中华皮肤科杂志 ›› 2023, Vol. 56 ›› Issue (9): 815-821.doi: 10.35541/cjd.20230255

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克立硼罗软膏早期缓解儿童特应性皮炎临床症状及改善缓解期临床症状的多中心临床研究

王珊1    王星宇1    舒虹2    张斌1，3    石航4    杨欢5    钱秋芳6    马红艳1    梁源1    赵牧童1    申春平1    焦磊1    田晶1    汪洋1    谷盈1    孙婧1    刘盈1    李萍4    王华5    马琳1   

  1. 1首都医科大学附属北京儿童医院皮肤科，北京  100045；2昆明市儿童医院皮肤科，昆明 650000；3河南省儿童医院皮肤科，郑州  450018；4深圳市儿童医院皮肤科，深圳  518038；5重庆医科大学附属儿童医院皮肤科，重庆  400014；6上海市儿童医院皮肤科，上海  200062
  • 收稿日期:2023-05-05 修回日期:2023-07-16 发布日期:2023-09-07
  • 通讯作者: 马琳；王华；李萍 E-mail:bch_maleen@aliyun.com; huawang@hospital.cqmu.edu.cn; liping20081110@126.com

Efficacy of crisaborole ointment in clinical symptom relief in the early stage of childhood atopic dermatitis and in symptom improvement in the remission stage: a multicenter clinical study

Wang Shan1, Wang Xingyu1, Shu Hong2, Zhang Bin1,3, Shi Hang4, Yang Huan5, Qian Qiufang6, Ma Hongyan1, Liang Yuan1, Zhao Mutong1, Shen Chunping1, Jiao Lei1, Tian Jing1, Wang Yang1, Gu Ying1, Sun Jing1, Liu Ying1, Li Ping4, Wang Hua5, Ma Lin1   

  1. 1Department of Dermatology, Beijing Children′s Hospital, Capital Medical University, Beijing 100045, China; 2Department of Dermatology, Kunming Children′s Hospital, Kunming 650000, China; 3Department of Dermatology, Henan Children′s Hospital, Zhengzhou 450018, China; 4Department of Dermatology, Shenzhen Children′s Hospital, Shenzhen 518038, China; 5Department of Dermatology, Children′s Hospital of Chongqing Medical University, Chongqing 400014, China; 6Department of Dermatology, Children′s Hospital of Shanghai, Shanghai 200062, China
  • Received:2023-05-05 Revised:2023-07-16 Published:2023-09-07
  • Contact: Ma Lin; Wang Hua; Li Ping E-mail:bch_maleen@aliyun.com; huawang@hospital.cqmu.edu.cn; liping20081110@126.com

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摘要： 【摘要】 目的 观察2%克立硼罗软膏对儿童特应性皮炎（AD）早期临床症状改善情况及不良反应耐受情况，并对比缓解期隔日给药1次（Qod）和每周给药2次（Biw）AD复发的情况。方法 采用多中心、随机对照、开放标签研究，纳入首都医科大学附属北京儿童医院等6家医院2 ~ < 18岁轻中度AD患儿150例，随机分为Qod组（76例）及Biw组（74例）。在AD急性期，两组均于皮损处外用2%克立硼罗软膏及全身润肤剂，每天2次，使用2 ~ 4周，评估早期临床症状改善及不良反应发生情况。至研究者静态整体评估（ISGA）评分 ≤ 1分，进入缓解期后，两组患儿分别按Qod和Biw频率使用克立硼罗软膏维持治疗，分别评估缓解期内AD患儿复发情况，并评估缓解期第4、8、12周皮损严重程度、瘙痒、生活质量情况以及不良事件的发生情况。两组间正态分布的连续性资料比较采用t检验，非正态分布资料则采用Mann-Whitney U检验，计数资料比较采用χ2检验，生存分析采用Kaplan-Meier法。结果 共142例纳入改良的意向治疗分析集，其中Qod组71例，Biw组71例。在急性期，AD患儿及家属自我评估的瘙痒及皮损改善分别发生在用药1.9（1.0，3.0） d和2.0（1.0，4.1） d后。急性期治疗结束时，89例（62.7%）患儿ISGA评分达到0/1分，成功进入缓解期。83例（Qod组44例，Biw组39例）完成缓解期随访，Qod组及Biw组分别复发19例（43.2%）和12例（30.8%），两组复发率差异无统计学意义（χ2 = 1.36，P = 0.243）；复发时间分别为64.2（95% CI：53.3 ~ 75.2） d和75.8（95% CI：65.5 ~ 86.1） d。在缓解期第4、8、12周未脱落的AD患儿中，仅第12周Biw组ISGA评分［0（0，1）分］显著低于Qod组［1（0，1）分，Z = -2.31，P = 0.021］，其余时间点两组湿疹面积及严重度指数（EASI）、ISGA、瘙痒数字评估量表（NRS）评分和生活质量评分差异均无统计学意义（均P＞0.05）。共146例患儿纳入安全性数据集，研究期间65例报告70例次不良事件，发生率为44.5%，均为一般不良事件，无严重不良事件发生，55例（37.7%）出现用药部位不适，主要为疼痛相关不适（45例，30.8%），多发生于皮肤薄嫩或皱褶部位。结论 2%克立硼罗软膏可有效改善儿童轻中度AD早期临床症状，缓解期间歇使用可持续改善临床症状，常见不良反应为早期用药部位不适；缓解期Qod给药和Biw给药的治疗方案对于AD复发的影响无差异。

