Table 1 Study details for the RCTs included in the quantitative analyses of the efficacy and safety of topical treatments for moderate-to-severe papulopustular rosacea

18170 Study (Gold et al. 2014a; Stein et al. 2014)

Part A (efficacy) and Part B (safety)

Additional data not included in Cochrane review from CSR

R, DB, AP,

MC-I, Phase III

Ivermectin 1 % cream QD (451)

Azelaic acid 15 % gel BID (210) – Part B only

Vehicle (232)

Inflammatory lesion count

Success rate

Any AE, any TRAE, any SAE

Specific AEs: burning/stinging, skin irritation, worsening of rosacea

All cause withdrawals

Withdrawal due to AE

Ivermectin 1 % cream QD was well-tolerated and safe for papulopustular rosacea, in particular, no notable difference was found between the ivermectin 1 % cream QD and azelaic acid 15 % gel BID. Ivermectin 1 % cream QD resulted in fewer skin-related AEs than with azelaic acid 15 % gel BID and vehicle

18171 study (Gold et al. 2014b; Stein et al. 2014)

Part A (efficacy) and Part B (safety)

Additional data not included in Cochrane review from CSR

R, DB, AP,

MC-I, Phase III

Ivermectin 1 % cream QD (459)

Azelaic acid 15 % gel BID (208)—Part B only

Vehicle (229)

Inflammatory lesion count

Success rate

Any AE, any TRAE, any SAE

Specific AEs: burning/stinging, skin irritation

All cause withdrawals

Withdrawal due to AE

Ivermectin 1 % cream QD was well-tolerated and safe, with less frequent AEs and a statistically significantly greater success rate at 12 weeks compared to azelaic acid 15 % gel BID when used to treat moderate-to-severe papulopustular rosacea

Beutner and Calverese (2005)

R, IB, AP, MC, PU

MET 1 % cream QD (553)

MET 1 % gel QD (557)

Vehicle (189)

Success rate

Metronidazole gel 1 % QD had a higher efficacy rate than its cream formulation and its vehicle and was equally well-tolerated for the treatment of rosacea

Bjerke et al. (1999)

R, DB, PC, MC, PU

Azelaic acid 20 % cream BID (76)

Vehicle (39)

Specific AEs: burning/stinging, skin irritation

Withdrawal due to AE

Azelaic acid 20 % cream BID was effective and well-tolerated with a significantly greater reduction inflammatory lesion count compared to vehicle for the treatment of papulopustular rosacea

Draelos et al. (2013)

R, DB, PC, MC, PU

Azelaic acid 15 % foam BID (198)

Vehicle (203)

Inflammatory lesion count

Success rate

Any TRAE

Specific AEs: burning/stinging, worsening of erythema, worsening of rosacea

All cause withdrawals

Withdrawal due to AE

Azelaic acid 15 % foam BID demonstrated a significant advantage over the vehicle in both primary measures of efficacy: therapeutic success rate (p = 0.017) and change in inflammatory lesion count (p = 0.001) for the treatment of papulopustular rosacea

Draelos et al. (2015)

Not included in Cochrane review

R, DB, PC, MC, Phase III

Azelaic acid 15 % foam BID (484)

Vehicle (477)

Inflammatory lesion count

Success rate

Any SAE

All cause withdrawals

Withdrawal due to AE

This study supported the efficacy and safety of azelaic acid foam in patients with papulopustular rosacea. Azelaic acid 15 % foam demonstrated a statistically significant advantage over vehicle in both primary measures of efficacy success rate and change in inflammatory lesion count

Elewski et al. (2003)

R, IB, AC, MC, PU

Azelaic acid 15 % gel BID (124)

MET 0.75 % gel BID (127)

Inflammatory lesion count

Success rate

Use of azelaic acid 15 % gel for 15 weeks demonstrated significant superiority over using MET 0.75 % gel in improving principal signs of rosacea (inflammatory lesions and erythema)

Fowler (2007a, b)

R, DB, PC, MC, PU

MET 1 % gel BID + Vehicle followed by Vehicle (36)

MET 1 % gel BID + DOX 40 mg QD followed by DOX 40 mg QD (36)

Inflammatory lesion count

Combination anti-inflammatory dose DOX and MET 1 % gel resulted in a faster reduction of inflammatory lesion count, when calculated at all interim and final data analysis. Anti-inflammatory dose DOX sustained the reduction in lesion count through 16 weeks in patients with mild-to-moderate rosacea

Koca et al. (2010)

R, OL, AC, SC, PU

MET 1 % cream bid (24)

