Efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild‐to‐moderate atopic dermatitis

Atopic dermatitis is a chronic inflammatory skin disease with a significant impact on the overall wellbeing of patients and their families. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild‐to‐moderate atopic dermatitis in multiple countries. However, in the key pivotal trials, a low proportion of the overall patient population was Asian, therefore the safety and efficacy of crisaborole in the Asian population with atopic dermatitis remains unclear. CrisADe CLEAR was a multicenter, randomized, double‐blind, vehicle‐controlled, phase 3 study (NCT04360187) to assess the efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild‐to‐moderate atopic dermatitis involving ≥5% treatable body surface area. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. The primary endpoint was percentage change from baseline in the Eczema Area and Severity Index total score at day 29. Additional endpoints were improvement and success per Investigator's Static Global Assessment score at day 29 and change from baseline on the Peak Pruritus Numerical Rating Scale at week 4. Safety was assessed using rates of treatment emergent adverse events, serious adverse events, and clinically significant changes in vital signs and clinical laboratory parameters. Crisaborole‐treated patients showed a significantly greater reduction versus vehicle in percentage change from baseline in Eczema Area and Severity Index total score at day 29 (P = 0.0002). Response rates for achievement of Investigator's Static Global Assessment improvement and success at day 29 were significantly higher for patients treated with crisaborole versus vehicle (P = 0.0124 and P = 0.0078, respectively). Crisaborole‐treated patients showed a significantly greater reduction versus vehicle in change from baseline on the Peak Pruritus Numerical Rating Scale at week 4 (P = 0.0009). No new safety signals were identified. Treatment with crisaborole was effective and well tolerated in Chinese and Japanese patients with mild‐to‐moderate atopic dermatitis.

the Asian population with atopic dermatitis remains unclear. CrisADe CLEAR was a multicenter, randomized, double-blind, vehicle-controlled, phase 3 study (NCT04360187) to assess the efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild-to-moderate atopic dermatitis involving ≥5% treatable body surface area. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. The primary endpoint was percentage change from baseline in the Eczema Area and Severity Index total score at day 29. Additional endpoints were improvement and success per Investigator's Static Global Assessment score at day 29 and change from baseline on the Peak Pruritus Numerical Rating Scale at week 4.
Safety was assessed using rates of treatment emergent adverse events, serious adverse events, and clinically significant changes in vital signs and clinical laboratory parameters.
Crisaborole-treated patients showed a significantly greater reduction versus vehicle in percentage change from baseline in Eczema Area and Severity Index total score at day 29 (P = 0.0002). Response rates for achievement of Investigator's Static Global Assessment improvement and success at day 29 were significantly higher for patients treated with crisaborole versus vehicle (P = 0.0124 and P = 0.0078, respectively). Crisaborole-treated patients showed a significantly greater reduction versus vehicle in change from baseline on the Peak Pruritus Numerical Rating Scale at week 4 (P = 0.0009). No new safety signals were identified. Treatment with crisaborole was effective and well tolerated in Chinese and Japanese patients with mild-to-moderate atopic dermatitis.

| INTRODUC TI ON
Atopic dermatitis (AD) is a chronic inflammatory skin disease that has a significant impact on the overall wellbeing of patients and their families. 1,2 AD-related symptoms such as pruritus, cosmetically visible manifestations including erythema, excoriation, and lichenification, as well as the chronic, relapsing nature of the disease have a significant effect on work, education, and social activities. [3][4][5][6] Global prevalence of AD is approximately 15%-30% in children and 2%-10% in adults. 7 The prevalence of AD varies worldwide; however, the prevalence of AD has increased in certain regions, particularly in the Asia-Pacific region. 8,9 As determined in a systematic review, the prevalence of AD in Asia over a period of 1 year was 1.2% in adults and ranged from 0.96% to 22.6% in children. 10 In China, the overall prevalence of AD in children aged 1-7 years has been reported to be about 12.9% (ranging from 9.0% to 24.7% between metropolises), and a study of 8758 Chinese adults found that the prevalence of AD in that population is approximately 4.6%. 11,12 A trend of increasing prevalence of AD has been observed in China. 9,13 The prevalence of AD in children in Japan is approximately 10%. 14 An international survey including 10 911 Japanese adults reported the prevalence of AD overall and the percentage of the study population being treated to be 2.1% and 1.5%, respectively. 15 For decades, emollients and topical corticosteroids (TCSs) have been the cornerstone of treatment for AD, with topical calcineurin inhibitors (TCIs) being added more recently as a second-line option. 3,16,17 Emerging treatment options include Janus kinase (JAK) inhibitors (ruxolitinib) and phosphodiesterase 4 (PDE4) inhibitors (roflumilast and crisaborole). 18 There are only a limited number of treatment options available, especially in the pediatric population; many are associated with unfavorable side effect profiles, leaving an unmet need for new drug therapy options in AD. 3,16 Crisaborole ointment, 2%, is a nonsteroidal PDE4 inhibitor approved for the treatment of mild-to-moderate AD in multiple countries and regions. [19][20][21] In some of the countries where crisaborole has been approved for use, it has only been approved for use in patients ≥2 years of age, while in other countries, such as Canada and the United States, crisaborole is approved for patients as young as 3 months of age. 19,21 Regulatory approvals of crisaborole have been based on the results of two identically designed, vehicle-controlled, randomized, doubleblind, pivotal phase 3 clinical studies, AD-301 (CORE 1) and AD-302 (CORE 2), and a long-term safety study (AD-303). [22][23][24] In the CORE 1 and CORE 2 studies, conducted in the United States in patients ≥2 years of age with mild-to-moderate AD, crisaborole showed improvement in Investigator's Static Global Assessment (ISGA) score and an acceptable safety profile. 23,24 However, only a low proportion (approximately 5%) of the overall patient population included in these studies were Asian, therefore the efficacy and safety of crisaborole in the Asian AD population is unclear. 23 The objective of the CrisADe CLEAR study was to analyze the efficacy and safety of crisaborole in Chinese and Japanese patients aged ≥2 years with mild-to-moderate AD.

