Kaweh Shakery, MD

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.