Table 4.

Recommendations for future ULT trials with gout flare end points

Recommendations	Purpose
Plan on reporting entire-period flare results (primary period of interest) as well as pre-specified partial periods (starting from the time of randomization) (secondary period of interest)	To accommodate gout-specific biology while retaining the advantage of the RCT design
Implement effective flare prophylaxis during the initial period of ULT, when risk of flare is paradoxically increased	To minimize dilution of the effect of the intervention in analysis of the entire trial period
Conduct long-term trials to overcome the initial worsening of flares in the intervention group	To avoid false-negative results while quantifying the clinical benefits and risks of ULT, given that ULT is a long-term care medication
Design and carry out the trial to minimize dropouts	To maximize the validity of the RCT in both entire-period and partial-period analyses
Specify a priori the statistical analysis plan for adherence-adjusted per-protocol analysisa for the entire period, as well as pre-specified partial-period analyses, in addition to ITT analysis	To account for dropouts and treatment adherence
Collect high-quality longitudinal data, including health care utilization, comorbidities and medication use	To effectively predict and account for treatment adherence
Consider using flare rate as the primary end point, as opposed to flare risk (proportional), and employ Poisson regression models	To best accommodate for recurrent events of gout, the time-dependent (non-proportional) risk and the paradoxical increase in flare risk after ULT initiation
Collect data on the use of prophylaxis and medication for acute gout care	To serve as a secondary end point and as a key variable to account for non-adherence and censoring events for primary flare end point

ITT, intention-to-treat; RCT, randomized controlled trial; ULT, urate-lowering therapy. ^aSee Box 1 for further explanation of adherence-adjusted per-protocol analysis.