Original Research

A Phase 3 Randomized, Double-blind, Vehicle-Controlled Trial of Azelaic Acid Foam 15% in the Treatment of Papulopustular Rosacea

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Rosacea is a chronic relapsing skin disorder primarily affecting the face. Although its etiology is not well defined, rosacea is associated with immune dysregulation and inflammation potentiated by external factors. These manifestations lead to skin sensitivity and impaired quality of life. Azelaic acid (AzA) is approved for the treatment of rosacea in a 15% gel formulation. This phase 3 study evaluated the efficacy and safety of AzA in a 15% foam formulation for the treatment of papulopustular rosacea (PPR). Coprimary efficacy end points were treatment success according to investigator global assessment (IGA) and the nominal change in inflammatory lesion count (ILC) from baseline to the end of treatment (EoT). Adverse events (AEs) were evaluated as a measure of safety. The IGA success rate at EoT was significantly greater in the AzA foam group versus vehicle (P<.001; Cochran-Mantel-Haenszel test). Likewise, nominal ILC change at EoT in the AzA foam group showed a significantly greater decrease versus vehicle (P<.001; F test). Drug-related AEs were mainly mild to moderate, cutaneous, and local. Overall, the study results support the efficacy and safety of twice-daily AzA foam 15% in patients with PPR.


 

References

Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.3 Reports of the gender distribution of the disease vary but often show female predominance.4 Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.1

The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.5 Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.2 These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.6 The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.2

Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.7

Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.8 Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).9 Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.10 Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.11 Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.12

In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.16

Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.17 Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.18 In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.19 The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.

We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.8

Methods

Study Design

This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.

Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.

The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.

Efficacy Evaluations

There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.

The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.

Safety

Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).

Statistical Analysis

Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)

Results

Study Participants

Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.

Figure 1. Study disposition and reasons for study discontinuation. Percentages of participants who discontinued prior to treatment randomization are based on the number of patients screened, whereas all other percentages are based on the number of participants randomized. After completion of treatment, all participants (including those who prematurely discontinued treatment) were invited to enter the follow-up phase.

Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.

Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.

Efficacy

Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.

Figure 2. Percentages of participants who had successful treatment outcomes based on investigator global assessment scores (clear or minimal) at weeks 4, 8, 12, and 16 (FU). P values were calculated from the Pearson c² test. Last observation carried forward was not applied to FU analysis. EoT indicates end of treatment; FU, after 4 weeks of follow-up without treatment.
Figure 3. Mean nominal change in inflammatory lesion count from baseline at weeks 4, 8, 12, and 16 (FU). P values were calculated from 2-sided t tests. Last observation carried forward was not applied to FU analysis. SD indicates standard deviation; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).

Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.

Safety

Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.

The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).

All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.

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