Influence of Season on Efficacy and Tolerability of Tazarotene 0.045% Lotion for the Treatment of Acne

Abstract

Objective

The condition of the skin can vary due to weather fluctuations. Therefore, this post-hoc analysis evaluated efficacy and safety of tazarotene 0.045% lotion in warmer versus colder months.

Methods

In two Phase III, double-blind, 12-week studies, participants aged nine years or older with moderate-to-severe acne were randomized 1:1 to once-daily tazarotene or vehicle lotion. The pooled population (N=1,614) was stratified by randomization date (warmer=May to September; colder=October to April). Evaluations included inflammatory/noninflammatory lesion counts, treatment success, adverse events, and safety/tolerability.

Results

Tazarotene 0.045% lotion was similarly efficacious over colder and warmer months. Compared with vehicle, tazarotene demonstrated significantly greater least-squares mean absolute reductions from baseline to Week 12 in inflammatory (colder/warmer tazarotene vs. vehicle: –16.6/–15.8 vs. –13.2/–12.9) and noninflammatory lesions (–23.2/–22.6 vs. –17.5/–15.1); treatment success rates were also significantly higher (30.1/30.8% vs. 18.2/17.6%) (P<0.001, all). No strong seasonal trends in safety were observed, though tazarotene led to slightly more discontinuations (3.4% vs. 1.9%) and related adverse events (12.0% vs. 10.3%) in colder versus warmer months. Transient increases in scaling, erythema, and itching at Weeks 2 to 8 of tazarotene treatment were slightly higher in colder versus warmer months but returned to baseline/improved by Week 12.

Limitations

Geographical variation across study sites can lead to varying temperatures and humidity within the same months.

Conclusion

Tazarotene 0.045% lotion was efficacious and well tolerated for acne treatment, regardless of season. Year-round tolerability of tazarotene 0.045% lotion may be due to its lower tazarotene concentration and polymeric emulsion technology, which simultaneously delivers moisturizers/humectants/emollients to skin.

Although retinoids, such as tazarotene, are a mainstay of acne treatment, the associated cutaneous irritation and drying—especially with older formulations of tazarotene gel and cream1,2—could lead to poor adherence and negatively impact treatment success.3,4 Moreover, the skin’s susceptibility to irritation can vary by season due to fluctuations in environmental factors like temperature and humidity. In healthy adults, facial skin shows increased redness5–8 and scaliness,5,9 and a possible decrease in hydration6,10–13 in the winter months compared to summer. Further, skin lipid content, which is essential for maintaining skin barrier function, is reduced in colder weather.11,14 Accordingly, transepidermal water loss is greater,5–7,13 and response to skin irritants is exacerbated.15 While these seasonal skin changes could influence the cutaneous tolerability of topical retinoids, to our knowledge, there are no published studies examining if seasonal variation impacts the tolerability or efficacy of topical retinoids for acne treatment.

To reduce irritation, a polymeric emulsion lotion formulation with a lower concentration of tazarotene (0.045%) and with hydrating excipients was developed, which evenly distributes tazarotene on the surface of the skin. The vehicle lotion demonstrated rapid and sustained increases in skin moisturization and improved barrier function.16 Further, tazarotene 0.045% lotion appeared to deliver drug more efficiently into the skin compared to 0.1% cream.17 With the lotion, sufficient tazarotene penetrates to deeper skin levels to provide clinical effect while less drug remains at or near the skin surface, potentially reducing safety and tolerability concerns.17 In a Phase II clinical study, tazarotene 0.045% lotion resulted in fewer adverse events than tazarotene 0.1% cream while maintaining comparable efficacy.18 Phase III studies showed that tazarotene lotion was well tolerated and efficacious in the treatment of moderate-to-severe acne.19 This post-hoc analysis evaluated the efficacy and safety of tazarotene 0.045% lotion in warmer versus colder months.

METHODS

Study design and participants. These analyses included data pooled from two previously described Phase III, multicenter, double-blind, randomized, vehicle-controlled, parallel-group studies (NCT03168334 and NCT03168321).19 Briefly, eligible patients were aged nine years or older with moderate-to-severe acne (a score of 3 or 4 on the Evaluator's Global Severity Score [EGSS]) and inflammatory and noninflammatory lesion counts between 20 to 50 and 25 to 100, respectively, with up to two facial nodules. Participants were equally randomized to tazarotene 0.045% lotion or vehicle lotion applied to the face once daily for 12 weeks.

