A phase 2b, randomized, double-blind, multicenter, vehicle-controlled study to assess the efficacy and safety of two crisaborole regimens in Japanese patients aged 2 years and older with mild-to-moderate atopic dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, xerosis, and eczematous lesions. In Japan, treatment options, such as topical corticosteroids and tacrolimus, are associated with efficacy and safety concerns. Crisaborole ointment, 2%, is a topical non-steroidal anti-inflammatory agent approved in several countries for the treatment of mild-to-moderate AD. This phase 2b, randomized, double-blind study (NCT03954158) assessed the efficacy and safety of two crisaborole regimens versus vehicle in the treatment of Japanese patients aged ≥2 years with mild-to-moderate AD. Each patient was assigned to one of two age cohorts (≥12 or 2-11 years) and randomized to crisaborole once daily (QD) or twice daily (BID). All patients had two target lesions that were each randomly assigned to crisaborole or vehicle at baseline and treated for 2 weeks. The primary endpoint was change from baseline in total sign score (TSS) in crisaborole- or vehicle-treated target lesions on day 15, and secondary endpoints included change from baseline in Investigator's Static Global Assessment (ISGA) and pruritic assessments (Cohort 1: peak pruritus numeric rating scale [NRS]; Cohort 2: Itch Severity Scale Self-Report and Caregiver-Reported Itch Severity NRS) and incidence of treatment-emergent adverse events (TEAEs). This study comprised 81 patients (Cohort 1: n = 41; Cohort 2: n = 40). Crisaborole-treated lesions showed statistically significant reductions in TSS versus vehicle-treated lesions at day 15 (p < 0.01), and numerically larger decreases in TSS were observed with crisaborole BID versus crisaborole QD in both cohorts. Furthermore, crisaborole-treated lesions generally demonstrated greater decreases in ISGA, peak pruritus NRS, Itch Severity Scale, and Caregiver-Reported Itch Severity NRS versus vehicle-treated lesions irrespective of regimen or cohort. Overall, TEAEs were mild; the most frequently reported TEAEs was application site irritation. In summary, both crisaborole regimens, particularly crisaborole BID, demonstrated efficacy and were well tolerated.

Keywords: Japan; atopic dermatitis; clinical trial; pruritus; safety.

FIGURE 1

Mean change (SE) from baseline to day 8 and day 15 in TSS for intrapatient comparison of crisaborole 2% QD and BID versus vehicle in (a,b) Cohort 1 and (c,d) Cohort 2 (full analysis set).^†,‡ *p < 0.05 and **p < 0.01 for intrapatient comparison of crisaborole 2% vs vehicle based on MMRM. ^†MMRM includes the fixed effect of visit, and an unstructured covariance structure was used. ^‡Adjustments for multiplicity were not conducted at day 8. BID, twice daily; MMRM, mixed‐effect model for repeated measures; QD, once daily; SE, standard error; TSS, total sign score

FIGURE 2

LSM change (SE) from baseline to day 8 and day 15 in TSS for patients receiving crisaborole 2% QD or crisaborole 2% BID in (a) Cohort 1 and (b) Cohort 2 (full analysis set).^{†,‡ †}Nominal p ≥ 0.05 for interpatient comparisons of crisaborole 2% BID vs crisaborole 2% QD in Cohort 1 and Cohort 2 based on MMRM at days 8 and 15. ^‡MMRM includes the fixed effects of dosing regimen, visit, dosing regimen‐by‐visit interaction, and baseline value, and an unstructured covariance structure was used. BID, twice daily; LSM, least squares mean; MMRM, mixed‐effect model for repeated measures; QD, once daily; SE, standard error; TSS, total sign score

FIGURE 3

Mean change (SE) from baseline up to day 15 in peak pruritus NRS for patients aged ≥12 years (Cohort 1) receiving (a) crisaborole 2% QD or (b) crisaborole 2% BID versus vehicle (full analysis set).^{†,‡ †}Nominal *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 for intrapatient comparison of crisaborole 2% vs vehicle based on MMRM. ^‡MMRM includes the fixed effect of visit, and an unstructured covariance structure was used. BID, twice daily; MMRM, mixed‐effect model for repeated measures; NRS, numeric rating scale; QD, once daily; SE, standard error

FIGURE 4

LSM change (SE) from baseline up to day 15 in peak pruritus NRS for patients aged ≥12 years (Cohort 1) receiving crisaborole 2% QD or crisaborole 2% BID (full analysis set). ^{†,‡ †}Nominal p ≥ 0.05 for interpatient comparisons of crisaborole 2% BID versus crisaborole 2% QD based on MMRM from baseline to day 15. ^‡MMRM includes the fixed effects of dosing regimen, day, dosing regimen‐by‐day interaction, and baseline value, and an unstructured covariance structure was used. BID, twice daily; LSM, least squares mean; MMRM, mixed‐effect model for repeated measures; NRS, numeric rating scale; QD, once daily; SE, standard error

FIGURE 5

Mean change (SE) from baseline up to day 15 in Itch Severity Scale for patients aged 6–11 years (Cohort 2) receiving (a) crisaborole 2% QD or (b) crisaborole 2% BID versus vehicle (full analysis set).^{†,‡ †}Nominal *p < 0.05 for intrapatient comparison of crisaborole 2% versus vehicle based on MMRM. ^‡MMRM includes the fixed effect of visit, and an unstructured covariance structure for (a) and first‐order autoregressive covariance structure for (b) were used. BID, twice daily; MMRM, mixed‐effect model for repeated measures; QD, once daily; SE, standard error

FIGURE 6

LSM change (SE) from baseline up to day 15 in Itch Severity Scale for patients aged 6–11 years (Cohort 2) receiving crisaborole 2% QD or crisaborole 2% BID (full analysis set).^{†,‡ †}Nominal p ≥ 0.05 for interpatient comparisons of crisaborole 2% BID versus crisaborole 2% QD based on MMRM from baseline to day 15. ^‡MMRM includes the fixed effects of dosing regimen, day, dosing regimen‐by‐day interaction, and baseline value, and an unstructured covariance structure was used. BID, twice daily; LSM, least squares mean; MMRM, mixed‐effect model for repeated measures; QD, once daily; SE, standard error

FIGURE 7

Mean change (SE) from baseline up to day 15 in Caregiver‐Reported Itch Severity NRS for patients aged 2–11 years (Cohort 2) receiving (a) crisaborole 2% QD or (b) crisaborole 2% BID versus vehicle (full analysis set).^{†,‡ †}Nominal *p < 0.05 and **p < 0.01 for intrapatient comparison of crisaborole 2% versus vehicle based on MMRM. ^‡MMRM includes the fixed effect of visit, and an unstructured covariance structure was used. BID, twice daily; MMRM, mixed‐effect model for repeated measures; NRS, numeric rating scale; QD, once daily; SE, standard error

FIGURE 8

LSM change (SE) from baseline up to day 15 in Caregiver‐Reported Itch Severity NRS for patients aged 2–11 years (Cohort 2) receiving crisaborole 2% QD or crisaborole 2% BID (full analysis set).^{†,‡ †}Nominal *p < 0.05 and **p < 0.01 for interpatient comparison of crisaborole 2% BID versus crisaborole 2% QD based on MMRM. ^‡MMRM includes the fixed effects of dosing regimen, day, dosing regimen‐by‐day interaction, and baseline value, and an unstructured covariance structure was used. BID, twice daily; LSM, least squares mean; MMRM, mixed‐effect model for repeated measures; NRS, numeric rating scale; QD, once daily; SE, standard error