potentially minimizing irritation. With polymeric emulsion technology, the active ingredient and moisturizing/hydrating ingredients are encapsulated within oil droplets, which are uniformly dispersed within an oil-in-water emulsion separated by a three-dimensional mesh matrix. Once applied to the skin, the mesh instantly breaks apart, ensuring rapid, uniform, and simultaneous release of ingredients, thus improving delivery and clinical efficacy.2 This technology has the potential to overcome several limitations of conventional topical drug delivery, including limited skin delivery and local cutaneous irritation, the latter which is known to be associated with poor patient adherence. 19,20 Polymeric emulsion technology has been applied to tazarotene, resulting in a 0.045% lotion which may afford similar efficacy to the higher concentration tazarotene formulations indicated for acne (0.1%) while reducing the potential for skin irritation.
In a phase 2 study comparing tazarotene 0.045% lotion with tazarotene 0.1% cream and vehicle lotion or cream (to ensure blinding), tazarotene 0.045% lotion demonstrated statistically significant superiority to vehicle in reducing lesion counts at week 12 (P=0.013 for inflammatory; P<0.001 for noninflammatory lesions).21 At less than half the active concentration, tazarotene 0.045% lotion was also more effective than the 0.1% cream in reducing lesion counts and in achievement of treatment success, defined as having ≥2-grade improvement from baseline in the Evaluator’s Global Severity Score (EGSS), and an EGSS score equating to ‘clear’ or ‘almost clear’. Treatmentrelated adverse events AEs were more common for the 0.1% cream (5.6% versus 2.9% for the 0.045% lotion), the most common being application site pain (4.2% versus 2.9% for 0.045% lotion).
Subsequently, two identical phase 3 double-blind, randomized, vehicle-controlled 12-week clinical studies confirmed the efficacy and safety of tazarotene 0.045% lotion versus vehicle lotion in patients with moderate-to-severe acne.22 In both studies, tazarotene 0.045% lotion demonstrated statistically significant reductions in inflammatory and noninflammatory lesions, with a greater percentage of patients achieving treatment success at week 12 than those receiving vehicle (P<0.001, all). The data from these two studies were pooled to examine the safety and efficacy of tazarotene 0.045% lotion in patients with moderateto- severe acne.
In a phase 2 study comparing tazarotene 0.045% lotion with tazarotene 0.1% cream and vehicle lotion or cream (to ensure blinding), tazarotene 0.045% lotion demonstrated statistically significant superiority to vehicle in reducing lesion counts at week 12 (P=0.013 for inflammatory; P<0.001 for noninflammatory lesions).21 At less than half the active concentration, tazarotene 0.045% lotion was also more effective than the 0.1% cream in reducing lesion counts and in achievement of treatment success, defined as having ≥2-grade improvement from baseline in the Evaluator’s Global Severity Score (EGSS), and an EGSS score equating to ‘clear’ or ‘almost clear’. Treatmentrelated adverse events AEs were more common for the 0.1% cream (5.6% versus 2.9% for the 0.045% lotion), the most common being application site pain (4.2% versus 2.9% for 0.045% lotion).
Subsequently, two identical phase 3 double-blind, randomized, vehicle-controlled 12-week clinical studies confirmed the efficacy and safety of tazarotene 0.045% lotion versus vehicle lotion in patients with moderate-to-severe acne.22 In both studies, tazarotene 0.045% lotion demonstrated statistically significant reductions in inflammatory and noninflammatory lesions, with a greater percentage of patients achieving treatment success at week 12 than those receiving vehicle (P<0.001, all). The data from these two studies were pooled to examine the safety and efficacy of tazarotene 0.045% lotion in patients with moderateto- severe acne.
METHODS
Study Design and Patients
Detailed methods for the studies (NCT03168334 and NCT03168321) have been reported.22 In brief, each of the two identical multicenter, double-blind, randomized, vehicle-controlled, parallel-group phase 3 studies enrolled patients 9 years of age or older with moderate (EGSS 3) or severe (EGSS 4) acne at 89 study centers. Eligible participants also must have had 20-50 facial inflammatory lesions (papules, pustules, and nodules), 25-100 noninflammatory lesions (open and closed comedones), and two or less facial nodules.
Patients were randomized 1:1 to receive tazarotene 0.045% lotion or vehicle to be applied to the face once daily for 12 weeks. The study protocol was approved by institutional review boards or ethics committees at all investigational sites. Studies were carried out in accordance with principles of Good Clinical Practice (GCP) and the Declaration of Helsinki. All patients provided written informed consent.
