Stepwise dose increase of Febuxostat is comparable with Colchicine prophylaxis for the prevention of gout flares during the initial phase of urate-lowering therapy: FORTUNE-1, A prospective, and multicentre randomized study

Stepwise dose increase of febuxostat and low-dose colchicine prophylaxis effectively reduces gout flares as compaared to fixed-dose febuxostat alone. Stepwise dose increase of febuxostat may be an effective alternative to low-dose colchicine prophylaxis during the introduction of uratelowering therapy (ULT). 

Gout is prevalent worldwide with consistent increase and affecting quality of life of affected patients. Gout and hyperuricemia are known to be closely associated with metabolic syndrome and renal impairment. Clinically, gouty arthritis and gouty tophus is crystal deposition of monosodium urate (MSU) which can only be treated by reducing the body urate level. This can decrease the long-term incidence of gout flares and urate tophi. The number of studies have reported that during the first months of treatment with urate-lowering therapy, gout flares frequently develop. During ULT the number of factors such as the initial serum urate level, the presence of tophus and the dose of urate-lowering drugs can affect the risk of gout flares. Thus, while initiating the ULT, the crucial key is to prevent gout flares. A recent publication recommends colchicine for at least first 6 months, but due to its toxicity, the caution is advised. It is known that ULT decreases the serum urate level that leads to prevention of gout flares.

The clinical trials conducted in Japan showed the more significant reduction in the gout flares by using stepwise increment in the dose of febuxostat than trials using fixed-dose febuxostat. Thus, the colchicine prophylaxis and stepwise increase in the dose are the two potential strategies to reduce early treatment-related gout flares. However, no study has been conducted to compare the efficacy of these two strategies. Therefore, the present study investigated the incidence of gout flares during early-stage febuxostat treatment, comparing fixed-dose monotherapy both to stepwise dose increase and to low-dose colchicine prophylaxis.

Rationale behind the research:

None of the study compared the stepwise increased dose and fixed monotherapy of febuxostat for the treatment of gout flares.

Therefore, this study was designed to compare fixed-dose monotherapy both to stepwise dose increase and to low-dose colchicine prophylaxis.

Objective:

To determine whether febuxostat with stepwise dose increase is as useful as colchicine prophylaxis in reducing gout flares during the initial introduction of ULT in gout when compared to febuxostat with no dose titration. 

Study outcome measures:

• Primary endpoint: Incidence rate of gouty arthritis (gouty aura not included) during the ‘treatment period’ (the first 12 weeks of the study). Patients were instructed to record symptoms and NSAID use in the specified patient record form. Moreover, swelling and other symptoms were verified by the attending investigator during the patient's next visit.
• Secondary endpoints: The number of gout flares per patient during the first 12 weeks (randomized period), the number of gout flares per patient during the second 12 weeks (observation period) and the percentage of patients with serum urate ≤6.0mg/dL (356.91 µmol/L) in the second 12 weeks (observation period)

Time period: 4 Weeks, 8 Weeks, 12 Weeks, 16 Weeks, 20 Weeks and 24 Weeks.

Study Outcomes:

Primary outcome:

• Incidence of gout flares in the first 12 weeks (randomized period):

Gout flares were experienced within the first 12 weeks (randomized period) by 20 of 96 (20.8%) patients in group A, 18 of 95 patients (18.9%) in group B and 18 of 50 patients (36.0%) in group C (Figure 2). In an overall χ2 test, the P value was 0.054, and for the comparison of groups A and C, the P value was 0.048. Although this P value was below 0.05, the null hypothesis for the primary endpoint was not rejected because the higher P value of the two tests (p=0.054) was above the 0.05 threshold. The difference in flare incidence was statistically significant between group B and group C (p=0.024) and between group A + group B and group C (19.9%, 95% CI 14.2 to 25.6, p=0.016) but not between group A and group B (p=0.744). 

