This is the largest randomised, double-blind, active-controlled, multicentre trial reported in English in the medical literature to date assessing prophylaxis against acute gouty arthritis flares during the initiation of ULT. We herein report that a single dose of canakinumab, 50–300 mg, or 4-weekly doses given over 4 months (two doses of 50 mg and two of 25 mg) produced a 62% to 72% reduction in the mean number of flares per patient and a 64% to 72% reduction in the risk of experiencing ≥1 flare at 16 weeks compared with colchicine. In addition, the percentage of patients experiencing at least one flare at 16 weeks was significantly lower for all canakinumab doses compared with colchicine. Target SU levels (<6 mg/dl) were achieved in 39% to 54% of patients treated with canakinumab and 46% of patients treated with colchicine at 16 weeks, consistent with results of other recent studies of allopurinol treatment in patients who were hyperuricaemic.17 21 22
All canakinumab doses were well tolerated. These results suggest that canakinumab can provide effective prophylaxis against gouty arthritis flares and is well tolerated in patients initiating ULT.
The results of this study validate the concept that IL-1β is a key mediator in the generation of acute gouty arthritis flares and hence an appropriate therapeutic target for treatment of acute gouty arthritis and prevention of flares. This has previously been demonstrated in a phase II, dose-ranging study of canakinumab as treatment for acute flares in patients with difficult-to-treat gouty arthritis.28
In this earlier study the highest dose of canakinumab tested, 150 mg, demonstrated consistently superior efficacy to triamcinolone acetonide 40 mg across all efficacy measures assessed including pain reduction at 72 h post dose, time to a 50% reduction in pain and the risk of recurrent flares. Therefore, the canakinumab 150 mg dose has been chosen for further assessment as treatment of acute gouty arthritis in phase III trials. Rilonacept, another inhibitor of IL-1β signalling in development, has demonstrated efficacy with weekly doses of 160 mg in the prevention of flares in patients initiating ULT compared with placebo,30
but has apparently failed to demonstrate efficacy in the treatment of acute gouty arthritis.31
The study reported here aimed to determine the dose of canakinumab for further study as prophylaxis for patients initiating ULT. However, no dose-response was evident with respect to the primary endpoint and the estimated dose with equivalent efficacy to colchicine was below the range of canakinumab doses tested. Results of secondary outcomes indicated that single canakinumab doses of 50–300 mg or 4-weekly doses given over 4 months have similar efficacy across all clinical endpoints assessed and are superior to colchicine 0.5 mg. The results of this study suggest that canakinumab may provide effective prophylaxis against flares in patients initiating ULT when given at doses lower than those used to treat acute gouty arthritis flares.
Accumulating data thus suggest that canakinumab is an effective new treatment option for patients with gouty arthritis and may be particularly valuable for patients with difficult-to-treat disease. Such patients frequently have comorbidities and may be unable to receive standard anti-inflammatory therapies.5
Results of a recent phase II study in patients with contraindications to non-steroidal anti-inflammatory drugs and/or colchicine have shown that canakinumab 150 mg provided effective pain relief and reduced the risk of new flares.28
This suggests that canakinumab is an effective treatment for acute gouty arthritis in patients with limited treatment options due to comorbidities. Ongoing phase III studies in this setting should help confirm the value of canakinumab for the treatment of this growing patient population who for whom improved treatment options are urgently required.
Canakinumab was generally well tolerated. Few patients experienced SAEs, severe AEs, or injection-site reactions. No organ toxicity and no dose-response for any AE were observed, and only one SAE was reported that was considered possibly related to canakinumab treatment. The safety profile of canakinumab reported here is consistent with that previously reported for treatment of acute gouty arthritis,28
and for patients with CAPS receiving canakinumab 150 mg at 8-week intervals for up to 48 weeks.32
Colchicine doses of 0.5–1.0 mg/day are recommended by The European League Against Rheumatism and the British Society for Rheumatology for prophylaxis against flares in patients initiating ULT.12 33
In this study we used a colchicine dose of 0.5 mg/day. The choice of dose was based on the clinical experience of the investigators and results of a study indicating that a dose of 0.6 mg/day is better tolerated than a higher dose.18
In this particular study, the planned dose of colchicine prophylaxis was 0.6 mg twice daily.18
However, dosing was reduced to once daily in approximately two-thirds of patients and 38% of patients experienced diarrhoea. In three other recent studies in patients initiating ULT, a colchicine dose of 0.6 mg/day was employed as prophylaxis and significant rates of diarrhoea were not reported.17 21 22
The rates of flares reported in these studies during colchicine prophylaxis (10% to 15% per month) are comparable with those reported in our study for the colchicine group.
There are a number of limitations to this study. First, colchicine 0.5 mg was only given for 16 weeks. The risk of flares following initiation of ULT is known to extend for up to a year or longer; thus a more prolonged period of colchicine prophylaxis may have been appropriate. However, key efficacy outcomes including the primary outcome were assessed at 16 weeks. Second, occurrence and duration of flares was dependent on patients’ assessment. This reflects the fact that there are currently no validated endpoints for the assessment of gouty arthritis flares. Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) have suggested possible endpoints for use in studies of gouty arthritis but these have yet to be validated.34
The endpoints used in our study overlap with those suggested by OMERACT and use of patient self-reporting for flares is unlikely to have had an impact on the results. Third, the study population is probably not representative of all patients who would benefit from canakinumab. This reflects the need to exclude patients with possible risks associated with either treatment and the use of the exclusion criteria generally used in clinical trials in patients with gouty arthritis. Fourth, allopurinol treatment was initiated at 300 mg (or 100 mg or 200 mg if creatinine clearance was <90 ml/min) instead of slowly up-titrating from a dose of 50–100 mg, as suggested in treatment recommendations.12 33
This may have increased the risk of flares compared with a dose-titration strategy. However, giving allopurinol at a fixed dose is a very common practice throughout Europe.12
In conclusion, in this double-blind, active-controlled, multicentre study assessing prophylaxis against gouty arthritis flares during the initiation of ULT, a single canakinumab dose of 50–300 mg or 4-weekly dosing over 4 months provided effective prophylaxis against flares, was superior to the standard of care (colchicine) and was well tolerated. Further studies of canakinumab 150 mg are being conducted to determine the full potential of this new drug for the prevention of flares in patients with gouty arthritis.