Terkeltaub 2010.

Study characteristics
Methods	Study design: double‐blind, three‐arm parallel placebo controlled, randomised trial Setting: multicentre (54 centres in the USA) Time period: between April 2007 and October 2008 Intervention: low‐dose colchicine (1.2 mg followed by 0.6 mg in 1 hour followed by placebo doses every hour for 5 hours) versus high‐dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours) versus placebo (2 placebo capsules initially, followed by 1 placebo capsule every hour for 6 hours) Sample size: not described Analysis: ITT analysis planned
Participants	Number of participants Screened: 813 Randomised: 575 participants randomised (prior to acute gout flare) to the trial (192 in low‐dose colchicine, 193 in high‐dose colchicine and 190 in placebo group) With gout flare (included in trial): 185 participants (74 in low‐dose colchicine, 52 in high‐dose colchicine and 59 in placebo group) had a flare and provided outcome data (390 did not have a flare or had a "non‐qualifying flare"). Analysed: 184 participants for ITT analysis (74 in low‐dose colchicine, 52 in high‐dose colchicine and 58 in placebo group) Inclusion criteria Adult male and postmenopausal female participants with a confirmed past diagnosis of gout (according to the American College of Rheumatology classification criteria) and having had ≥ 2 gout flares within the prior 12 months Exclusion criteria Not described Baseline characteristics (provided by 185 participants with a gout flare only) High‐dose colchicine group (n = 52) Age: mean (SD) 51.9 (10.02) Male: no. (%) 49 (94.2) Weight, in Lb: mean (SD) 228 (38.10) BMI, in kg/m2: mean (SD) 32.9 (4.63) Race American Indian/Alaska Native, n (%): 0 (0) Asian, n (%): 0 (0) Black/African American, n (%): 10 (19.2) White/Caucasian, n (%): 40 (76.9) Other, n (%): 2 (3.8) Age at first gout onset: mean (SD) 40.7 (11.83) No. gout flares in year prior to screening: mean (SD) 4.7 (3.28) No. months since most recent gout flare: mean (SD) 1.4 (1.44) Urate concentration, in mg/dL: mean (SD) 9.2 (1.7) Concurrent allopurinol use, n (%): 10 (19.2) Presence of ≥ 1 tophi, n (%): 7 (14) Previously met ACR preliminary criteria for acute gout, n (%): 52 (100) Low‐dose colchicine group (n = 74) Age: mean (SD) 51.4 (11.79) Gender: 72 (97.3%) male Weight, in Lb: mean (SD) 228 (42.44) BMI, in kg/m2: mean (SD) 33.2 (6.27) Race: American Indian/Alaska Native, n (%): 1 (1.4) Asian, n (%): 1 (1.4) Black/African American, n (%): 4 (5.4) White/Caucasian, n (%): 66 (89.2) Other, n (%): 2 (2.7) Age at first gout onset: mean (SD) 40.7 (12.38) No. gout flares in year prior to screening: mean (SD) 4.4 (2.24) No. months since most recent gout flare: mean (SD) 1.6 (1.36) Urate concentration, in mg/dL: mean (SD) 8.5 (1.8) Concurrent allopurinol use, n (%): 29 (39.2) Presence of ≥ 1 tophi, n (%): 5 (7) Previously met ACR preliminary criteria for acute gout, n (%): 74 (100) Placebo group (n = 59) Age: mean (SD) 51.2 (11.36) No. (%) male: 55 (93.2) Weight, in lb: mean (SD) 228 (41.69) BMI, in kg/m2: mean (SD) 32.8 (5.82) Race: American Indian/Alaska Native, n (%): 0 (0) Asian, n (%): 1 (1.7) Black/African American, n (%): 11 (18.6) White/Caucasian, n (%): 47 (79.7) Other, n (%): 0 (0) Age at first gout onset: mean (SD) 41.6 (13.20) No. gout flares in year prior to screening: mean (SD) 3.8 (2.02) No. months since most recent gout flare: mean (SD) 1.7 (1.84) Urate concentration, in mg/dl: mean (SD) 8.9 (1.9) Concurrent allopurinol use, n (%): 15 (25.4) Presence of ≥ 1 tophi, n (%): 5 (9) Previously met ACR preliminary criteria for acute gout, n (%): 59 (100) Groups were similar at baseline.
Interventions	Intervention group 1 (low‐dose colchicine) Low‐dose colchicine (1.2 mg followed by 0.6 mg in 1 hour followed by placebo doses every hour for 5 hours (1.8 mg total)) Intervention group 2 (high‐dose colchicine) High‐dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours (4.8 mg total)) Control group (placebo) Placebo (2 placebo capsules initially, followed by 1 placebo capsule every hour for 6 hours) Co‐intervention Rescue medication (individualised to each participant by his or her study physician, e.g. NSAIDs) was permitted if intolerable pain continued after taking at least 1 dose of trial drug. Uric acid‐lowering therapy was not to be discontinued at the onset of flare. Participants were permitted to stop trial medication due to adverse events.
