Roddy 2020.

Study characteristics
Methods	Study design: multicentre, parallel‐arm, open‐label randomised controlled trial Setting: 100 GP practices across England Time period: 29 January 2014 to 31 December 2015 Intervention: naproxen (NSAID) 750 mg immediately then 250 mg every 8 hours for 7 days, or low‐dose colchicine 500 mcg three times per day for 4 days. Sample size: a sample size of 200 participants per arm was required to detect a small standardised effect size of 0.3 for the primary outcome of change in pain intensity from baseline measured over the first 7 days, allowing for the repeated measures structure (assumed autocorrelation 0.6), 20% loss to follow‐up, 1:1 allocation ratio, 90% power and two‐sided type 1 error of 0.05. This trial aimed to assess the superiority of naproxen or colchicine (two‐tailed hypothesis testing). Analysis: ITT
Participants	Number of participants Randomised: 399 participants were randomised (199 to the low‐dose colchicine group out of which 14 cross‐overs and 2 ineligible; and 200 to the naproxen group out of which 9 cross‐overs, 3 ineligible and 2 not randomised properly). Analysed: 177/199 in the colchicine group and 172/200 in the naproxen group were available for analysis, however multiple imputation was used for all outcomes and 199/199 in colchicine group and 200/200 in naproxen were analysed (ITT). Inclusion criteria Adults (18 years and over), consulting a GP for a current gout flare with capacity and willingness to give consent and complete study documentation. Clinical diagnosis of gout was made by the GP without joint aspiration, blood tests, imaging or diagnostic criteria. Exclusion criteria Unstable medical conditions (e.g. ischaemic heart disease, impaired liver function) Known stage 4/5 chronic kidney disease (estimated glomerular filtration rate/creatinine clearance < 30 mL/min) Recent surgery or gastrointestinal bleed History of gastric ulcer Current anticoagulant use Allergy to aspirin or NSAID Previous inability to tolerate naproxen or low‐dose colchicine Other contraindication to either trial drug described in the Summary of Product Characteristics, which includes: hypersensitivity reactions (e.g. asthma, rhinitis, nasal polyps, angioedema or urticaria) in response to ibuprofen, aspirin, or other NSAIDs; history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy; active or prior history of peptic ulcer, active gastrointestinal bleeding, gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding; haemorrhoids or predisposition to rectal bleeding. Prescription of naproxen or colchicine in the previous 24 hours Pregnancy or lactation Potentially vulnerable participants Participation in the CONTACT trial during a previous gout flare Involvement in another clinical trial in the last 90 days or other research within the last 30 day Baseline characteristics Colchicine group (n=199) Age: mean (SD) 60.0 (13.4) Gender: 174 (87.4%) male Pain NRS: mean (SD) (0‐10): 6.9 (2.2) First instance of gout, n (%): 51 (26.2) Duration of disease: 6.6 years Body part affected, n (%): first MTP joint: 135 (69.2) other foot joints: 48 (24.6) other lower limb: 47 (24.1) upper limb: 31 (15.9) Number of body parts affected, n (%): 1 = 145 (74.3) 2 = 27 (13.8) 3 = 9 (4.6) 4 = 13 (6.7) ≥5 = 1 (0.5) EQ‐5D‐5L score: mean (SD) 0.666 (0.225) Naproxen group (n=200) Age: mean (SD) 58.7 (14.4) Male: no. (%) 173 (86.5%) Pain NRS (0‐10): mean (SD) 7.1 (2.1) First instance of gout, n (%): 35 (17.9) Duration of disease: 6.6 years Body part affected, n (%): First MTP joint: 142 (72.4) Other foot joints: 58 (29.6) Other lower limb: 46 (23.5) Upper limb: 23 (11.7) Number of body parts affected, n (%): 1 = 139 (70.9) 2 = 34 (17.3) 3 = 13 (6.6) 4 = 6 (3.1) ≥5 = 4 (2.0) EQ‐5D‐5L score: mean (SD) 0.665 (0.210) Pretreatment group differences: none
Interventions	Low‐dose colchicine group Oral colchicine 500 mcg (1 tablet) every 8 hours for 4 days. Participants prescribed a statin were advised to omit the statin during colchicine treatment. Control (naproxen group) Single initial dose of oral naproxen 750 mg (3 250 mg tablets) followed by 250 mg (1 tablet) every 8 hours for up to 7 days. Co‐prescription of a proton‐pump inhibitor was at the GP's discretion. Co‐intervention Participants from both groups received a drug‐specific advice leaflet that included advice about non‐pharmacological treatment (rest, application of ice) and were offered reimbursement for prescription charges.
