into skin, thus resulting in an efficient and clinically effective delivery system. This formulation approach has been used to develop tazarotene 0.045% lotion, providing uniform distribution of tazarotene onto the skin and providing a more efficient delivery into the epidermis; which may afford similar efficacy to the higher concentrations of tazarotene formulations currently available (gel, foam, and cream) while reducing the irritation potential.
In a phase 2 comparative study with tazarotene 0.045% lotion versus tazarotene 0.1% cream, tazarotene 0.045% lotion demonstrated statistically significant superiority to vehicle in reducing inflammatory and noninflammatory lesion counts (P=0.013 and P<.001) at week 12.15 At less than half the concentration, tazarotene 0.045% lotion was numerically more effective than tazarotene 0.1% cream in terms of reduction in lesion counts and treatment success. Treatment Emergent Adverse Events (TEAEs) were twice as common with tazarotene 0.1% cream (26.8% versus 14.7% with tazarotene 0.045% lotion and 13.4% with vehicle) and there were also more treatmentrelated AEs with tazarotene 0.1% cream (5.6% versus 2.9%); most common being application site pain (4.2%) which is likely a manifestation of irritation.
Here we present data from two large multicentred, doubleblind vehicle-controlled studies of tazarotene 0.045% lotion in subjects with moderate or severe acne.
In a phase 2 comparative study with tazarotene 0.045% lotion versus tazarotene 0.1% cream, tazarotene 0.045% lotion demonstrated statistically significant superiority to vehicle in reducing inflammatory and noninflammatory lesion counts (P=0.013 and P<.001) at week 12.15 At less than half the concentration, tazarotene 0.045% lotion was numerically more effective than tazarotene 0.1% cream in terms of reduction in lesion counts and treatment success. Treatment Emergent Adverse Events (TEAEs) were twice as common with tazarotene 0.1% cream (26.8% versus 14.7% with tazarotene 0.045% lotion and 13.4% with vehicle) and there were also more treatmentrelated AEs with tazarotene 0.1% cream (5.6% versus 2.9%); most common being application site pain (4.2%) which is likely a manifestation of irritation.
Here we present data from two large multicentred, doubleblind vehicle-controlled studies of tazarotene 0.045% lotion in subjects with moderate or severe acne.
METHODS
Study Design
Two multicenter, double-blind, randomized, vehicle-controlled, parallel-group phase 3 studies to assess safety, tolerability, and efficacy of tazarotene 0.045% lotion in subjects with moderate or severe acne (with an Evaluator’s Global Severity Score [EGSS] of 3 [moderate] or 4 [severe]). Treatment was topically applied once-daily to the face, excluding mouth, eyes, inside the nose, and lips. Power calculations were computed using the results from the phase 2 study.15 Active and vehicle were identical formulations, with the absence of tazarotene in the vehicle comparator, with identical physical appearance and packaging to ensure blinding.
Studies were registered on clinicaltrials.gov NCT03168334 and NCT03168321, conducted at 89 clinical sites in the United States and Canada from June 2017 to July 2018.
Subjects and Randomization
Key inclusion criteria included subjects of either gender, 9 years or older with moderate (EGSS=3) or severe (EGSS=4) acne. Specifically, subjects had 20-50 facial inflammatory lesions (papules, pustules, and nodules), 25-100 noninflammatory lesions (open and closed comedones) and two or less facial nodules. A washout period of up to 1 month was required for patients who used previous prescription and over-the-counter acne treatments longer for systemic retinoids. Specifically, the following mandatory washout periods and restrictions applied to these topical and systemic treatments: topical astringents and abrasives (1 week); topical anti-acne products, including soaps containing antimicrobials, and known comedogenic products (2 weeks); topical retinoids, retinol, and systemic acne treatments, such as hormonal or antibiotic treatments (4 weeks); and systemic retinoids (6 months). Approximately 1600 subjects (800 in each study) were planned for enrollment.
Study drug kits were assigned based on a randomization code. Subjects were randomized (1:1) to receive tazarotene 0.045% lotion or vehicle applied topically to the face once daily for 12 weeks. The initial topical application was made at the investigational center. Subjects were asked to apply their daily treatment in the evening at home. During the studies, each subject was permitted to use only approved cleansers, moisturizers, and sunscreens, and noncomedogenic makeup and shaving products. Investigators were trained thoroughly to ensure consistency in the evaluation of the subjects for lesion count and EGSS. Assessments were carried out at screening, baseline, weeks 2, 4, 8, and 12 (end of treatment). The EGSS was determined prior to performing lesion counts. Subjects also completed an Acne- Specific Quality of Life (Acne-QoL) questionnaire and were asked to answer questions pertaining to their QoL as it related to their facial acne at baseline and at week 12.