| Study design
This was a multicenter, randomized, double-blind, vehicle-controlled phase 3 study (NCT04360187) that included Chinese and Japanese patients aged ≥2 years with mild-to-moderate AD involving ≥5% treatable body surface area (BSA). At baseline (day 1), patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily (BID), respectively, for a 28-day treatment course. Patient followup was on days 36 and 60 after the end of the treatment period ( Figure 1).

| Patients and treatment
All patients were aged ≥2 years at the time of informed consent/assent and had a confirmed clinical diagnosis of AD at screening and baseline (day 1) per Hanifin and Rajka criteria. 25 Patients were required to have mild-to-moderate AD, defined as an ISGA score of 2 (mild) or 3 (moderate) and a percentage of treatable body surface area (%BSA) of ≥5, excluding the scalp.
Patients with clinically significant medical conditions (including non-AD dermatological conditions and genetic dermatological conditions overlapping with AD), patients using any prohibited medications as per the study protocol that may alter the course of AD without the required minimum washout periods, and patients who had participated in previous crisaborole clinical studies were excluded from this study. The use of systemic corticosteroids was prohibited within 28 days before baseline/day 1, and the application of TCS or TCIs was prohibited 14 days before baseline/day 1.
Patients and/or their parents or legal guardians were instructed to apply the study treatment (crisaborole ointment or vehicle) to cover each lesion twice daily during the 28-day treatment period. Patients were also instructed to apply the study drug F I G U R E 1 Study design. Japanese patients in Japan whose enrollment rolled over into study C3291027 without a posttreatment follow-up period prior to October 21, 2020, were considered completers in this study. BID, twice daily; BL, baseline; d, days; D, day of treatment period; EOS, end of study; EOT, end of treatment.
to newly identified AD lesions that appeared after baseline/day 1. This included all treatable areas affected by AD (excluding the scalp) identified at baseline/day 1 regardless of whether or not they became clinically clear prior to day 29. All relevant medication precautions were communicated to the patient and/or parent/legal guardians.
Patients were permitted to use emollients, moisturizer, and sunscreen during the study to manage dry skin in areas surrounding but not on or overlapping the treatable AD-involved areas. Another key secondary endpoint is the change from baseline on the Peak Pruritus Numerical Rating Scale (PP-NRS; used with permission from Regeneron Pharmaceuticals, Inc., and Sanofi) at week 4 (for patients aged ≥12 years). This is a patient-rated pruritus score of lesions, rating the severity of pruritus (suffered in the past 24 h) on an 11-point scale, where 0 represents no pruritus and 10 represents the most severe pruritus. 28 Other secondary endpoints included improvement and success in ISGA over time, percentage change from baseline in EASI total score over time, and change from baseline in %BSA over time (other than day 29).

| Safety assessments
Patients were assessed for treatment-emergent adverse events (TEAEs) during study visits (Figure 1). Unscheduled safety assessments could have been performed at any time during the study to assess any perceived safety concerns. TEAEs were defined as adverse events that first occurred on or after the day of the first study drug dose. TEAEs were classified as treatment-related if they were determined by the study investigator to be definitely, probably, or possibly related to the treatment with crisaborole. AEs were recorded and classified using the Medical Dictionary for Regulatory Activities terminology.
Safety was assessed using rates of TEAEs, serious adverse events (SAEs), and clinically significant changes in vital signs and clinical laboratory parameters.