Study Assessments
Efficacy evaluations included inflammatory and noninflammatory lesion counts and treatment success, defined as the proportion of patients achieving ≥2-grade reduction from baseline in EGSS and a score of ‘clear’ (0) or ‘almost clear’ (1). Assessments were performed at screening, baseline, and weeks 2, 4, 8, and 12 (end of treatment). At baseline and week 12, patients also completed an Acne Specific Quality of Life (Acne-QoL) questionnaire covering four different domains (selfperception, role-emotional, role-social, and acne symptoms); higher scores for each domain reflect improved health-related QoL. Cutaneous safety (scaling, erythema, hypopigmentation, hyperpigmentation) was evaluated by investigators using a 4-point scale where 0=none and 3=severe. Tolerability (itching, burning, stinging) was reported by patients at all post-screening visits. AEs were evaluated throughout the study.
Statistical Analysis
The co-primary endpoints for the individual studies were the percentage of patients achieving treatment success at week 12 and absolute reductions from baseline to week 12 in inflammatory and noninflammatory lesion counts. The intent-to-treat (ITT) population consisted of all patients who were randomized and provided with study drug. The safety population was defined as all randomized patients who were presumed to have used study medication or vehicle at least once and who had at least one post-baseline evaluation.
For pooled study analyses of the mean percent changes from baseline in noninflammatory and inflammatory lesion counts, significant skewness was observed; as such, a nonparametric method was used in which the data were rank transformed prior to the analysis of covariance (ANCOVA), with factor of treatment and the respective baseline lesion count as a covariate. EGSS reductions were analyzed via logistic regression using Firth’s Penalized Likelihood with a factor of treatment group. Values were adjusted for multiple imputations. Missing efficacy data was handled based on estimation using the Markov Chain Monte Carlo multiple imputation method. Results of the Acne-QoL questionnaire were summarized using descriptive statistics with no imputation of missing values.
Detailed methods for the studies (NCT03168334 and NCT03168321) have been reported.22 In brief, each of the two identical multicenter, double-blind, randomized, vehicle-controlled, parallel-group phase 3 studies enrolled patients 9 years of age or older with moderate (EGSS 3) or severe (EGSS 4) acne at 89 study centers. Eligible participants also must have had 20-50 facial inflammatory lesions (papules, pustules, and nodules), 25-100 noninflammatory lesions (open and closed comedones), and two or less facial nodules.
Patients were randomized 1:1 to receive tazarotene 0.045% lotion or vehicle to be applied to the face once daily for 12 weeks. The study protocol was approved by institutional review boards or ethics committees at all investigational sites. Studies were carried out in accordance with principles of Good Clinical Practice (GCP) and the Declaration of Helsinki. All patients provided written informed consent.
Study Assessments
Efficacy evaluations included inflammatory and noninflammatory lesion counts and treatment success, defined as the proportion of patients achieving ≥2-grade reduction from baseline in EGSS and a score of ‘clear’ (0) or ‘almost clear’ (1). Assessments were performed at screening, baseline, and weeks 2, 4, 8, and 12 (end of treatment). At baseline and week 12, patients also completed an Acne Specific Quality of Life (Acne-QoL) questionnaire covering four different domains (selfperception, role-emotional, role-social, and acne symptoms); higher scores for each domain reflect improved health-related QoL. Cutaneous safety (scaling, erythema, hypopigmentation, hyperpigmentation) was evaluated by investigators using a 4-point scale where 0=none and 3=severe. Tolerability (itching, burning, stinging) was reported by patients at all post-screening visits. AEs were evaluated throughout the study.
Statistical Analysis
The co-primary endpoints for the individual studies were the percentage of patients achieving treatment success at week 12 and absolute reductions from baseline to week 12 in inflammatory and noninflammatory lesion counts. The intent-to-treat (ITT) population consisted of all patients who were randomized and provided with study drug. The safety population was defined as all randomized patients who were presumed to have used study medication or vehicle at least once and who had at least one post-baseline evaluation.
For pooled study analyses of the mean percent changes from baseline in noninflammatory and inflammatory lesion counts, significant skewness was observed; as such, a nonparametric method was used in which the data were rank transformed prior to the analysis of covariance (ANCOVA), with factor of treatment and the respective baseline lesion count as a covariate. EGSS reductions were analyzed via logistic regression using Firth’s Penalized Likelihood with a factor of treatment group. Values were adjusted for multiple imputations. Missing efficacy data was handled based on estimation using the Markov Chain Monte Carlo multiple imputation method. Results of the Acne-QoL questionnaire were summarized using descriptive statistics with no imputation of missing values.