PIM 1 % cream bid (25)

All cause withdrawals

PIM 1 % cream was equally effective in reducing inflammatory lesion count as MET 1 % cream in the treatment of papulopustular rosacea

Leyden (2014)

R, DB, AP, MC, Phase II

Silica encapsulated benzoyl peroxide 1 % gel QD (32)

Silica encapsulated benzoyl peroxide 5 % gel QD (30)

Vehicle (30)

Success rate

Silica encapsulated benzoyl peroxide 1 % and 5 % gels were superior to vehicle in reducing papulopustular lesions

NCT00617903 (2013)

R, DB, PC, MC, Phase II

Azelaic acid 15 % foam BID (41)

Vehicle (42)

Inflammatory lesion count

Success rate

Any AE

Specific AEs: worsening of erythema, worsening of rosacea

All cause withdrawals

Withdrawal due to AE

Authors’ conclusions about the study drug could not be ascertained from the NCT ID from where the trial data were extracted, no publication for the trial could be retrieved

RD.03.SRE.40027 (Galderma 2006)

Additional data not included in Cochrane review from CSR

R, IB, AP,

MC-I, Phase II

Ivermectin 0.1 % cream QD (51)

Ivermectin 0.3 % cream QD (47)

Ivermectin 1 % cream BID (48)

Ivermectin 1 % cream QD (52)

MET 0.75 % cream BID (48)

Vehicle (50)

Inflammatory lesion count

Success rate

Any AE, any TRAE, any SAE

Specific AEs: burning/stinging, skin irritation, worsening of erythema, worsening of rosacea

All cause withdrawals

Withdrawal due to AE

Both ivermectin 1 % cream QD and BID were effective and safe, with similar efficacy results between the two dosages. Compliance was enhanced by the ivermectin 1 % QD application for the treatment of papulopustular rosacea

RD.03.SPR.40173 (ATTRACT) (Galderma 2014; Taieb et al. 2015a, b)

Additional data not included in Cochrane review from CSR

R, IB, AC,

MC-I, Phase III

Ivermectin 1 % cream QD (478)

MET 0.75 % cream BID (484)

Inflammatory lesion count

Success rate

Ivermectin 1 % cream resulted in a statistically significant delayed and extended remission when compared to MET 0.75 % cream when used to treat papulopustular rosacea

Tan et al. (2002)

R, DB, PC, MC, PU

MET 1 % cream BID (61)

Vehicle (59)

Inflammatory lesion count

Any AE, any TRAE

Specific AEs: burning/stinging, worsening of erythema

All cause withdrawals

Withdrawal due to AE

The combined topical formulation of MET 1 % cream with sunscreen SPF 15 was effective and well tolerated for the treatment of patients with moderate-to-severe rosacea

Thiboutot et al. (2003)

R, DB, PC, MC, Phase III

Azelaic acid 15 % gel BID (164)

Vehicle (165)

Inflammatory lesion count

Success rate

Any AE

All cause withdrawals

Withdrawal due to AE

The results of these two controlled studies demonstrate that azelaic acid 15 % gel, used twice daily, is an efficacious, safe, and well-tolerated topical treatment for moderate papulopustular rosacea

Thiboutot et al. (2003)

R, DB, PC, MC, Phase III

Azelaic acid 15 % gel BID (169)

Vehicle (166)

Inflammatory lesion count

Success rate

Any AE

All cause withdrawals

Withdrawal due to AE

Thiboutot et al. (2008)

R, DB, DR, MC, PU

Azelaic acid 15 % gel BID (47)

Azelaic acid 15 % gel QD (45)

Inflammatory lesion count

Success rate

Any AE, any TRAE

Once-daily azelaic acid 15 % gel can be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of azelaic acid 15 % gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist

Torok et al. (2005)

R, DB, AC, MC, PU

Sodium sulfacetamide 10 % cream BID + sulfur 5 % cream BID (75)

MET 0.75 % cream BID (77)

Inflammatory lesion count

Any AE, any TRAE

All cause withdrawals

In patients without sulfur drug allergies, sodium sulfacetamide 10 % and sulfur 5 % cream with sunscreen offers greater efficacy than MET 0.75 % cream and has the added benefit of sun protection

Wolf et al. (2006)

R, IB, AC, MC, PU

Azelaic acid 15 % gel BID (78)

MET 1 % gel QD (82)

Success rate

MET 1 % gel and azelaic acid 15 % gel showed similar reductions in inflammatory lesion count and high success rates in both global severity and erythema in patients with moderate rosacea