RESULTS
Participant Disposition and Demographics
Participant disposition is shown in Supplementary Table S4. Across the 4 trials, a total of 376 participants were randomized, with a low discontinuation rate (5.1%). In the cumulative skin irritation and skin sensitization trials, all 15 discontinuations were due to voluntary withdrawal by the participants. Among the participants who discontinued from the photoallergy trial, 2 discontinued due to AEs that were not deemed to be treatment related and 2 voluntarily withdrew from the trial. There were no discontinuations in the phototoxicity trial. Baseline demographics and characteristics are shown in Supplementary Table S5.
Cumulative Skin Irritation
Of 57 screened participants, 45 were randomized. At baseline, the mean age was 49.9 years and the majority of participants had Fitzpatrick skin types III to V ([III (22.2%), IV (31.1%), and V (26.7%)] (Supplementary Table S5). From baseline through day 22 (n=21 applications), the mean irritation score was 0.92 for tapinarof cream 1%, 0.02 for vehicle (P<0.0001 vs tapinarof), and 0.10 for 0.9% saline (P<0.0001 vs tapinarof) (Table 2). The total irritation score was 19.28 for tapinarof cream 1%, 0.49 for vehicle (P<0.0001 vs tapinarof), and 2.03 for 0.9% saline (P<0.0001 vs tapinarof). The positive control, 0.2% SLS, had significantly higher mean irritation (2.45) and total irritation (51.38) scores compared with tapinarof, vehicle, and 0.9% saline (P<0.0001 for all comparisons). The normalized total score, which is measured on a scale of 0 to 630, was 193 for tapinarof cream 1% (slight potential for very mild cumulative irritation under test conditions), 5 for vehicle (no significant irritation under test conditions), 20 for 0.9% saline (no significant irritation under test conditions), and 514 for 0.2% SLS (strong potential for mild-to-moderate cumulative irritation under test conditions; Supplementary Table S2).16
Skin Sensitization
Of 260 screened participants, 240 were randomized. At baseline, the mean age was 54.6 years and the majority of participants had Fitzpatrick skin type IV (37.9%) or V (35.0%) (Supplementary Table S5).
During the challenge phase, no reactions experienced by participants were classified as indicative of sensitization to tapinarof cream 1% (Table 3). For tapinarof cream 1%, 38.7% of participants (89/230) had a maximum score of 1, 1.7% (4/230) had a maximum score of 2, and 0.4% (1/230) had a maximum score of 3. No participant required a rechallenge phase patch application.
Photoallergy
Of 64 screened participants, 58 were randomized. At baseline, the mean age was 50.4 years and all participants had Fitzpatrick skin types II or III, with 58.6% having type III (Supplementary Table S5).
During the challenge phase, no evidence of photosensitization was observed. The maximum dermal response observed was a score of 1 (mild erythema/edema) for sites treated with tapinarof cream 1% or vehicle at 24, 48, and 72 hours for both irradiated and non-irradiated sites (Table 4). The maximum dermal response score with tapinarof cream 1% and vehicle was mainly attributed to properties of the vehicle, as supported by similar scores between the irradiated and non-irradiated test sites.
Phototoxicity
Of 39 screened participants, 33 were randomized. At baseline, the mean age was 48.5 years, and all participants had Fitzpatrick skin types II or III, with 75.8% having type III (Supplementary Table S5).
No evidence of phototoxicity was observed. The mean dermal response score (average of 24 and 48 hours) was lower in the tapinarof cream 1% irradiated site compared with the vehicle irradiated site and the untreated irradiated site (0.14, 0.17, and 0.20, respectively); however, these differences were not statistically significant (Table 4). At 24 hours post-irradiation, a maximum dermal response score of 1 (mild erythema/edema) was observed for 27.3% (9/33) of participants at the tapinarof cream 1% sites. At 48 hours post-irradiation, no participants had a maximal dermal response score of >1 at the tapinarof cream 1% sites compared with 1 participant (3.0%) at the vehicle irradiated site and 1 participant (3.0%) at the untreated irradiated site. All 3 irradiated sites had significantly higher mean dermal
Participant disposition is shown in Supplementary Table S4. Across the 4 trials, a total of 376 participants were randomized, with a low discontinuation rate (5.1%). In the cumulative skin irritation and skin sensitization trials, all 15 discontinuations were due to voluntary withdrawal by the participants. Among the participants who discontinued from the photoallergy trial, 2 discontinued due to AEs that were not deemed to be treatment related and 2 voluntarily withdrew from the trial. There were no discontinuations in the phototoxicity trial. Baseline demographics and characteristics are shown in Supplementary Table S5.
