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Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.

ABSTRACT: INTRODUCTION:Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST). METHODS AND ANALYSIS:FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60?years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357?µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3?years. The primary endpoint is first occurrence of the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3. ETHICS AND DISSEMINATION:FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal. TRIAL REGISTRATION NUMBER:FAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728).

SUBMITTER: MacDonald TM

PROVIDER: S-EPMC4120410 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.

MacDonald Thomas M TM Ford Ian I Nuki George G Mackenzie Isla S IS De Caterina Raffaele R Findlay Evelyn E Hallas Jesper J Hawkey Christopher J CJ Ralston Stuart S Walters Matthew M Webster John J McMurray John J Perez Ruiz Fernando F Jennings Claudine G CG

BMJ open 20140710 7

<h4>Introduction</h4>Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat ...[more]

PMID: 25011991

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Project description:BackgroundThe relative efficacy and safety of allopurinol and febuxostat when used according to current guidelines for the treatment of hyperuricemia are unknown. This double-blind noninferiority trial examined these issues.MethodsParticipants with gout and hyperuricemia (with at least 33% having stage 3 chronic kidney disease) were randomly assigned to allopurinol or febuxostat in this 72-week trial, with doses titrated to target serum urate. The trial had three phases: titration (weeks 0 to 24), maintenance (weeks 25 to 48), and observation (weeks 49 to 72). Allopurinol and febuxostat were initiated at daily doses of 100 and 40 mg, with maximum titration to 800 and 120 mg, respectively. Antiinflammatory prophylaxis was given during phases 1 and 2. The primary end point was the proportion of patients experiencing one or more flares during phase 3, with a prespecified noninferiority margin of less than 8 percentage points between allopurinol and febuxostat. Secondary end points included efficacy in patients with chronic kidney disease, proportion achieving target serum urate levels, and serious adverse events.ResultsThis study included 940 participants; 20.1% withdrew, with similar proportions in treatment arms. During phase 3, 36.5% of allopurinol-treated participants had one flare or more compared with 43.5% of febuxostat-treated participants (P<0.001 for noninferiority). Overall, 80% of participants achieved mean target urates during phase 2 with no differences by treatment. There were no treatment differences (including cardiovascular events) in serious adverse events.ConclusionsAllopurinol and febuxostat achieved serum urate goals in patients with gout; allopurinol was noninferior to febuxostat in controlling flares. Similar outcomes were noted in participants with stage 3 chronic kidney disease. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; ClinicalTrials.gov identifier, NCT02579096.).

Project description:ObjectivesBecause of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including endpoints rigorously evaluated by a blinded adjudication committee. The objective of this study was to assess if celecoxib is associated with a lower incidence of clinically significant upper and/or lower GI events than nonselective NSAIDs (nsNSAIDs) in standard clinical practice.MethodsThis was a PROBE study carried out at 783 centers in the United States, where a total of 8,067 individuals aged ≥ 55 years, requiring daily NSAIDs to treat osteoarthritis, participated. The participants were randomized to celecoxib or nsNSAIDs (1:1) for 6 months and stratified by Helicobacter pylori status. Treatment doses could be adjusted as per the United States prescribing information; patients randomized to nsNSAIDs could switch between nsNSAIDs; crossover between treatment arms was not allowed, and patients requiring aspirin at baseline were excluded. The primary outcome was the incidence of clinically significant upper and/or lower GI events.ResultsSignificantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval, 1.31-2.55); P = 0.0003). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035). Other non-GI adverse events were similar between treatment groups. One limitation is the open-label design, which presents the possibility of interpretive bias.ConclusionsCelecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs. Furthermore, this trial represents a successful execution of a PROBE study, where therapeutic options and management strategies available in clinical practice were incorporated into the rigor of a prospective RCT.

Project description:BackgroundOpioid-induced constipation is the most prevalent patient complaint associated with longer-term opioid use and interferes with analgesic efficacy, functionality, quality of life, and patient compliance.ObjectivesWe aimed to compare the effects of prolonged-release (PR) oxycodone plus PR naloxone (OXN) vs PR oxycodone (OXY) vs PR morphine (MOR) on bowel function under real-life conditions in chronic low-back pain patients refractory to World Health Organization (WHO) step I and/or II analgesics.Research design and methodsThis was a post hoc analysis of the complete data set from a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study (German pain study registry: 2012-0012-05; European Union Drug Regulating Authorities Clinical Trials [EudraCT]: 2012-001317-16), carried out in 88 centers in Germany, where a total of 901 patients requiring WHO step III opioids to treat low-back pain were enrolled and prospectively observed for 3 months. Opioid allocation was based on either optional randomization (n=453) or physician decision (n=448). In both groups, treatment doses could be adjusted as per the German prescribing information, and physicians were free to address all side effects and tolerability issues as usual. The primary endpoint was the proportion of patients maintaining normal bowel function throughout the complete treatment period, assessed with the Bowel Function Index (BFI). Secondary analyses addressed absolute and relative BFI changes, complete spontaneous bowel movements, use of laxatives, treatment emergent adverse events, analgesic effects, and differences between randomized vs nonrandomized patient groups.ResultsBFI changed significantly with all three WHO step III treatments, however significantly less with OXN vs OXY and MOR despite a significantly higher use of laxatives with the latter ones (P<0.001). The percentage of patients who maintained normal BFI scores despite opioid treatment was 54.5% (164/301) with OXN and was significantly superior to those seen with OXY (32.8% [98/300]) (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.77-3.44; P<0.001) or MOR (29.7% [89/300]) (OR: 2.84, 95% CI: 2.03-3.97; P<0.001). Absolute BFI changes of ≥12mm 100 mm horizontal visual analog scale (VAS100) vs. baseline were seen for OXN in 41.4%, for OXY in 68.7%, and for MOR in 72.3%. Complete spontaneous bowel movements decreased at least by one per week in 10.3% with OXN vs 42.3% for OXY (OR: 6.39, 95% CI 4.13-9.89; P<0.001) and 42.0% for MOR (OR: 6.31, 95% CI: 4.08-9.76; P<0.001). Overall, 359 treatment emergent adverse events (78 [OXN], 134 [OXY], and 147 [MOR]) in 204 patients (41 [OXN], 80 [OXY], and 83 [MOR]) occurred, most affecting the gastrointestinal (49.3%) and the nervous system (39.3%). Treatment contrasts between randomized vs nonrandomized patients were insignificant.ConclusionIn this post hoc analysis of data from a real-life 12-week study, OXN treatment was associated with a significantly lower risk of opioid-induced constipation, superior tolerability, and significantly better analgesic efficacy compared with OXY and MOR.

Dataset Information

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.

Publications

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.

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