Studies were approved by relevant independent ethics committees or institutional review boards at each study site and were conducted in accordance with the International Conference on Harmonization, the Declaration of Helsinki, Good Clinical Practice Guidelines, and local regulations. All participants or their legal guardians provided written informed consent or assent.

Study assessments. For each study, efficacy evaluations included inflammatory and noninflammatory lesion counts and global treatment success (defined as the proportion of participants achieving ≥2-grade reduction from baseline in EGSS and a score of 0 [clear] or 1 [almost clear]). Safety evaluations comprised investigator-assessed cutaneous safety (scaling, erythema, hypopigmentation, hyperpigmentation) and participant-assessed tolerability (itching, burning, stinging) using a four-point scale (0=none to 3=severe). Adverse events (AEs) were also monitored throughout the studies.

Statistical and subgroup analysis. For this post-hoc analysis, the pooled population was stratified by randomization date into warmer (May–September) and colder month (October–April) groups in accordance with weather patterns of the study sites all located within the United States and Canada. The intent-to-treat (ITT) population was defined as all participants who were randomized and received study drug. The safety population included all randomized participants who used study drug at least once with a minimum of one post-baseline evaluation. Analyses included least-squares (LS) mean percent changes from baseline in inflammatory and noninflammatory lesion counts by visit and the percentage of participants achieving treatment success at Week 12. Because significant skewness was observed for lesion counts, a nonparametric method was used in which data were rank transformed prior to an analysis of covariance, with a factor of treatment and covariate of baseline lesion count. For all efficacy assessments, multiple imputation was used to impute missing values using the Markov Chain Monte Carlo method. All statistical analyses were performed using SAS® version 9.3 or later. Statistical significance was set at P<0.05.

Descriptive statistics were used to summarize cutaneous safety/tolerability assessments. AEs were recorded and classified using Medical Dictionary for Regulatory Activities terminology. Imputations were not made for missing safety data.

RESULTS

Of 1,614 participants in the pooled ITT population, treatment randomization dates occurred during the colder months for 975 (60.4%) and warmer months for 639 (39.6%) participants. In both colder and warmer month groups, compared to vehicle, tazarotene led to significantly greater absolute changes from baseline in inflammatory (colder/warmer tazarotene vs. vehicle: −16.6/−15.8 vs. –13.2/–12.9, P<0.001; Figure 1A) and noninflammatory lesions (–23.2/–22.6 vs. –17.5/–15.1, P<0.001; Figure 1A). Nearly one-third of participants treated with tazarotene achieved treatment success at Week 12 versus less than one-fifth with vehicle, regardless of season (colder/warmer: 30.1%/30.8% vs. 18.2%/17.6%, P<0.001 both; Figure 1B).

FIGURE 1.

Seasonal efficacy measures with tazarotene 0.045% lotion at Week 12 (ITT population, pooled). ***P<0.001 vs vehicle. aAt least a 2-grade improvement from baseline in EGSS and a score of 0 (clear) or 1 (almost clear). Colder months=October to April; Warmer months=May to September. Colder months: n=480 TAZ, 495 VEH; Warmer months: n=319 TAZ, 320 VEH. EGSS: Evaluator’s Global Severity Score; ITT: intent-to-treat; LS: least squares; TAZ: tazarotene 0.045% lotion; VEH: vehicle lotion.

In the colder months versus warmer months, tazarotene treatment led to slightly more discontinuations (3.4% vs. 1.9%) and related TEAEs (12.0% vs. 10.3%). The most common adverse events with tazarotene (in ≥2% of participants in any treatment group) occurred at the application site (colder vs warmer: pain [4.9% vs. 5.8%], dryness [3.6% vs. 4.2%], erythema [1.5% vs. 2.6%], and exfoliation [1.9% vs. 2.3%]). There were no notable seasonal differences in rates of burning, stinging, hyperpigmentation, and hypopigmentation (Figure 2 and data not shown). Transient increases in rates of scaling, erythema, and itching at Weeks 2 to 8 of tazarotene treatment were slightly higher in the colder months versus warmer months, though rates had returned to baseline or improved by Week 12 (Figure 2).

FIGURE 2.

Seasonal cutaneous safety and tolerability with tazarotene 0.045% lotion by visit (safety population). Data for participants who reported “none” are not shown. No imputation of missing data. There were no drug-related trends in hypo- and hyper-pigmentation; values at each week were similar to baseline (data not shown). Colder months=October to April; Warmer months=May to September. BL: baseline; Wk: week.