Outcomes	Outcomes were measured at days 0 to 7 and week 4 Primary outcome Change in worst pain intensity in the last 24 hours (0–10 NRS), where 0 is no pain and 10 is worst pain) measured daily on days 0 to 7 and at week 4. Mean change from baseline was compared between groups over days 1 to 7. Secondary outcomes Time‐to‐treatment effect Complete pain resolution (reporting 0 or 1 on NRS) Self‐reported side effects (nausea, vomiting, headache, skin rash, dyspepsia, abdominal pain, constipation and diarrhoea) assessed daily during days 1–7 and at week 4. Patient global assessment of treatment response (completely better/much better/somewhat better/about the same/somewhat worse/much worse) assessed at day 7 and week 4 Use of glucocorticoids, paracetamol, NSAIDs or opioids for gout pain assessed daily during days 1–7 and at week 4 Treatment adherence (measured using participant's self‐report) assessed daily during days 1–7 and at week 4 Relapse/recurrent gout flare during 4‐week follow‐up Quality of life (EQ‐5D‐5L) assessed at day 7 and week 4 Attendance at GP, emergency department or primary care out‐of‐hours service Absence from work/education at 4‐week follow‐up Outcome measures were collected by self‐completed daily diary (days 1–7) and a questionnaire at week 4. Outcomes used in this review Mean pain on NRS Participant global assessment of treatment success Adverse events Time pointsused in this review 7 days and 4 weeks
Source of funding	This trial was funded by the National Institute for Health Research School for Primary Care Research (NIHR SPCR).
Notes	Trial registration: this trial was prospectively registered at ISRCTN (identifier: 69836939) on 21 November 2013 and at ClinicalTrials.gov (NCT01994226) on 25 November 2013. The total number of participants in each treatment arm (colchicine = 199, NSAIDs = 200) was less than sample size calculated a priori for an adequately powered study (200 per arm), allowing for a 20% loss to follow‐up. Competing interests: the authors declared no competing interests for this trial. Withdrawals: 6/199 (3%) in the colchicine group and 10/200 (5%) in the naproxen group. No reasons for withdrawal given. Total number of participants reporting adverse events* Low‐dose colchicine group: 106/199 (53.3%) Naproxen group: 100/200 (50.0%) *The corresponding author was contacted via email requesting unpublished data for number of participants who experienced "any side effects" over the 4‐week follow‐up period in this trial. These data (the number of participants who reported "any side effect") were provided and are reported as total adverse events. The type of adverse events that participants reported include nausea and/or vomiting, dyspepsia, abdominal pain, headache, constipation, diarrhoea, skin rash and "other" (free nominated text). Serious adverse events Low‐dose colchicine group (n = 199): one participant who received colchicine was hospitalised with osteomyelitis. Naproxen group (n = 200): two participants who received naproxen were hospitalised; one for non‐cardiac chest pain and one for hospital‐acquired pneumonia following a transcatheter aortic valve implantation. None of the three serious adverse events outlined above were related to study interventions, and there were no deaths.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly allocated 1:1 to naproxen or low‐dose colchicine groups using simple randomisation, which was undertaken by a healthcare professional using web access to a secure remote allocation system or, if this could not be accessed, a telephone randomisation service.
Allocation concealment (selection bias)	Low risk	Clinicians and participants did not know which treatment a participant would receive prior to randomisation, ensuring allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	High risk	The GP prescribed the allocated medication. Participants and treating clinicians were aware of treatment allocation.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (pain, treatment success, reduction of inflammation, function, serious adverse events, total adverse events, withdrawals due to adverse events)	High risk	This trial had an open‐label design without blinded outcome assessment or placebo. Baseline data were collected by self‐complete questionnaire prior to randomisation. Outcome measures were collected by self‐completed daily diary (days 1–7) and a questionnaire at week 4.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (reduction of inflammation, function)	Low risk	No assessor reported outcomes were measured in this trial.
Incomplete outcome data (attrition bias) All outcomes	Low risk	399 eligible participants were randomised into naproxen group (n = 200), and low‐dose colchicine group (n = 199). ITT was used for the main analysis, evaluating participants as per allocation assignment.
Selective reporting (reporting bias)	Low risk	This trial was prospectively registered with ClinicalTrials.gov (NCT01994226) and ISRCTN registry (ISRCTN69836939). The registered primary and secondary outcomes in the ISRCTN registry match the collected outcomes data of the trial, except for the secondary outcomes time‐to‐treatment effect and complete pain resolution, which were added to the trial using data that was collected for other outcome measures. All measured outcomes from baseline to week 4 follow‐up reported descriptive statistics (mean, SD and number of participants) for continuous outcomes, and the number of events and number of participants for dichotomous outcomes. Days to complete pain resolution and number of days taken off work because of gout during 4‐week follow‐up were reported as median (IQR).
Other bias	Low risk	No other potential bias detected.