Background/Purpose: Allopurinol at higher than CrCL based doses remains controversial due to concerns over increased risk of adverse events (AE). A recent 12month randomized controlled trial (RCT) reported that allopurinol above CrCL-based doses is effective and well tolerated. Here, we report the results of the 12month open label extension phase of this RCT. The aims were to determine the long-term safety and efficacy of allopurinol dose escalation to achieve target serum urate (SU) in people with gout.

Methods: People who completed the first 12months of a randomized, controlled, parallel-group, comparative clinical trial continued into a 12month open label extension study (from Month 12 to 24). Participants randomised to the control group who continued their usual dose of allopurinol for the first 12months began allopurinol dose escalation at month 12 if SU was ≥6mg/dl (control (C)/dose escalation (DE)). Those in the DE arm for the first 12months who had achieved target SU maintained the dose of allopurinol, while those with SU≥6mg/dl continued dose escalation (DE/DE). Allopurinol was increased monthly until SU was <6mg/dl. The primary endpoints were reduction in SU and AEs at month 24. Secondary endpoints included the proportion of individuals with gout flares.

Results:  Of the 183 participants who entered the study, 143 (78.1%) completed the month 12 visit and 137 (74.9%) completed month 24. The mean (SE) change in SU from month 12 to month 24 was -1.1 (0.2) mg/dl in the C/DE group and 0.1 (0.2) mg/dl in the DE/DE group (p<0.001) with a mean difference of 1.3mg/dl (95%CI 0.8-1.7), p<0.001). In the C/DE group mean (SE) SU was 7.13 (0.16) mg/dl at baseline and 5.7 (0.2) mg/dl at final visit, and 7.18 (0.2) mg/dl and 5.4 (0.1) mg/dl in the DE/DE group (Fig). SU was <6mg/dl at final visit in 69.1% of the C/DE group and 79.7% in the DE/DE group (p=0.16); odds ratio (OR) 1.8 (95%CI 0.8-3.8). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to month 12 and month 24 in both groups (p<0.001), but no difference between randomised groups (p=0.29). There were similar numbers of AEs and serious AEs between groups. Mild elevations of AST, ALT and ALP were noted while some higher grade abnormalities in GGT were observed.

Conclusion: The majority of people with gout can achieve and maintain target SU with dose escalation of allopurinol above CrCL-based doses. Higher doses of allopurinol are well tolerated.