outcomes	The primary efficacy endpoint: ‐ serum uric acid < 6.0 mg/dL at day 28. Secondary efficacy endpoints: ‐ proportion of subjects with serum uric acid < 6.0 mg/dL at each visit. ‐ percentage reduction from baseline in the serum uric acid concentration at day 28. ‐ incidence of gout flares. Adverse events.
Notes	Source of funding: TAP Pharmaceutical Products, Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Reported as a double‐blind trial, but methods of masking were not described (only 2 weeks of double blind treatment).
Incomplete outcome data (attrition bias)   All outcomes	High risk	Efficacy analyses were based on a modified intention‐to‐treat population (only those that received treatment). There is no description on how incomplete outcome data was analysed
Selective reporting (reporting bias)	Unclear risk	The study protocol is not available, but the authors did not report on 6 of the 9 outcomes recommended by OMERACT(OMERACT 9).
Other bias	Low risk	Drs Becker, Schumacher, and Wortmann have received consulting fees from TAP Pharmaceutical Products, but role of the sponsor was not stated. 4 of the 7 authors are from TAP Pharmaceutical Products.

Methods	Open label extension study (3 years findings). No of patients randomised =1280 subjects who previously completed one of the 2 Phase III double‐blind trials (Becker 2005a; Schumacher 2008). No. of patients completing the study = 1086. No. of patients analysed for harms and gout flares = 664
Participants	Inclusion criteria: preliminary criteria of the ACR for gout. Exclusion criteria: pregnancy or lactation; serious drug‐related AE in the prior study; other significant medical conditions that would interfere with treatment harms or compliance; or known intolerance to allopurinol.. Location: 174 centres in the USA and Canada.
Interventions	3 groups: 1. Febuxostat 80 mg/day N = 606 2. Febuxostat 120 mg/day N = 388 3.Allopurinol N = 92 During the first six months of treatment, subjects could switch their febuxostat doses if necessary. Subsequent gout flares treated at the investigators' discretion.
Outcomes	The primary efficacy endpoint: ‐ serum uric acid < 6.0 mg/dL at each visit. Secondary efficacy endpoints: ‐ proportion of subjects with serum uric acid < 6.0 mg/dL at each visit. ‐ percentage reduction from baseline in the serum uric acid concentration at each visit. ‐ incidence of gout flares. ‐ reduction in number of tophi ‐ reduction in the size or disappearance of the index tophus Adverse events.
Notes	Source of funding: TAP Pharmaceutical Products, Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Open label extension from FACT and APEX studies
Allocation concealment (selection bias)	Low risk	Open label extension from FACT and APEX studies
Blinding (performance bias and detection bias)   All outcomes	High risk	Open label extension study
Incomplete outcome data (attrition bias)   All outcomes	High risk	Efficacy analyses were based on a modified intention‐to‐treat population (only those that received treatment). There is no description on how incomplete outcome data was analysed
Selective reporting (reporting bias)	Unclear risk	The study protocol is not available, but the authors did not report on 5 of the 9 outcomes recommended by OMERACT(OMERACT 9).
Other bias	Unclear risk	Source of funding: TAP Pharmaceutical Products, Inc.