Figure 2: Incidence of gout flares during the randomized period

Secondary outcome:

• Number of gout flares per patient in the study period:

To investigate the characteristic time, course of gout flares in each group, the number of gout flares in each study period were analyzed. During the first 12 weeks (randomized period), a total of 27 flares were identified in 20 patients (1.35 flares/patient) in group A, 24 flares in 18 patients (1.33 flares/patient) in group B and 37 flares in 18 patients (2.06 flares/patient) in group C. There was no significant difference between group A and group C or between group B and group C. In the second 12 weeks (observation period), there were 18 flares in 15 patients (1.20 flares/ patient) in group A, 26 flares in 17 patients (1.53 flares/patient) in group B and 8 flares in six patients (1.33 flares/patient) in group C. There was no significant difference between treatment groups. The number of flares in each patient who had gout flares in the first 12 weeks and the second 12 weeks is illustrated in Figure 3A and B, respectively. During the 24 weeks (randomized + observational periods), there were 45 flares in 30 patients (1.50 flares/patient) in group A, 59 flares in 28 patients (1.79 flares/patient) in group B and 45 flares in 19 patients (2.37 flares/patient) in group C. 

Figure 3 (A): Number of gout flares during the study period. Number of gout flares per patient during the first 12 weeks

Figure 3 (B): Number of gout flares during the study period. Number of gout flares per patient during the second 12 weeks

• Percentage of patients with serum urate ≤6.0mg/dL (356.91 µmol/L):

Urate-lowering effects of treatment were investigated in 241 patients. Some data was missing as the treatment was discontinued or were otherwise unavailable. The percentage of patients whose serum urate decreased to 6.0mg/ dL (356.91 µmol/L) or below at weeks 4, 8, 12, 16, 20 and 24, and the number of patients used for calculations for each time point and each group. A significantly lower percentage of patients reached the target level of serum urate at 4 weeks (p<0.001) and 8 weeks (p<0.001) in group A compared with group B or group C. There was no significant difference among the three treatment groups after 12 weeks.

Safety profile:

No clinically important adverse events (AEs) or serious AEs were reported. No differences were identified in the incidence of adverse reactions among the three groups. Moderate diarrhoea was reported in one patient from group B, but not in any patients from group A or group C. 

Febuxostat is a potent xanthine oxidase inhibitor with a serum urate-lowering effect. According to the literature, during the initial stages of ULT, the two possible ways to reduce gout flares are colchicine prophylaxis and stepwise dose increase. The present study is the first to compare these two strategies, using febuxostat as the urate-lowering drug.

The primary endpoint, the incidence of gout flares was significantly lower in group A (stepwise dose increase) than that in group C (without stepwise dose increase or colchicine prophylaxis) and was also significantly lower in group B (low-dose colchicine prophylaxis) than that in group C. There was no difference in the number of gout flares between group A and group B, suggesting that stepwise increase in the dose of febuxostat is better than both single-dose of febuxostat and low-dose colchicine prophylaxis for the prevention of gout flares.

Also, results of non-inferiority or equivalence testing between group A and group B confirmed febuxostat stepwise dose increase is comparable with colchicine prophylaxis in reducing gout flares. However, such tests were not performed in the present study because of insufficient sample size. Under the current concept of treat to target, the recommended serum urate level is to be maintained below 6.0mg/dL (356.91 µmol/L). Under stepwise dose increase, lowering of urate to the target level (6.0mg/dL (356.91 µmol/L)) was delayed in group A, but by week 12, the same percentage of patients was achieved serum urate at or below 6.0mg/dL (356.91 µmol/L) as in the other two groups. This suggests that stepwise dose increase is a practical treatment option. This is particularly important because colchicine can be toxic in large amounts and thus, its use should potentially be restricted in patients with multiple comorbidities. Thus, this study proposes a stepwise dose increase of febuxostat as a useful alternative option to minimize the occurrence of gout flares when starting ULT.

Stepwise increase in the dose of febuxostat more significantly reduced the incidence of gout flares as compared to the low-dose colchicine prophylaxis.