Table 3 Efficacy results of the RCTs

CAN (N = 3)

Schlesinger et al., 2011a [20]

NR

Primary endpoint: % of patients with no/mild pain was numerically greater in most CAN groups vs TA from 24 to 72 h; the difference was significant for the 150-mg group

The reduction in pain intensity from BL was also greater for CAN 150 mg vs TA from 48 h to 7 d

NR

Primary endpoint:

All treatments reduced visible inflammation in the target joint by 72-h. At 72-h, CAN 150 mg had a lower score for tenderness and swelling vs TA; the difference remained significant at 7 d. Erythema was absent in 74.1% (CAN 150 mg) and 69.6% (TA) at 72-h and in 96.3% (CAN 150 mg) & 83.9% (TA) at 7 d

NR

Schlesinger et al., 2011b [21]

Primary endpoint:

Mean GFs PP (least-squares mean [SE]; ANCOVA):

CAN 25 mg: 0.5 (0.2)

CAN 50 mg: 0.5 (0.2)

CAN 100 mg: 0.2 (0.2)

CAN 200 mg: 0.4 (0.2)

CAN 300 mg: 0.2 (0.2)

CAN q4wk: 0.7 (0.2)

CLC 0.5 mg: 0.8 (0.1)

Significant for CAN 100 mg and 300 mg vs CLC 0.5 mg

NR

Time to first GF (HR [95% CI]):

CAN 25 mg: 0.6 (0.3‒1.0)

CAN 50 mg: 0.3 (0.2‒0.7)

CAN 100 mg: 0.3 (0.1‒0.6)

CAN 200 mg: 0.4 (0.2‒0.7)

CAN 300 mg: 0.3 (0.1‒0.6)

CAN q4wk: 0.3 (0.2‒0.7)

Average duration of GFs (least-squares mean [SD]):

CAN 25 mg: 4.6 (1.0)

CAN 50 mg: 3.7 (1.2)

CAN 100 mg: 2.8 (1.4)

CAN 200 mg: 3.6 (1.3)

CAN 300 mg: 3.1 (1.3)

CAN q4wk: 3.3 (1.2)

CLC: 5.1 (0.6)

NR

Patients experiencing ≥ 1 GF (n [%]):

CAN 25 mg: 15 (27.3)

CAN 50 mg: 9 (16.7)

CAN 100 mg: 8 (14.8)

CAN 200 mg: 10 (18.5)

CAN 300 mg: 8 (15.1)

CAN q4wk: 9 (16.7)

CLC: 48 (44.4)

All CAN patients were significantly less likely to experience ≥ 1 GF vs CLC patients (OR: 0.22–0.47)

Schlesinger et al., 2012 [19]

 ≥ 1 GF:

CAN: 16.0%

TA: 35.8% (OR: 0.34)

Mean number of new GFs:

CAN: 0.19

TA: 0.51 (rate ratio: 0.37)

 ≥ 2 GFs:

CAN: 2.7%

TA: 11.4%

Median time to new GFs:

CAN: > 168 d

TA: 131 d

Primary endpoint:

Mean pain scores at 72 h:

CAN: 25.0 mm

TA: 35.7 mm

MD: ‒10.7 mm (95% CI: ‒15.4 to ‒6.0)

CAN delayed time to first new GF and reduced new GF risk over the 12-wk period by 62% vs TA

72 h (OR vs TA [95% CI]):

Tenderness:

CAN: 2.2 (1.5‒3.1)

Swelling:

CAN: 1.7 (1.2‒2.5)

Erythema:

CAN: 0.6 (0.4‒0.9)

Taking rescue medication:

CAN: 37.3% (oral steroids: 11.1%)

TA: 54.6% (oral steroids: 23.6%)

ANK (N = 2)

Janssen et al., 2019 [16]

NR

Primary endpoint:

Pain scores decreased to a similar extent in both groups. Estimated marginal mean difference between treatment arms: ‒0.13 points in favour of ANK. The upper 95% CI (-0.44 to 0.18) did not surpass the NI margin of 0.4

NR

For all the secondary outcomes, pattern of change was similar for ANK and TaU over 5 d

During the first 7 d, numerically more patients in ANK (n = 20; 46.5%) vs TaU (n = 16; 35.6%), took pain-relieving medication.

