Background/Purpose: Allopurinol is the most widely used urate lowering therapy. Many patients on allopurinol fail to achieve target serum urate (SU), in part due to concerns about the relationship between allopurinol dose and adverse events (AEs). The aim of this randomised controlled trial was to determine the efficacy and safety of allopurinol dose escalation using a treat to target SU approach.

Methods: An open randomised controlled trial comparing creatinine clearance (CrCL)-based allopurinol dose and allopurinol dose escalation was undertaken. Patients with gout, defined by 1977 ARA criteria, receiving at least CrCL-based allopurinol dose for ≥1 month and SU ≥6mg/dL were recruited. Severe chronic kidney disease was not an exclusion. Patients were randomised to continue current dose (control) or dose escalation (DE) for 12 months. In the DE group, allopurinol was increased monthly by 50mg-100mg/d until SU was <6mg/dL. The primary endpoint was reduction in SU and AEs coded according to Common Terminology Criteria for Adverse Events.

Results: One hundred and eighty-three participants (93 control and 90 DE) were recruited. At baseline, mean CrCL was 60 (SD 27) ml/min, urate was 7.2 (SD 1.6) mg/dL and allopurinol dose 269mg/d (range 100-600mg/d). In intention to treat analysis, mean ± SEM SU was 6.7 ± 0.2mg/dL in control participants compared to 5.7 ± 0.2mg/dL DE (p<0.001) at 12 months (Figure). SU <6mg/dL at month 12 was achieved in 32% control participants and 69% DE participants (p<0.001). During the 12-month period, 58.9% of the control group and 54.3% of the DE group experienced a gout flare (p=0.58). There were 43 serious adverse events in 25 controls and 35 events in 22 DE participants. Only one was considered probably related to allopurinol (increased INR in a DE patient on warfarin). Five control participants and 5 DE participants died; no deaths were considered allopurinol related. There were no cases of allopurinol hypersensitivity syndrome.  Eleven control participants developed rash; one was thought to be probably allopurinol related leading to allopurinol discontinuation. Eight DE participants’ developed rash; 2 were considered possibly related but settled despite continuing allopurinol and 1 was probably related and allopurinol was discontinued. Mild elevations in liver function tests were common in both groups and a few moderate increases in GGT were noted. One DE patient stopped allopurinol due to abnormal LFTs.  There was no significant difference in renal function changes between randomised groups.

Conclusion: Higher than CrCL-based doses of allopurinol can effectively lower SU in the majority of patients. Allopurinol dose escalation is well tolerated.