Table 1 Intervention details of the RCTs

CAN (N = 3)

 Schlesinger et al., 2011a [20]

Adaptive single-dose, single-blind, active-controlled study (8 wk)

CAN: n = 143

TA: n = 57

Intervention: One dose of CAN (10, 25, 50, 90, or 150 mg) and saline on day 1

Comparator: One dose of TA 40 mg and PBO on day 1

Pain (note: pain was the primary endpoint of the original study but is also reported in this study)

 Schlesinger et al. 2011b [21]

Dose-ranging, multicentre, double-blind, double-dummy, active-controlled study (16 wk + 8-wk FU)

CAN 25‒300 mg: n = 270

CAN q4wk: n = 53

CLC: n = 108

Intervention: One dose of CAN (25, 50, 100, 200 mg, 300 mg) or CAN q4wk

Comparator: CLC 0.5 mg q.d

CAN dose producing equivalent efficacy to CLC 0.5 mg (mean number of GFs PP)

 Schlesinger et al., 2012 [19]

2 multicentre, active-controlled, double-blind, parallel-group, double-dummy, phase 3 studies (12 wk + 12-wk ext)

CAN: n = 225

TA: n = 229

Intervention: CAN 150 mg; PBO matching for each GF

Comparator: TA 40 mg; PBO matching for each GF

Pain intensity in the most affected joint at 72 h post-dose and time to first new GF

ANK (N = 2)

 Janssen et al., 2019 [16]

Randomised, double-blind, double-dummy, active comparator, PBO-controlled trial (5 d + 2-d safety FU)

TaU: n = 45

ANK: n = 43

Intervention: 5-d treatment with ANK (100 mg q.d.) + PBO up to t.i.d. (CLC), b.i.d. (NAP) or q.d. (PRED)

Comparator: TaU (0.5 mg up to t.i.d. for CLC; 500 mg up to b.i.d. for NAP; 35 mg q.d. for 5 d for PRED) + PBO q.d. for 5 d

Mean change in pain in the most affected joint from BL to the average of pain scores at days 2‒4 with a prespecified non-inferiority margin of 0.4

 Saag et al., 2021 [18]

Randomised, double-blind, double-dummy, active-control, multicentre trial (15 d + 52-wk post-randomisation ext)

TA: n = 55

ANK: n = 110

Intervention: ANK 100 mg q.d. for 5 d/ANK 200 mg q.d. for 5 d

Comparator: TA 40 mg single injection on day 1

Change in pain intensity from BL to 24–72 h

RL (N = 5)

 Mitha et al., 2013 [17]

Randomised, double-blind, PBO-controlled, phase 3 study (16 wk + 5-wk safety FU)

PBO: n = 82

RL: n = 166

Intervention: RL 80 mg/160 mg. q.w with loading doses of RL 160 mg (80-mg group) & 320 mg (160-mg group) on day 1, followed by 15 q.w. doses alongside AP 300 mg q.d

Comparator: PBO q.w. Loading doses on treatment day 1 followed by 15 q.w. Patients also initiated on AP 300 mg q.d

Mean number of GFs PP up to week 16

 Schumacher et al., 2012a [23]

Phase 2, randomised, double-blind, PBO-controlled trial (16-wk + 6-wk FU)

PBO: n = 42

RL: n = 41

Intervention: RL 160 mg q.w. (loading dose: RL 320 mg) and AP 300 mg q.d

Comparator: PBO q.w. and AP 300 mg q.d

Number of GFs PP through week 12

 Schumacher et al., 2012b [22]

Phase 3, randomised, double-blind, PBO-controlled, confirmatory efficacy study (16-wk + 4-wk safety FU)

PBO: n = 79

RL: n = 161

Intervention: RL 80 mg/160 mg q.w. Loading doses of RL 160 mg (80-mg group), 320 mg (160-mg group) on treatment day 1, alongside AP q.d

Comparator: PBO q.w. Loading doses of PBO were administered on treatment day 1, alongside AP q.d

Mean number of GFs PP through week 16

 Sundy et al., 2014 [24]

Phase 3, randomised, double-blind, PBO-controlled trial (16-wk + 4-wk safety FU)

PBO: n = 330

RL: n = 985

Intervention: RL 160 mg q.w. Loading dose of RL 320 mg was administered in 2 equal volumes on day 1

Comparator: Loading dose of PBO was administered in 2 equal volumes on day 1, followed by 15 q.w. doses of PBO

Safety (AE, SAE, and clinical laboratory variables) over 20 weeks

 Terkeltaub et al., 2013 [25]

Phase 3, randomised, double blind, double-dummy, active- and PBO-controlled study (3‒9 d + safety FU on d 31)

PBO + IND: n = 75

RL + IND: n = 74

RL + PBO: n = 73

Intervention: RL 320 mg at BL + IND (50 mg t.i.d. for 3 d [then 25 mg t.i.d. for up to 9 d]) or RL 320 mg at BL + PBO t.i.d. for 3 d (then PBO t.i.d. for up to 9 d)

Comparator: PBO at BL + IND 50 mg t.i.d. for 3 d (then 25 mg t.i.d. for up to 9 d)

Pain in the index joint at 24, 48 and 72 h