After 2 d, numerically more patients on ANK achieved ≥ 50% decrease in NRS pain scores (OR: 1.4; 95% CI: 0.5‒3.7) vs TaU. On day 3‒5, ORs were in favour for ANK (only significant on day 3)

Saag et al., 2021 [18]

Treated for 1 GF:

TA: n = 54

ANK 100 mg: n = 55

ANK 200 mg: n = 52

Treated for 2 GFs:

TA: n = 17

ANK 100 mg: n = 23

ANK 200 mg: n = 21

Treated for 3 GFs:

TA: n = 5

ANK 100 mg and 200 mg: n = 13

Primary endpoint:

Change in pain from BL to 24‒72 h after first GF (mean [95% CI]):

TA: − 39.4 (− 46.8 to − 32.0)

ANK 100 mg: − 41.8 (− 48.9 to − 34.8)

ANK 200 mg: − 40.7 (− 47.9 to − 33.4)

Pain intensity for the first GF at 6, 12, 18, 24, 36, 48, and 72 h and 5, 6, 7, and 8 d was similar in ANK and TA groups

Across treatment arms, reduction in pain intensity for the second and third GF was similar to the first GF

Median time to pain resolution for the first GF:

ANK total: 120.5 h

TA: 167.5 h (HR: 1.3 [95% CI: 0.9‒1.9])

Median time to response:

ANK total: 46.7 h

TA 40 mg: 47.6 h (HR: 1.2 [95% CI: 0.8‒1.7])

Median time to onset of effect for the first GF:

ANK total: 17.8 h

TA: 22.3 h (HR: 1.1 [95% CI: − 0.8 to 1.6])

Resolution of pain by day 15:

ANK total: 70 (63.6%)

TA 40 mg: 36 (65.5%)

Mean physician assessment of tenderness and swelling at 72 h:

ANK total: − 0.5 (95% CI: − 0.7 to − 0.2; significant)

TA: − 0.3 (95% CI: − 0.6 to − 0.1) and was also better for swelling on day 8 (− 0.3 [95% CI: − 0.6 to − 0.1])

Significantly less presence of erythema was reported in ANK total vs TA group at 72 h (OR: 0.5 [95% CI: 0.2‒1.0])

Between BL and day 15, 44.5% of patients in the ANK total group and 47.3% in the TA group received rescue medication

RL (N = 5)

Mitha et al., 2013 [17]

Primary endpoint:

Number of GFs at week 16:

PBO: 101

RL 80 mg: 29

RL 160 mg: 28

RL 160 mg had significantly fewer GFs PP (0.3; 95% CI: 0.2‒0.5) vs PBO (1.2; 95% CI: 0.9‒1.6), a 72.6% rate reduction (95% CI: 58.4%‒82.0%)

Wk-16 GF days PP:

PBO: mean of 11.2 (95% CI: 6.6‒15.8)

RL 80 mg: 4.3 (95% CI: 0.5‒8.1) RL 160 mg: 1.9 (95% CI: 0.6‒3.1)

Treatment with RL resulted in significantly fewer days PP with a pain severity score ≥ 5 vs PBO. For the 80-mg group, this reduction was from 4.3 d (95% CI: 2.6‒6.0) with PBO to 1.7 d (95% CI: 0.0‒3.5), and for RL 160 mg, the reduction was to 0.9 d (95% CI: 0.3‒1.5)

The estimated median time to first GF in the PBO group was 34 d, significantly earlier than for either of the RL groups. Median time could not be estimated as < 50% of RL patients reported a GF

NR

The RR of ≥ 1 GF over 16 wk:

RL 80 mg: 0.5 (95% CI: 0.3‒0.7); risk reduction: 54.3% (95% CI: 30.8%‒69.9%)

RL 160 mg: 0.4 (95% CI: 0.2‒0.6); risk reduction: 63.5% (95% CI: 41.9‒77.1)

Patients with ≥ 1 GF:

