CONFIRMS

Incomplete

Becker MA, et al. "The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial". Arthritis Research & Therapy. 2010. 12(2):1-12.
PubMed • Full text • PDF

Clinical Question

Among patients with gout and serum urate (sUA) >8.0mg/dL, how does febuxostat fare against allopurinol in lowering sUA to a concentration <6.0mg/dL?

Bottom Line

Febuxostat 80mg is most efficacious at lowering sUA compared to febuxostat 40mg and allopurinol 200mg/300mg.

Guidelines

ACR Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia (2012, adapted) [1]

• Febuxostat or allopurinol are first line urate-lowering therapy (ULT) agents.
• Treat to target approach should be adopted: a concentration <6.0mg/dL for all cases of gout, with a stringent target of <5.0mg/dL for patients with tophaceous gout.

Design

• Multicenter, phase 3 double-blind randomised controlled trial
• N = 2269
  • Febuxostat 40mg (n = 757) and febuxostat 80mg (n = 756)
  • Allopurinol (n = 755)
• Setting: 324 sites in United States
• Enrollment:
• Mean follow-up: 6 months
• Analysis: modified intention-to-treat (Excluded 1 subject who had baseline sUA <8.0mg/dL)
• Primary outcome: Proportion of patients in each treatment group with sUA <6.0mg/dL at final visit

Population

Inclusion Criteria

• Age 18 to 85 years
• Gout diagnosis fulfils ACR preliminary criteria [2] and sUA >8.0mg/dL

Exclusion Criteria

• Secondary hyperuricemia
• Xanthinuria
• Severe renal impairment (CrCl <30ml/min)
• ALT and AST values >1.5x ULN
• Consumption of >14 alcoholic drinks per week or a history of alcoholism or drug abuse within five years
• Any medical condition that would interfere with treatment, safety or adherence to the protocol

Baseline Characteristics

From febuxostat 80mg group (N=756)

• Male gender: 710 (93.9%)
• Caucasians: 618 (81.7%)
• Age (mean ± SD): 53.0±11.79
• BMI (mean ± SD): 32.9±6.39
• sUA (mg/dL) (mean ± SD): 9.6±1.20
• Years with gout (mean ± SD): 11.7±9.64
• Completed previous febuxostat study[3] [4]: 88 (11.6%)
• Renal function:
  • Normal: 253 (33.5%)
  • Mildly impaired: 367 (48.5%)
  • Moderately impaired: 136 (18.0%)
• Medical history:
  • CV diseases: 440 (58.2%)
  • Diabetes Mellitus: 113 (14.9%)
  • Hypercholesterolemia: 52 (7.0%)
  • Hyperlipidemia: 308 (40.7%)
  • Aspirin use (≤325mg/day): 133 (17.6%)

No significant differences across treatment groups in demographic, gout-related or co-morbid characteristics

Interventions

• Patients were randomised 1:1:1 on Day 1 to receive febuxostat 40mg, febuxostat 80mg or allopurinol 200mg (30-59ml/min)/ 300mg (≥60ml/min)
  • Randomisation stratified by baseline renal function and prior completion of either of two trials [5] [6]
• Subsequent visits occur bimonthly during the six-month treatment period
• Choice of gout prophylaxis regimen were made by physician and patient: colchicine 0.6mg QD or naproxen 250mg BID with lansoprazole 15mg QD\
  • No patients with CrCl <50ml/min received naproxen

Outcomes

Febuxostat 40mg vs. febuxostat 80mg vs. allopurinol 200mg/300mg

Primary Outcome

Patients achieving sUA <5.0mg/dL at the end of six-month treatment period: 45.2% vs. 67.1% vs. 42.1% (p<0.001)

• Febuxostat 40mg non-inferior to allopurinol (3.1%) but difference is not significant

Secondary Outcomes

Renally impaired patients attaining sUA<6.0mg/dL at the end of six-month treatment period

• 49.7% vs. 71.6% vs. 42.3% (p<0.001 for febuxostat 80mg, p<0.021 for febuxostat 40mg)

At any sUA endpoints (<6.0mg/dL, <5.0mg/dL, <4.0mg/dL)

• More patients on febuxostat 80mg achieved target endpoint (p<0.001) at any scheduled visit

sUA <6.0mg/dL endpoint

• More patients in febuxostat 40mg group than allopurinol group achieved endpoint at Month 2 (p=0.031)

sUA <5.0mg/dL endpoint

• More patients in febuxostat 40mg group than allopurinol group achieved endpoint at Months 2 and 6 (p≤0.05)

sUA <4.0mg/dL endpoint

• No difference between febuxostat 40mg group and allopurinol group

Subgroup Analysis

Primary endpoint was stratified by baseline sUA, renal functional status, presence of tophi at baseline and prior participation in earlier two trials [7] [8]

Higher sUA at baseline and presence of tophi were associated with lower rates of attaining sUA <6.0mg/dL at Month 6 (p<0.001)

Mild renal impairment resulted in higher rates of attaining sUA <6.0mg/dL at Month 6 (p<0.001)

Prior participation in either of 2 febuxostat trials resulted in higher rates of attaining sUA <6.0mg/dL (p≤0.05). These patients also had lower rates of flares requiring treatment compared to patients in the corresponding group without prior participation (p≤0.001)

Adverse Events

Majority of AEs reported were mild or moderate in severity

Rates of AEs reported by patients with renal impairment were similar to those reported by the overall study population: 56% vs. 54% vs. 58%

• Most frequently reported AEs by patients with renal impairment were same as those reported for all patients
• Rates of abnormal LFTs were lower amongst patients with mild (6-7%) or moderate (3-6%) renal impairment compared to patients with normal renal impairment (9-10%) in all groups (p=NS)
• Among patients with moderate renal impairment, rates of diarrhea were higher in those receiving febuxostat (8-10%) compared with patients receiving allopurinol (7%) (p value not stated)

5 patients died during the study; none of the deaths were attributed to a study drug

AEs leading to drug discontinuation

• Most common AE: abnormal LFT (2% vs. 1% vs. 1%)

Organ-specific AEs

• Rash (5.8% vs. 5.6% vs.7.3%)
  • Dermatitis and eczema (2% vs. 2% vs. 3%)
  • Rashes, eruptions and exanthems (2% vs. 2% vs. 1%)
  • 18 patients withdrew prematurely due to a rash AE

• Liver function (8.3% vs. 6.9% vs. 6.6%)

• Cardiovascular
  • 3 patients each in febuxostat 80mg and allopurinol groups had a CV event. All patients had prior medical history of, or underlying risk factors for CV disease
    • Febuxostat 80mg group: non-fatal MI (n=1), non-fatal stroke (n=2)
    • Allopurinol group: CV death (n=2), non-fatal MI(n=1)

• Others
  • Numerically higher incidence of other events in febuxostat group compared to allopurinol group (10 vs. 9. vs. 7)

Criticisms

• Primary endpoint of sUA <6.0mg/dL does not address clinical endpoint of reduction in number of acute flares
• Allopurinol dose was kept at 200mg or 300mg despite FDA recommended maximum dose of 800mg daily. Hence, it is unknown if a higher allopurinol dose may increase proportion of patients attaining primary endpoint

Funding

• Trial was sponsored by a Takeda subsidiary company
• Manuscript was reviewed and prepared by Takeda