Methods	Randomized, double‐blind, allopurinol‐controlled. 6‐month multicentre study. Stratification by renal function ( normal, mildly impaired = eCLcr 60 to 89 ml/min, or moderately impaired = eCLcr 30 to 59 ml/min) and prior completion of either of two open‐label febuxostat or febuxostat/allopurinol extension trials. No of patients randomised = 2269. No of patients analysed (modified intent‐to‐treat cohort) = 2268 ( one subject randomised to allopurinol was excluded from the efficacy analyses because baseline sUA was < 8.0 mg/dL).
Participants	Inclusion criteria: preliminary criteria of the ACR for gout, serum uric acid of ≥ 8.0 mg/dL, age 18‐85. Subjects successfully completing either of two prior open label extension studies were eligible (subjects from FACT, FOCUS, APEX were eligible for one of these two open label studies) . Exclusion criteria: secondary hyperuricaemia; xanthinuria; severe renal dysfunction (eCLcr < 30 ml/min);hepatic dysfunction (ALT and AST > 1.5 times upper limit of normal);consumption of more than 14 alcoholic drinks per week or a history of alcoholism or drug abuse within five years;or a medical condition that, in the investigator's opinion, would interfere with treatment, harms, or adherence to the protocol. Location: centres in the USA.
Interventions	Patient randomised to 3 groups: 1. Febuxostat 40 mg/day N = 757 2. Febuxosatat 80 mg/day N = 756 3. Allopurinol 200/300 mg (for moderately impaired/ normal to mildly impaired renal function respectively) N = 755 (145/610) [modified intent‐to‐treat cohort]. 30‐day washout period before randomisation for subjects already on uric acid‐lowering therapy. Prophylaxis with naproxen (250 mg BID) or colchicine (0.6 mg daily) given to all subjects during the washout period and the study period (6 months). All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily. Subjects with eCLcr < 50 ml/min were not to receive naproxen. Gout flares were regarded as expected gout manifestations rather than as AEs. Serum uric acid was blinded after baseline determination at Day‐4.
Outcomes	The primary efficacy endpoint: ‐ serum uric acid < 6.0 mg/dL at the final visit. Treatment with febuxostat 40 mg was compared with allopurinol with regard to non‐inferiority in uric acid lowering. If non‐inferiority of febuxostat 40 mg was established, superiority to allopurinol was to be assessed. Treatment with febuxostat 80 mg was compared with the allopurinol and febuxostat 40 mg for superiority. "In subgroup analyses, the primary endpoint was stratified by baseline serum uric acid, renal functional status, presence of tophi at baseline, and prior participation in a ULT trial" Secondary efficacy endpoints: ‐ patients with renal impairment and serum uric acid < 6.0 mg/dL at the final visit. ‐ patients with serum uric acid < 6.0mg/dL, < 5.0mg/dL, < 4.0mg/dL at each visit. Pairwise comparisons were made between treatment groups. Adverse events.
Notes	Source of funding: TAP Pharmaceutical Products, Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Authors stated that "An Interactive Voice Response System was utilized by site personnel during screening visits to initiate double blind randomisation. Subjects were randomised 1:1:1 on Day 1 to receive daily febuxostat 40 mg, febuxostat 80 mg, or allopurinol".
Allocation concealment (selection bias)	Low risk	No details provided, but considered probable due to randomisation type.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No details provided other than stating that this is a double‐blind trial
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Only one subject out of 2268 was not included in the efficacy analysis because his serum uric acid was < 8 mg/dL; the rest included in a modified ITT analysis.
Selective reporting (reporting bias)	Unclear risk	The study protocol is not available, but the authors did not report on 5 of the 9 outcomes recommended by OMERACT (OMERACT 9).
Other bias	Low risk	Source of funding: TAP Pharmaceutical Products, Inc.

Methods	Open label extension study (5 years findings). No. of patients randomised =145 subjects who previously completed one of the 1 Phase II double‐blind trial (Becker 2005b). No. of patients completing the study.=.116. No. of patients analysed for harms and gout flares.= 116
Participants	Inclusion criteria: enrolment and completion of the 28‐day Phase II study. Exclusion criteria: pregnancy or lactation;use of uric acid‐lowering agents, azathioprine, 6‐mercaptopurine, or medications containing aspirin (> 325 mg/day) or other salicylates; BMI > 50; history of xanthinuria, active liver disease, or hepatic dysfunction; use of prednisone at > 10 mg/day; change in thiazide or steroid therapy (within 1 month of study) or hormone‐replacement therapy or oral‐contraceptive therapy (within 3 months of study); and history of alcohol abuse or alcohol intake of ≥ 14 drinks/week. Location: centres in the USA.
Interventions	3 groups: 1. Febuxostat 40 mg/day N = 8 2. Febuxostat 80 mg/day N = 79 3. Febuxostat 120 mg/day N = 29 Subsequent gout flares treated at the investigators' discretion.
Outcomes	The primary efficacy endpoint: ‐ proportion of subjects with serum uric acid < 6.0 mg/dL at each visit. Secondary efficacy endpoints: ‐ percentage reduction from baseline in the serum uric acid concentration at each visit. ‐ incidence of gout flares. ‐ disappearance of the index tophus Adverse events.
Notes	Source of funding: TAP Pharmaceutical Products, Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Open label extension from FOCUS study
Allocation concealment (selection bias)	Unclear risk	Open label extension from FOCUS study
Blinding (performance bias and detection bias)   All outcomes	High risk	Open label extension study
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Efficacy analyses were based on a modified intent‐to‐treat population (only those that received treatment). There is no description on how incomplete outcome data was analysed
Selective reporting (reporting bias)	Unclear risk	The study protocol is not available, but the authors did not report on 5 of the 9 outcomes recommended by OMERACT(OMERACT 9).
Other bias	Low risk	Source of funding: TAP Pharmaceutical Products, Inc.