PBO: 56.1%

RL 80 mg: 25.6%

RL 160 mg: 20.5%

Patients with ≥ 2 GFs:

PBO: 32.9%

RL 80 mg: 8.5%

RL 160 mg: 6.0%

Schumacher et al., 2012a [23]

Primary endpoint:

Mean number of GFs PP:

PBO: 0.8 (33 GFs)

RL: 0.2 (6 GFs)

81% decrease in GFs with RL with decrease maintained at ext and FU

Fewer GFs in RL groups as early as 4 wk

Days with pain score ≥ 5 PP (mean [SD]):

PBO: 2.0 (4.5)

RL: 0.2 (0.8)

GF at week 4:

PBO: 26.2%

RL: 4.9%

Median time to first GF:

PBO: 77 d

RL: N/A

GF days PP (mean [SD]):

PBO: 5.2 (8.0)

RL: 1.4 (5.2)

NR

Patients with ≥ 1 GF (n [%]):

PBO: 19 (45.2)

RL: 6 (14.6)

Schumacher et al., 2012b [22]

Primary endpoint:

Number of GFs over 16-wk:

PBO: 84

RL 80 mg: 23

RL 160 mg: 17

Mean number of GFs PP:

PBO: 1.1 (95% CI: 0.7–1.4)

RL 80 mg: 0.3 (95% CI: 0.1–0.5)

RL 160 mg: 0.2 (95% CI: 0.1–0.3)

Reduction in GFs vs PBO:

RL 80 mg: 73.0% (95% CI: 57.1–83.0%)

RL 160 mg: 80.0% (95% CI: 66.3–88.1%)

Observed as early as 4 wk

Days PP with pain severity score ≥ 5 (mean [95% CI]):

PBO: 2.1 (1.4‒2.8)

RL 80 mg: 0.9 (0.0‒1.7)

RL 160 mg: 0.4 (0.1‒0.6)

GF days PP (mean [95% CI]):

PBO: 5.5 (3.3‒7.7)

RL 80 mg: 2.4 (0.0‒4.9)

RL 160 mg: 1.0 (0.3‒1.6)

NR

Patients using rescue medication up to week 16:

PBO: 54.4%

RL 80 mg: 25.0%

RL 160 mg: 23.5%

RR for ≥ 1 GFs:

RL 80 mg: 0.4 (95% CI 0.2–0.7)

RL 160 mg: 0.4 (95% CI 0.2–0.6)

Percentage of patients > 1 GFs:

PBO: 31.6%

RL 80 mg: 5.0%

RL 160 mg: 3.8%

Sundy et al., 2014 [24]

Mean number of GFs PP at week 16:

RL: 70.3% reduction vs PBO: 1.7 (95% CI: 1.4‒2.0) to 0.5 [95% CI: 0.4‒0.6]

 ≥ 1 GF by week 16:

PBO: 51.1%

RL: 25.7% (49.6% reduction)

 ≥ 2 GFs by week 16:

PBO: 34.7%

RL: 11.7% (66.4% reduction)

NR

Median time to first GF:

PBO: 87 d

RL: N/A as < 50% of patients (25.7%) reported GFs

Total number of GF days PP at week 16:

PBO: 7.7 (95% CI: 6.4‒9.0)

RL: 2.7 (95% CI: 2.2‒3.2, 64.9% reduction)

NR

At week 16, GFs PP with tophi (mean [SD]):

PBO: 2.1 (2.9)

RL: 0.9 (1.6)

Without tophi:

PBO: 1.6 (2.6)

RL: 0.4 (0.9)

Terkeltaub et al., 2013 [25]

NR

Primary endpoint:

All groups had significant pain reductions from BL when averaged at 24-, 48- and 72 h

RL + IND mean pain reduction (1.6 points) was not significantly greater than IND alone (1.4 points): least squares mean difference: ‒0.1 (95% CI: ‒0.4 to 0.2)

The difference between IND and RL favoured IND

NR

NR

Patients taking rescue medication at > 24‒48 h:

RL + IND: 3.0%

IND: 4.3%

Mean change in pain at 24, 48, and 72 h were similar between groups except IND alone was significantly superior to RL alone at all time points