Study Oversight
Subjects provided written informed consent before study-related procedures were performed; protocol and consent were approved by institutional review boards (IRBs) or ethics committees at all investigational sites. The studies were conducted in accordance with the principles of Good Clinical Practice (GCP) and Declaration of Helsinki.
Statistical and Analytical Plan
The intent-to-treat (ITT) population comprised all subjects randomized and provided with study drug. The safety population comprised all randomized subjects who were presumed to have used the study medication or vehicle at least once and who had at least one post baseline evaluation. The primary method of handling missing efficacy data in the ITT analysis set was based on estimation using the Markov Chain Monte Carlo multiple imputation method. For analyses of the changes from baseline in noninflammatory and inflammatory lesion counts in both pivotal phase 3 studies, significant skewness was observed, and a nonparametric method used in which the changes in lesion counts were rank-transformed prior to being submitted to the ANCOVA. Values were adjusted for multiple imputations. Significance of EGSS reductions were obtained from logistic regression (using Firth’s Penalized Likelihood) with factors of
Two multicenter, double-blind, randomized, vehicle-controlled, parallel-group phase 3 studies to assess safety, tolerability, and efficacy of tazarotene 0.045% lotion in subjects with moderate or severe acne (with an Evaluator’s Global Severity Score [EGSS] of 3 [moderate] or 4 [severe]). Treatment was topically applied once-daily to the face, excluding mouth, eyes, inside the nose, and lips. Power calculations were computed using the results from the phase 2 study.15 Active and vehicle were identical formulations, with the absence of tazarotene in the vehicle comparator, with identical physical appearance and packaging to ensure blinding.
Studies were registered on clinicaltrials.gov NCT03168334 and NCT03168321, conducted at 89 clinical sites in the United States and Canada from June 2017 to July 2018.
Subjects and Randomization
Key inclusion criteria included subjects of either gender, 9 years or older with moderate (EGSS=3) or severe (EGSS=4) acne. Specifically, subjects had 20-50 facial inflammatory lesions (papules, pustules, and nodules), 25-100 noninflammatory lesions (open and closed comedones) and two or less facial nodules. A washout period of up to 1 month was required for patients who used previous prescription and over-the-counter acne treatments longer for systemic retinoids. Specifically, the following mandatory washout periods and restrictions applied to these topical and systemic treatments: topical astringents and abrasives (1 week); topical anti-acne products, including soaps containing antimicrobials, and known comedogenic products (2 weeks); topical retinoids, retinol, and systemic acne treatments, such as hormonal or antibiotic treatments (4 weeks); and systemic retinoids (6 months). Approximately 1600 subjects (800 in each study) were planned for enrollment.
Study drug kits were assigned based on a randomization code. Subjects were randomized (1:1) to receive tazarotene 0.045% lotion or vehicle applied topically to the face once daily for 12 weeks. The initial topical application was made at the investigational center. Subjects were asked to apply their daily treatment in the evening at home. During the studies, each subject was permitted to use only approved cleansers, moisturizers, and sunscreens, and noncomedogenic makeup and shaving products. Investigators were trained thoroughly to ensure consistency in the evaluation of the subjects for lesion count and EGSS. Assessments were carried out at screening, baseline, weeks 2, 4, 8, and 12 (end of treatment). The EGSS was determined prior to performing lesion counts. Subjects also completed an Acne- Specific Quality of Life (Acne-QoL) questionnaire and were asked to answer questions pertaining to their QoL as it related to their facial acne at baseline and at week 12.
Study Oversight
Subjects provided written informed consent before study-related procedures were performed; protocol and consent were approved by institutional review boards (IRBs) or ethics committees at all investigational sites. The studies were conducted in accordance with the principles of Good Clinical Practice (GCP) and Declaration of Helsinki.
Statistical and Analytical Plan
The intent-to-treat (ITT) population comprised all subjects randomized and provided with study drug. The safety population comprised all randomized subjects who were presumed to have used the study medication or vehicle at least once and who had at least one post baseline evaluation. The primary method of handling missing efficacy data in the ITT analysis set was based on estimation using the Markov Chain Monte Carlo multiple imputation method. For analyses of the changes from baseline in noninflammatory and inflammatory lesion counts in both pivotal phase 3 studies, significant skewness was observed, and a nonparametric method used in which the changes in lesion counts were rank-transformed prior to being submitted to the ANCOVA. Values were adjusted for multiple imputations. Significance of EGSS reductions were obtained from logistic regression (using Firth’s Penalized Likelihood) with factors of
