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This double blind study was conducted in 54 centres on patients with presumed acute gout comparing the efficacy and safety of low-dose branded colchicine with placebo and high dose, branded colchicine. The high dose was a positive comparator based on a prior small study,1 although likely no rheumatologists utilised this high dose protocol due to its known GI side effects. The primary efficacy outcome was accepted by the FDA, and this trial was pivotal in achieving registration of this branded version of previously available unbranded preparations of colchicine.
A total of 575 patients with a history of clinically assumed (ACR classification criteria) or confirmed gout who had >1 attack in the prior 12 months were randomised in a blinded manner to receive low dose colchicine (1.2 mg followed in 1 h by 0.6 mg with subsequent placebo doses – 1.8 mg total), placebo doses or high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 h – 4.8 mg total). Patients were given identically appearing blister packs of medication/placebo at time of screening with instructions as to the timing of self-administration.
When patients felt that they were having a gout flare, they phoned into the ‘Gout Flare Call Center’ (24 h/day) and if the call centre nurse felt that the symptoms were likely a gout flare, and it was within 12 h of onset of flare, the patients were advised to take all of the medication in their blister pack as prescribed. The goals of the study included documenting efficacy of the branded colchicine product compared to placebo and to a previously published efficacious (but known to be very poorly tolerated) regimen. The previous study had utilised a different colchicine preparation.
The primary trial outcome was the percentage of evaluable patients who had ≥50% reduction in pain within 24 h of the first dose of study medication without the use of rescue medication. Randomisation and medication allocation was done in advance of presumed flare. The conduct of the study was excellent with only one placebo patient reportedly removed from intent to treat analysis. Patients were divided into the three groups. There were 184 evaluable patients.
Notable in this design using the 24-h call-in centre was that patients were able to initiate their randomly prescribed therapy rapidly following recognition of a presumed flare. Patient diaries were used to track pain and side effects. Patients were followed for collection of safety data with planned follow-up visits up to 7 days after dosing. After 24 h, patients were treated at the discretion of their personal physicians; thus useful data on flare resolution were not available.
There were 184 patients in the intent-to-treat analysis. Both colchicine dosing regimens were statistically more effective at 24 h than placebo. In the placebo group, 15.5% of the patients had 50% relief of pain within 24 h, as compared to 37.8% (p=0.005) and 32.7% (p=0.034) in the low- and high-dose colchicine groups. Rescue medication (mostly NSAID) was utilised within 24 h of self-administration of the study medication by 50% of placebo, 31.1% low-dose and 34.6% of high-dose colchicine group; there was a significant difference in rescue medicine use between low-dose and placebo group (p=0.027). As expected, the high-dose colchicine group suffered many adverse effects: 76.9% as compared to 36.5% in the low dose and 27.1% in placebo. The difference between the high-dose and the low-dose or placebo group was significant; low dose and placebo were similar. Diarrhea was the most common in all, nausea was more common in the high dose and emesis only occurred in the high group (17.3%).
Pharmacokinetic data indicated a greater than twofold higher exposure in the high dose group where side effects were much more common, but efficacy was similar. The peak colchicine blood level was similar between the two dosing groups.
This well-designed, well-executed study fulfilled the goal of the sponsor in generating data sufficient to gain registration by the FDA on the basis of documentation of efficacy in comparison with placebo and a comparator dosing regimen.
The study design mimics the ability of patients with known gout to initiate prompt therapy, if a plan had been made with their physician. The study does not relate to patients experiencing their first attack of gout, as time will be required to achieve a diagnosis and a prescribed medication. There is a longstanding clinical impression by many that gout flares respond most rapidly with early initiation of therapy.
The placebo response rate (15.5%), using the outcome measure of 50% pain relief by 24 h seems high if these were true gout attacks (the decision as to whether the attacks were ‘real’ was made by phone discussion), but, given the sample size this is comparable to the placebo rate of 9% in hospitalised patients with gout attacks.1 The blood pharmacokinetic data suggest that peak colchicine level correlates with efficacy whereas total exposure over time correlates with toxicity; this may explain why formerly available single-dose (1–2 mg) intravenous colchicine had (presumably) high efficacy with low frequency of GI toxicity.
The study provides little impetus to affect the prescribing habits of clinicians experienced in the management of patients with gout. It is recognised that a few patients with known gout will respond dramatically to very low dose colchicine if taken at the outset of a gout attack. Few, if any, experienced clinicians utilise the ‘high dose’ colchicine regimen, due to GI side effects; the authors of the initial trial, demonstrating efficacy of a similar regimen, concluded “…oral colchicine be used only in those patients in whom effective and less toxic…agents are contraindicated.”1
This study provides no information as to the efficacy or side effects of the colchicine regimens if used with a real-world goal of providing complete resolution of the gout attack, and at least some clinicians quite experienced in the study and management of gout have found low-dose colchicine to be suboptimal therapy in many patients.2 No data are provided as to the efficacy and side effects in patients with chronic kidney disease, a group of patients in whom NSAID therapy would be relatively contraindicated. Finally, there were no data that can be used to guide management of patients who are already utilising low dose (0.6–1.2 mg daily) colchicine to prophylax against gout attacks.
Competing interests BFM had consulted once for URL, the sponsor of this study. However, he did not have any role in the study design or conduct.