| Statistical analysis
Efficacy analyses were performed on the full analysis set, which encompassed all patients who were randomly assigned to the study drug or vehicle, regardless of discontinuation. The safety populations contained all randomly assigned patients who received one or more doses of the study drug. Statistical significance was defined as P ≤ 0.05.
Percentage change from baseline in EASI total score at day 29 and change from baseline to week 4 in the weekly average of the PP-NRS score for patients aged ≥12 years were analyzed using a linear mixed-effect model for repeated measures that included treatment group, visit, and treatment group-by-visit interactions as factors and baseline value as a covariate.
The percentages of patients who achieved improvement or success in ISGA at day 29 were compared between the crisaborole arm and the vehicle arm, and the differences were tested based on normal approximation to response rates.

| Ethics statement
The final protocol, any amendments, and informed consent docu-

| Baseline characteristics
The full analysis set of the phase 3 study consisted of 391 patients.
Of the 391 enrolled patients, 260 and 131 were randomly assigned to crisaborole and vehicle groups, respectively (Figure 2). The demographic and baseline characteristics between the two groups were balanced and are shown in Table 1.  Table 1).
The medications most used by patients prior to baseline/day 1 included hydrocortisone butyrate, a TCS, and tacrolimus monohydrate, a TCI ( Table 2).
During the study treatment period, 23 (17.6%) of the vehicle-

| Key secondary endpoint: Achievement of improvement and success in ISGA at day 29
Response rates for achievement of ISGA score improvement at day 29 were significantly higher for patients treated with crisaborole than vehicle-treated patients (41.4% vs 28.5%). The percentage of patients who achieved improvement in ISGA score was 12.9% higher for crisaborole-treated patients versus vehicle-treated patients (P = 0.0124). The percentage of patients who achieved ISGA success was also found to be significantly higher in the crisaborole-treated F I G U R E 2 Flow diagram of the CrisADe CLEAR study. BID, twice daily. group versus the vehicle-treated group (27.6% vs 15.9%). The percentage of patients who achieved success in ISGA score was 11.7% higher for the crisaborole-treated group versus vehicle-treated patients (P = 0.0078) (Figure 4).

| Safety
Overall, 46.2% and 44.3% of patients who were treated with crisaborole and vehicle, respectively, experienced all-causality TEAEs (

F I G U R E 3
Least squares mean of percentage change from baseline in EASI total score at day 29. BID, twice daily; BL, baseline; EASI, Eczema Area and Severity Index; LSM, least squares mean.
F I G U R E 4 Achievement of improvement and success in ISGA at day 29. Improvement was defined as an ISGA score of (0) clear or (1) almost clear. Success was defined as an ISGA score of 0/1 with grade ≥2 improvement from baseline. BID, twice daily; ISGA, Investigator's Static Global Assessment.
Treatment-related AEs occurred in 23.5% of patients in the crisaborole-treated group and 18.3% of the vehicle-treated group; none were serious ( Table 5). Treatment-related AEs were application site discoloration, irritation, pain, and paresthesia, folliculitis, atopic dermatitis, contact dermatitis, and pruritus.
One SAE was reported in each group (abnormal myocardial enzymes in the vehicle-treated group and exacerbation of carpal tunnel syndrome in the crisaborole-treated group); both SAEs were considered unrelated to treatment. The abnormal myocardial enzymes and exacerbated carpal tunnel syndrome SAEs resolved within 6 and 14 days, respectively.
No safety signals were identified from vital signs and laboratory testing in either group.

| DISCUSS ION
This phase 3 study addressed the efficacy and safety of crisab-  Table 2).
Compared with the safety data from the CORE 1/CORE 2 studies, the overall TEAE rates were higher, but the severity and classification of TEAEs were similar. 23

| CON CLUS IONS
Previous studies mainly evaluated populations in Western countries, thus it was important to evaluate the safety and efficacy of crisaborole ointment in an Asian patient population. In the CrisADe CLEAR study, crisaborole-treated patients had favorable outcomes in all primary and key secondary endpoints versus vehicle-treated patients, and no new safety signals were identified. Crisaborole was effective and well tolerated in Chinese and Japanese patients aged ≥2 years with mild-to-moderate AD.

ACK N OWLED G M ENTS
Editorial and medical writing support, under the guidance of the au-

FU N D I N G I N FO R M ATI O N
This study was funded by Pfizer Inc.

DATA AVA I L A B I L I T Y S TAT E M E N T
On request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/ scien ce/clini cal-trial s/trial -data-and-results for more information. TA B L E 5 TEAEs by system organ class and preferred term (treatment related) in ≥5% of subjects.