DISCUSSION

Tazarotene 0.045% lotion was efficacious and well tolerated in participants with moderate-to-severe acne across both warmer and colder months. Rates of the most common AEs with tazarotene treatment were similar between the seasons, though the slightly higher rates in the warmer versus colder months (≤1.1% difference) might be due to the relatively small sample sizes (warmer/colder n=319/480) or other seasonal differences (e.g., increased sun exposure or decreased moisturizer use during warmer months). Transient increases in rates of scaling, erythema, and itching were slightly greater in colder months, though there were no seasonal differences in rates of burning, stinging, hyperpigmentation, or hypopigmentation. Skin is more likely to be exposed to the drying effects of colder temperatures, lower humidity and forced-air heating in the winter months; this exposure may further exacerbate the cutaneous irritation that could occur with topical retinoid use, especially with older, less hydrating formulations. Concurrent moisturizer application, however, has been shown to prevent dryness and enhance tolerability of retinoids, including a cream formulation of tazarotene 0.1%.20,21 While participants in the Phase III studies were provided CeraVe® hydrating cleanser and moisturizing lotion (L’Oreal; New York, New York) as an option for cleansing and moisturization, the year-round tolerability of tazarotene 0.045% lotion might be due, in part, to its polymeric emulsion formulation, which simultaneously delivers moisturizers, humectants, and emollients along with the active ingredient.

Limitations. Three key limitations impact the interpretation of these clinical data. First, there was considerable geographical variation across study sites, ranging in latitude from southern Canada to the southeastern United States (Figure 3). Climates across these study sites can be classified as arid, cold, temperate, and tropical; this can lead to varying temperatures and humidity within the same season. For instance, warmer months at study sites in Oregon might be warm and dry, but those in Texas might be hot and humid. By collapsing data across these study sites with varied climates, the effects of true colder versus warmer months might be partially masked. Further, the difference between seasons may be less drastic in some study sites than others. To address these challenges, data could be stratified by climate zones based upon the geographic region of a study site. However, as study sites spanned over 10 climate zones, these additional stratifications would result in very low participant numbers per season in each region, precluding any meaningful conclusions on the possible effect of warmer versus colder months on the efficacy and safety of tazarotene 0.045% lotion. Second, inclusion of transitional months could minimize seasonal effects of very cold and very warm months. However, these transitional months were included in the winter season to capture additional timepoints in which drier and colder temperatures—even if not extreme—may impact drug tolerability. Third, in participants randomized to treatment around the transition of warmer to colder months or vice versa (i.e., September/April), tazarotene treatment would extend over both seasons as the lotion was applied once daily for twelve weeks. While this is an unavoidable source of bias, for 99.7 percent of study participants the randomization date and date of first dose were the same [randomization and dosing dates differed for five participants by one day (n=4) or 16 days (n=1)]. As most tolerability issues associated with retinoids, including tazarotene, are observed within the first few weeks of treatment, this suggests that any cutaneous tolerability issues observed would likely arise within the month during which randomization occurred. As such, the slight increase in transient cutaneous scaling, erythema, and itching in the colder months compared to warmer months may not be an artifact, but reflective of seasonal variation in tolerability. Finally, it is important to note that the tazarotene lotion Phase III studies were not powered to detect potential differences in efficacy in warmer versus colder months. Therefore, P values from the post-hoc analyses in this manuscript are for informative purposes only.

FIGURE 3.

Map of study sites used for analysis. United States study sites: Alabama, 1; Arkansas, 2; Arizona, 1; California, 11; Colorado, 2; Florida, 10; Georgia, 2; Idaho, 1; Illinois, 1; Indiana, 2; Kansas, 1; Kentucky, 2; Louisiana, 1; Maryland, 1; Michigan, 6; Minnesota, 1; North Carolina, 1; New Mexico, 1; New York, 5; Ohio, 2; Oklahoma, 1; Oregon,1; Pennsylvania, 2; Rhode Island, 2; Tennessee, 3; Texas, 10; Utah, 3; Virginia, 2; Washington, 2. Canadian study sites: British Columbia, 1; Manitoba, 1; Ontario, 5; Quebec, 2.

CONCLUSION

In these two pooled Phase III studies, tazarotene 0.045% lotion was well tolerated during both colder and warmer months, with significant acne improvements observed after 12 weeks of treatment regardless of the season. Tazarotene 0.045% polymeric emulsion lotion may be considered as an ideal treatment year-round for moderate-to-severe acne.