Study design
A pilot 6-month, randomized, open-label clinical trial was undertaken (ACTRN12617000539336p). Participants were enrolled between July 2014 and November 2018. Ethical approval was obtained from the New Zealand Health and Disability Ethics committee (17/NTB/68) and all participants provided written informed consent. All study procedures were carried out in accordance with relevant guidelines and regulations.
Participants
People ≥ 18 years of age with gout as defined by the 2015 Gout Classification Criteria [6] with serum urate ≥ 0.36 mmol/l and either on a stable dose of allopurinol for at least one month or on no urate lowering therapy were recruited. People with a history of intolerance or allergy to omega three fatty acid supplements or an allergy to fish or shellfish were excluded as were people with an implantable defibrillator or receiving warfarin or dabigatran.
Randomization and masking
The randomization sequence was generated electronically by an independent statistician. The randomization sequence was stratified by allopurinol use and arranged in permuted blocks of size four. Participants were randomized on a 1:1 ratio to receive omega-3 fatty acid supplementation or not (controls). Randomization codes were provided to the study coordinator in a sealed opaque envelope which was opened after the participant had consented.
Study treatment and procedures
Those participants randomized to receive omega 3 fish oil were provided with commercial fish oil manufactured by Melrose (Mt Waverley, Victoria, Australia) at baseline and week 12 (i.e. three-month supply) with instruction to store per the manufacturer’s recommendation. Participants were instructed to take 20 ml daily to provide a total of 6.2 g omega-3 fatty acids. Melrose fish oil was chosen as it is easily available, has been used in other recent clinical trials of omega-three supplementation in both osteoarthritis and rheumatoid arthritis in Australia [6]. The control group received no intervention. For those on allopurinol the dose remained stable during the entire study period.
Participants were seen at baseline, week 12, and week 24 by the study coordinator with monthly telephone assessment. At each assessment, concomitant medications, self-reported gout flares requiring treatment, and adverse events were recorded. Blood was obtained monthly for serum urate and creatinine and three-monthly for full blood count and liver function tests. HBA1c, cholesterol, HDL, and LDL concentrations were measured at baseline and week 24. For people on allopurinol oxypurinol was also measured at baseline and week 24. Adherence was assessed at each in-person study visit by volume of fish oil remaining and red cell EPA and DHA concentrations. Red cell EPA and DHA were measured using a blood spot collection system as previously described [7, 8]. Samples were stored and analyzed in two batches in Adelaide, Australia.
Adverse and serious advent event reporting
Adverse events (AEs) and serious adverse events (SAEs) were coded according to Common Terminology Criteria for Adverse Events (CTCAE v4.0). Participants were asked about occurrence of any AEs as well as specific fish oil related AEs (abdominal pain, nausea, bloating, reflux). Treatment emergent AEs were defined as any AE occurring after entry into the study until the end of week 28. Worsening laboratory AEs were defined as those where there was an increase in CTCAE grade between baseline and week 28. Serious adverse events were defined as an event that was life-threatening, required hospital admission or resulted in death. AEs and SAEs adverse events were classified as not related, possibly, probably, or definitely related to fish oil. Management of AEs was at the discretion of the treating physician.
Study outcomes
The primary efficacy outcome was the change in serum urate between baseline and week 24 (or the final visit for those who discontinued fish oil or were lost to follow-up). Secondary outcomes included (1) change in weight and BMI between baseline and week 24, (2) mean number of flares per month between 0 and week 24, (3) percentage of participants with flares at each month, (4) cessation of fish oil therapy prior to week 24 due to adverse effects or intolerance and (5) change in HBA1c, cholesterol, HDL, and LDL concentrations between baseline and week 24 and in oxypurinol for people on allopurinol.
Sample size and power
This pilot study was designed to answer our basic aims which will allow us to design a large clinical trial examining the role of omega-3 fatty acids in gout prophylaxis. The sample size of 20 per group was not based on formal statistical considerations but to allow sufficient information meet aims and, if appropriate, to inform design of an appropriately powered clinical trial.
Statistical analysis
Baseline demographics and clinical features were summarized using descriptive statistics including means, standard deviation (SD), median, range, number and percent as appropriate. All randomized participants were included within the intention-to-treat (ITT) analysis population and analyzed within their randomized group. The primary efficacy outcome, change in serum urate, was compared between randomized groups using a general linear model which included randomized group and allopurinol use as fixed factors and baseline serum urate as a co-variate. The analyses of continuous secondary outcomes were undertaken using the same statistical model as for the primary outcome with the appropriate baseline variable as the covariate and the mean differences in the changes summarized with 95% confidence intervals. The percentage of participants with at least one gout flare were compared between randomized groups using Chi square or Fisher’s exact test as appropriate. The associations between the changes in total omega three, EPA and DHA and change in serum urate were tested using Pearson’s correlation coefficient. Correlations between omega three fatty acid concentrations and gout flares were tested using Spearman’s correlation coefficient. A two-tailed p value < 0.05 was taken to indicate statistical significance. The variables, analysed using parametric methods, were adequately normally distributed and this were confirmed by visual inspection of the residual plots from the general linear models. All analyses were undertaken using SPSSv27.