Cumulative Skin Irritation
Of 57 screened participants, 45 were randomized. At baseline, the mean age was 49.9 years and the majority of participants had Fitzpatrick skin types III to V ([III (22.2%), IV (31.1%), and V (26.7%)] (Supplementary Table S5). From baseline through day 22 (n=21 applications), the mean irritation score was 0.92 for tapinarof cream 1%, 0.02 for vehicle (P<0.0001 vs tapinarof), and 0.10 for 0.9% saline (P<0.0001 vs tapinarof) (Table 2). The total irritation score was 19.28 for tapinarof cream 1%, 0.49 for vehicle (P<0.0001 vs tapinarof), and 2.03 for 0.9% saline (P<0.0001 vs tapinarof). The positive control, 0.2% SLS, had significantly higher mean irritation (2.45) and total irritation (51.38) scores compared with tapinarof, vehicle, and 0.9% saline (P<0.0001 for all comparisons). The normalized total score, which is measured on a scale of 0 to 630, was 193 for tapinarof cream 1% (slight potential for very mild cumulative irritation under test conditions), 5 for vehicle (no significant irritation under test conditions), 20 for 0.9% saline (no significant irritation under test conditions), and 514 for 0.2% SLS (strong potential for mild-to-moderate cumulative irritation under test conditions; Supplementary Table S2).16
Skin Sensitization
Of 260 screened participants, 240 were randomized. At baseline, the mean age was 54.6 years and the majority of participants had Fitzpatrick skin type IV (37.9%) or V (35.0%) (Supplementary Table S5).
During the challenge phase, no reactions experienced by participants were classified as indicative of sensitization to tapinarof cream 1% (Table 3). For tapinarof cream 1%, 38.7% of participants (89/230) had a maximum score of 1, 1.7% (4/230) had a maximum score of 2, and 0.4% (1/230) had a maximum score of 3. No participant required a rechallenge phase patch application.
Photoallergy
Of 64 screened participants, 58 were randomized. At baseline, the mean age was 50.4 years and all participants had Fitzpatrick skin types II or III, with 58.6% having type III (Supplementary Table S5).
During the challenge phase, no evidence of photosensitization was observed. The maximum dermal response observed was a score of 1 (mild erythema/edema) for sites treated with tapinarof cream 1% or vehicle at 24, 48, and 72 hours for both irradiated and non-irradiated sites (Table 4). The maximum dermal response score with tapinarof cream 1% and vehicle was mainly attributed to properties of the vehicle, as supported by similar scores between the irradiated and non-irradiated test sites.
Phototoxicity
Of 39 screened participants, 33 were randomized. At baseline, the mean age was 48.5 years, and all participants had Fitzpatrick skin types II or III, with 75.8% having type III (Supplementary Table S5).
No evidence of phototoxicity was observed. The mean dermal response score (average of 24 and 48 hours) was lower in the tapinarof cream 1% irradiated site compared with the vehicle irradiated site and the untreated irradiated site (0.14, 0.17, and 0.20, respectively); however, these differences were not statistically significant (Table 4). At 24 hours post-irradiation, a maximum dermal response score of 1 (mild erythema/edema) was observed for 27.3% (9/33) of participants at the tapinarof cream 1% sites. At 48 hours post-irradiation, no participants had a maximal dermal response score of >1 at the tapinarof cream 1% sites compared with 1 participant (3.0%) at the vehicle irradiated site and 1 participant (3.0%) at the untreated irradiated site. All 3 irradiated sites had significantly higher mean dermal
