Background/Purpose:
No
clinical trials had previously investigated the characteristics of joint damage
in early gout or the benefit of instituting urate-lowering therapy (ULT)
earlier in the course of the disease. The objectives of this study were to
evaluate 1) the effect of febuxostat vs. placebo on joint damage after 2 years
of treatment in subjects with early gout and 2) the safety of febuxostat.

Methods:
Subjects
with serum urate [sUA] ≥7.0 mg/dL received either febuxostat 40/80 mg or
placebo for up to 2 years. Febuxostat was up titrated from
40 to 80 mg at the Month 1 visit if sUA ≥6.0 mg/dL at the Day 14 visit. Early
gout was defined as having experienced ≤2 gout flares total, and only 1
flare during the previous 12 months. Joint damage was evaluated utilizing x-ray
and magnetic resonance imaging (MRI). X-rays were assessed using a modified
Sharp-van der Heijde (mSvdH) method validated in gout patients.
MRI images were assessed using the rheumatoid arthritis MRI scoring (RAMRIS)
system. For both X-ray and MRI assessments, the joint with the first gout flare
was identified as the primary affected joint. Contrast-enhanced MRI images were
used for scoring of synovitis. Safety assessments included adverse events (AEs),
serious AEs and clinical laboratory measures.

Results:
At baseline, mSvdH erosion score >0 in the primary affected joint was
present in 9% of the placebo group and 14% of the febuxostat group.  After 2
years of treatment, the placebo and   febuxostat groups showed no differences
in the changes from baseline in mSvdH erosion scores   from the primary
affected joint or from full hand and foot radiographs. At baseline, RAMRIS
synovitis score >0 in the primary affected joint was present in 89% of the
placebo group and 94% of the febuxostat group. There was a significant
reduction in the RAMRIS synovitis score for the primary affected joint in the
febuxostat group compared to the placebo group after 1 (p=0.025) and 2
(p<0.001) years of treatment. The RAMRIS erosion and bone edema scores
showed no differences for the primary affected joint comparing febuxostat and
placebo groups. The percentage of subjects with sUA levels <6.0 mg/dL was
62.8% and 5.7% after 2 years of treatment with febuxostat and placebo,
respectively. 

The most frequent treatment emergent adverse events
(TEAE) and adjudicated major adverse cardiovascular events (MACE) are
summarized in Table 1.

Conclusion:
This
first clinical trial in early gout subjects demonstrated that treatment with
febuxostat can achieve a significant reduction in synovitis compared to placebo.
No measurable change in the affected joint erosion score was observed with and
without ULT during the observation period. Febuxostat was generally well
tolerated in this population of early gout subjects.

Table 1. Treatment Emergent Adverse Events (TEAE)
and Major Adverse Cardiovascular Events (MACE)

^aReported with Medical Dictionary
for Regulatory Activities high level term.