were conducted in accordance with local and regulatory requirements and the principles set forth in the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.
Cumulative Skin Irritation Trial
Following once-daily application for 21 days of tapinarof cream 1%, vehicle, 0.2% sodium lauryl sulfate (SLS, positive control), and 0.9% saline (negative control) to randomly assigned test application sites (Table 1), dermal reactions at application sites were assessed clinically using a visual scale that rated the degree of erythema, edema, and other signs of cutaneous irritation (Supplementary Table S1). The primary outcome was mean cumulative irritation score (mean of observed scores for day 2 through day 22). The total cumulative irritation score for each participant and treatment was also calculated as the sum of irritation scores, and interpreted using a normalized scale ranging from 0 to 630, where higher scores denote greater potential for cumulative irritation under test conditions (Supplementary Table S2).14
Skin Sensitization Trial
This trial comprised an induction phase of repeated applications of tapinarof cream 1%, vehicle, and 0.9% saline; a rest period; and a single application challenge phase (Table 1). Dermal sensitization potential was determined by the Investigator based on specific scoring criteria derived from observed responses after challenge (Supplementary Table S1). A rechallenge was performed if a cutaneous response observed during the challenge phase indicated possible sensitization, or at the discretion of the investigator. Mean and total irritancy scores were also assessed, during the induction phase, using the same scale used in the cumulative skin irritation trial (Supplementary Table S1).
Photoallergy Trial
This trial comprised an induction phase of repeated applications of tapinarof cream 1% and vehicle, followed by a rest period and a single-application challenge phase, with irradiation of selected sites performed to assess photosensitization (Table 1). Sites were clinically examined for dermal reactions after the induction phase at approximately 48 and 72 hours post-irradiation and after the challenge phase application at approximately 24, 48, and 72 hours post-irradiation using a visual scale that rated the degree of erythema, edema, and other signs of cutaneous irritation (Supplementary Table S3). A rechallenge was performed if a cutaneous response was observed during the challenge phase that indicated possible photosensitization, or at the discretion of the Investigator.
Phototoxicity Trial
Following a single application of tapinarof cream 1% and vehicle (day 1) and irradiation of selected sites (day 2; Table 1), application sites and the untreated (irradiated) control site were evaluated on days 3 and 4, approximately 24 and 48 hours after irradiation, respectively, using the same visual scale used in the photoallergy trial (Supplementary Table S3).
Statistical Analysis
For all studies, assigned scores were summarized using descriptive statistics. For the cumulative skin irritation trial, pairwise comparisons for cumulative irritancy scores were conducted using Fisher's protected least significant differences with a 2-way analysis of variance (ANOVA), including main effects of participant and product, without interaction. For the phototoxicity trial, pairwise comparisons for average numerical dermal response score (sum of erythema and edema) at 24 and 48 hours after irradiation were conducted with an ANOVA using Fisher’s least significant differences, with effects of participant and treatment.
Cumulative Skin Irritation Trial
Following once-daily application for 21 days of tapinarof cream 1%, vehicle, 0.2% sodium lauryl sulfate (SLS, positive control), and 0.9% saline (negative control) to randomly assigned test application sites (Table 1), dermal reactions at application sites were assessed clinically using a visual scale that rated the degree of erythema, edema, and other signs of cutaneous irritation (Supplementary Table S1). The primary outcome was mean cumulative irritation score (mean of observed scores for day 2 through day 22). The total cumulative irritation score for each participant and treatment was also calculated as the sum of irritation scores, and interpreted using a normalized scale ranging from 0 to 630, where higher scores denote greater potential for cumulative irritation under test conditions (Supplementary Table S2).14
Skin Sensitization Trial
This trial comprised an induction phase of repeated applications of tapinarof cream 1%, vehicle, and 0.9% saline; a rest period; and a single application challenge phase (Table 1). Dermal sensitization potential was determined by the Investigator based on specific scoring criteria derived from observed responses after challenge (Supplementary Table S1). A rechallenge was performed if a cutaneous response observed during the challenge phase indicated possible sensitization, or at the discretion of the investigator. Mean and total irritancy scores were also assessed, during the induction phase, using the same scale used in the cumulative skin irritation trial (Supplementary Table S1).
Photoallergy Trial
This trial comprised an induction phase of repeated applications of tapinarof cream 1% and vehicle, followed by a rest period and a single-application challenge phase, with irradiation of selected sites performed to assess photosensitization (Table 1). Sites were clinically examined for dermal reactions after the induction phase at approximately 48 and 72 hours post-irradiation and after the challenge phase application at approximately 24, 48, and 72 hours post-irradiation using a visual scale that rated the degree of erythema, edema, and other signs of cutaneous irritation (Supplementary Table S3). A rechallenge was performed if a cutaneous response was observed during the challenge phase that indicated possible photosensitization, or at the discretion of the Investigator.
Phototoxicity Trial
Following a single application of tapinarof cream 1% and vehicle (day 1) and irradiation of selected sites (day 2; Table 1), application sites and the untreated (irradiated) control site were evaluated on days 3 and 4, approximately 24 and 48 hours after irradiation, respectively, using the same visual scale used in the photoallergy trial (Supplementary Table S3).
Statistical Analysis
For all studies, assigned scores were summarized using descriptive statistics. For the cumulative skin irritation trial, pairwise comparisons for cumulative irritancy scores were conducted using Fisher's protected least significant differences with a 2-way analysis of variance (ANOVA), including main effects of participant and product, without interaction. For the phototoxicity trial, pairwise comparisons for average numerical dermal response score (sum of erythema and edema) at 24 and 48 hours after irradiation were conducted with an ANOVA using Fisher’s least significant differences, with effects of participant and treatment.