Outcomes	Outcomes recorded by participants at prespecified time points for pain using a standardised diary: pain was recorded at baseline, hourly for the first 8 hours and every 8 hours thereafter (while awake) until 72 hours following the initial dose or symptom resolution; recording at 24 hours mandatory. Study physicians at each site assessed participants within 48 hours after onset of symptoms and up to 3 more visits, the last being 7 days after flare onset (they reviewed the participant diaries and recorded pertinent data on standardised case report forms). Primary outcome Number who responded to treatment: responders were defined as having a pretreatment pain score within 12 hours of flare onset and a 50% reduction in pain within 24 hours of the first dose of trial medication without the use of rescue medication during that time frame with pain recorded on an 11‐point Likert scale that ranged from 0 (no pain) to 10 (worst possible pain) Intensity of pain recorded on an 11‐point Likert scale that ranged from 0 (no pain) to 10 (worst possible pain) Rescue medication use within the first 24 hours (individualised to each participant by his or her trial physician, e.g. NSAIDs) if intolerable pain continued after taking at least 1 dose of trial drug Secondary outcomes Treatment response based on the target joint pain score 32 hours after the first dose Treatment response based on at least a 2‐unit reduction in the target joint pain score 24 hours after the first dose Treatment response based on at least a 2‐unit reduction in the target joint pain score 32 hours after the first dose Adverse events: nausea, vomiting, diarrhoea and abdominal pain at each time point of the participant‐rated pain, along with an open‐ended question about other adverse events. The intensity of adverse events was graded as mild, moderate or severe based on the trial physicians' clinical judgement Serious adverse events were recorded based upon established US Food and Drug Administration (FDA) definitions Outcomes used in this review Proportion with 50% or greater decrease in pain score Adverse events Serious adverse events Withdrawals due to adverse events Time points used in this review 24 hrs, 36 hrs, end of trial
Source of funding	The trial was sponsored by URL Pharma. The Chief Medical Officer for URL Pharma had key roles in the study design data collection, data analysis and writing of the manuscript. Prior to the start of the trial, URL Pharma agreed that the authors had full rights to submit the manuscript for publication; URL Pharma approval of the content of the submitted manuscript was not required, and publication of the manuscript was not contingent upon the approval of URL Pharma.
Notes	Trial registration: this trial was registered at ClinicalTrials.gov (NCT00506883) on 23 July 2007. Withdrawals: 1 participant in the placebo group withdrew without recording any data ("non‐responder") and was not included in the ITT analysis. The number of participants in each group included as the "safety population" was not equal due to the method of inclusion in the trial (many participants were randomised but only those who had a gout flare were included). Only a responder analysis was presented ‐ mean (SD) pain scores at each time point were not presented. Competing interests: "Dr. Terkeltaub has received consulting fees from Altus, Ardea, BioCryst, Novartis, Pfizer, Procter & Gamble, Regeneron, Savient, EnzymeRx, Takeda, URL Pharma, and UCB (less than $10,000 each) and has received Research Service grants from the VA (more than $10,000). Dr. Furst has received consulting fees from Abbott, Actelion, Amgen, Bristol‐Myers Squibb, Biogen Idec, Centocor, Gilead, Genentech, GlaxoSmithKline, Merck, Nitec, Novartis, UCB, Wyeth, and Xoma (less than $10,000 each), speaking fees from Abbott, Actelion, and UCB (less than $10,000 each), and honoraria from Abbott, Actelion, Amgen, Bristol‐Myers Squibb, Biogen Idec, Centocor, Genentech, Gilead, Merck, and Nitec (less than $10,000 each); he has received grants from Abbott, Actelion, Amgen, Bristol‐ Myers Squibb, Genentech, Gilead, GlaxoSmithKline, the NIH, Nitec, Novartis, Roche, UCB, Wyeth, and Xoma. Salamandra, LLC (employer of Drs. Bennett and Kook) is a regulatory and clinical consulting firm contracted by URL Pharma. D.A.T.A. Inc. (employer of Dr. Crockett) is a contract statistics company retained by United Bio‐ source (a contract research organization) to provide statistical services for this clinical trial. Dr. Davis owns stock options in URL Pharma, and he holds 2 patents pertaining to the dosing of colchicine with clarithromycin." Total adverse events High‐dose colchicine group: 40/52 (76.9%), includes diarrhoea, nausea, vomiting and melena Low‐dose colchicine group: 27/74 (36.5%), includes diarrhoea and nausea Placebo group: 16/59 (27.1%), includes diarrhoea, nausea and severe gout symptoms Serious adverse events There were no serious adverse events reported in any treatment arm.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation is not described
Allocation concealment (selection bias)	Low risk	At the randomisation visit the investigator dispensed a blister card containing 8 identical‐looking capsules (in a combination of active drug and placebo capsules) for use during their next gout flare. Quote: "over encapsulated (to preserve double‐blindedness) colchicine and matching over encapsulated placebo were provided"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both participants and study personnel were blinded to treatment
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)	Low risk	The participant assessed pain, symptoms, adverse events and rescue medication by using a standardised diary; and were unaware of treatment.
Blinding of outcome assessment (detection bias) Assessor‐reported outcomes (reduction of inflammation, function)	Low risk	The study physicians at each site were blinded to treatment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	7/52 (13.5%) in the high‐dose colchicine group, 3/74 (4%) in the low‐dose colchicine group and 4/59 (6.8%) in the placebo group did not complete full follow‐up, either because of lack of benefit, loss to follow‐up or for other unclear reasons (ClinicalTrials.gov: NCT00506883 on 23 July 2007)
Selective reporting (reporting bias)	Unclear risk	This trial was registered 23 July 2007 but recruitment began in April 2007 and final data collection occurred in October 2007. For benefit only a responders analysis was presented. The mean (SD) pain scores were not presented. The methods also state that symptoms were collected but this is not reported.
Other bias	Unclear risk	Site of flare and number of joints affected were not presented. If baseline differences existed this may have affected the results. The numbers of participants by group treated at each site was not specified but it is stated that some sites did not have participants in all treatment groups. While the number of randomised participants in each group was approximately equal, the numbers of participants in each group who had an acute flare of gout and therefore had outcome data available was not equal.