Study	Reason for exclusion
Becker 2008	Meta‐analysis of individual data
Komoriya 2004	Pharmacokinetics (Phase 2)

Trial name or title	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
Methods	Phase 2, randomised, double‐blind, parallel assignment efficacy trial. 24 months multicentre study Estimated enrolment 240
Participants	Inclusion criteria: ≥18 years old; preliminary ACR criteria for gout and have experienced only one gout flare; hyperuricaemia. Exclusion criterias: secondary hyperuricaemia; Previously on uric acid‐lowering therapy; xanthinuria; known hypersensitivity to any component of the febuxostat formulation; rheumatoid arthritis; cancer, except basal cell carcinoma of the skin, not in remission for at least 5 years prior to the first dose of study medication; MI or stroke within 90 days prior to the Screening visit; ALT and/or AST > 2.0 times the upper limit of normal;significant medical condition and/or conditions; eCLcr ≥ 60 mL/min; serum creatinine at Screening > 2.0 mg/dL; known history of hepatitis B, hepatitis C or HIV; hypersensitivity to gadolinium; severe asthma; electronically, magnetically or mechanically activated implanted device; object as potential hazard or interfere with MRI interpretation
Interventions	Patients will be randomised to 2 groups: 1. Febuxostat 40 mg/day or 80 mg/day (based on serum uric acid levels) 2. Placebo
Outcomes	Primary Outcome Measures: ‐ Mean Change from Baseline to Month 24 in a modified Sharp/van der Heijde Erosion Score of the single affected joint Secondary Outcome Measures: ‐ Mean Change from Baseline to Month 24 in the modified Sharp/van der Heijde Total Scores from full hand and foot radiographs.   ‐ Mean Change from Baseline to Month 24 in the modified Sharp/van der Heijde Erosion Scores from full hand and foot radiographs.   ‐ Mean change from baseline to Month 24 in the Rheumatoid Arthritis MRI Scoring System (RAMRIS) score.   ‐ Mean change from baseline to Month 24 in a modified Sharp/van der Heijde Total Score of the single affected joint.
Starting date	March 2010
Contact information	Takeda Study Registration Call Center 800‐778‐2860 medicalinformation@tpna.com
Notes

Trial name or title	A Multicenter, Randomized, Active‐Control, Phase 3B Study to Evaluate the Cardiovascular harms of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
Methods	Phase 3, randomised, double‐blind, parallel assignment harms trial. 60 months multicentre study. Estimated Enrollment 240.
Participants	Inclusion criteria: ≥ 50 years old; a major cardiovascular or cerebrovascular disease (MI, unstable angina, cardiac or cerebrovascular revascularization procedure, stroke, hospitalised for transient Ischaemic attack, peripheral vascular disease, diabetes mellitus with evidence of micro‐ or macrovascular disease); ACR criteria for gout; serum uric acid level ≥ 7.0 mg/dL at the Day ‐7 Visit OR ≥ 6.0 mg/dL at the Day ‐7 Visit AND inadequately controlled gout Exclusion criteria: secondary hyperuricaemia; on uric acid‐lowering therapy; xanthinuria; known hypersensitivity to any component of the febuxostat or allopurinol formulation; active peptic ulcer disease; cancer within 5 years prior to the first dose of study medication; MI or stroke within 60 days prior to the Screening visit; ALT and/or AST > 2.0 times the upper limit of normal; eCLcr < 30 mL/min; known history of hepatitis B, hepatitis C or HIV; history of drug abuse or a history of alcohol abuse within 5 years prior to the Screening; more than14 alcoholic beverages per week; received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study; required to take excluded medications
Interventions	Patients will be randomised to 2 groups: 1. Febuxostat 40 mg/day or 80 mg/day (dependent on serum uric acid levels) 2. Allopurinol 200 mg/day to 600 mg/day (dependent on renal function)
Outcomes	Primary Outcome Measures: ‐ First occurrence of any event in the predefined Major Adverse Cardiovascular Events Composite (Cardiovascular death, Non‐fatal Myocardial Infarction, Nonfatal Stroke and Unstable Angina with Urgent Coronary Revascularization) Secondary Outcome Measures: ‐ First occurrence of any Antiplatelet Trialists' Collaborative Event (Cardiovascular Death, Non‐fatal Myocardial Infarction or Non‐fatal Stroke)   ‐ First occurrence of Cardiovascular Death death   ‐ First occurrence of Non‐fatal Myocardial Infarction   ‐ First occurrence of Non‐fatal stroke   ‐ First occurrence of Unstable Angina with Urgent Coronary Revascularization
Starting date	May 2010
Contact information	Takeda Study Registration Call Center 800‐778‐2860 medicalinformation@tpna.com
Notes