关键词: 皮炎, 特应性, 儿童, 随机对照试验, 早期, 缓解期, 克立硼罗

Abstract: 【Abstract】 Objective To evaluate the efficacy and tolerability of crisaborole 2% ointment in the treatment of childhood atopic dermatitis （AD） at the early stage, and to compare the efficacy of every-other-day （Qod） regimen versus twice-a-week （Biw） regimen against recurrence in the remission stage of AD. Methods A multicenter, randomized, open-label clinical trial was conducted. Totally, 150 children with mild to moderate AD aged 2 - < 18 years were enrolled from 6 hospitals （including Beijing Children′s Hospital, Capital Medical University, etc）, and randomly divided into the Qod group （76 cases） and the Biw group （74 cases）. In the acute stage of AD, both groups were treated with topical crisaborole 2% ointment on skin lesions twice a day for 2 - 4 weeks, as well as with emollients throughout the whole body. The improvement of early clinical symptoms was evaluated, and the occurrence of adverse reactions was recorded in the follow up. Once the investigator′s static global assessment （ISGA） scores decreased to 1 point or less, the patient would be enrolled into the remission stage. In the remission stage of AD, patients in the Qod group and Biw group were treated with crisaborole ointment every other day and twice a week respectively; the recurrence rate of AD in the remission stage was evaluated, as well as the severity of skin lesions, itching, life quality, and the occurrence of adverse reactions at weeks 4, 8, and 12. Statistical analysis was carried out with SPSS 23.0 software by using t test for comparisons of normally distributed continuous data between two groups, Mann-Whitney U test for non-normally distributed data, chi-square test for enumeration data, and Kaplan-Meier method for analysis of survival rates. Results A total of 142 patients were enrolled in the modified intention-to-treat population, including 71 in the Qod group and 71 in the Biw group. In the acute stage of AD, the improvement of itching and skin lesions self-reported by the children or their family members occurred on days 1.9 （1.0, 3.0） and 2.0 （1.0, 4.1） after the application of crisaborole ointment, respectively. At the end of treatment in the acute stage, 89 children （62.7%） achieved ISGA 0/1 and successfully transferred into the remission stage. The follow-up in the remission stage was completed in 83 patients （44 in the Qod group and 39 in the Biw group）. In addition, recurrence occurred in 19 （43.2%） and 12 （30.8%） patients in the Qod group and Biw group respectively, and there was no significant difference in the recurrence rate between the two groups （χ2 = 1.36, P = 0.243）; the average time to recurrence was 64.25 （95% CI: 53.33 - 75.17） days and 75.78 （95% CI: 65.46 - 86.10） days in the Qod group and Biw group respectively. Among the patients who were in the remission stage and had not yet experienced relapse at weeks 4, 8, and 12, there were no significant differences in the eczema area and severity index （EASI） scores, ISGA scores, pruritus numerical rating scale （NRS） scores, or quality-of-life scores between the two groups （all P > 0.05） at any time points, except for the ISGA scores at week 12 （Biw group: 0 ［0, 1］ point vs. Qod group: 1 ［0, 1］ point; Z = -2.31, P = 0.021）. A total of 146 patients were enrolled in the safety set. During the study period, 70 adverse events occurred in 65 patients, with an incidence rate of 44.5%, and all were mild or moderate adverse events; 55 （37.7%） patients experienced discomfort at the medication site, which mainly referred to pain （45 cases, 30.8%） and mostly occurred in the tender and skinfold areas. Conclusions Crisaborole 2% ointment could effectively relieve clinical symptoms in children with mild to moderate AD in the early stage, and intermittent treatment could continuously relieve clinical symptoms in the remission stage. The common adverse reaction was discomfort at the application site in the early stage of AD. There was no significant difference in the impact on AD recurrence in the remission stage between the Qod regimen and Biw regimen.

Key words: Dermatitis, atopic, Child, Randomized controlled trial, Early stage, Remission stage, Crisaborole

引用本文

王珊 王星宇 舒虹 张斌 石航 杨欢 钱秋芳 马红艳 梁源 赵牧童 申春平 焦磊 田晶 汪洋 谷盈 孙婧 刘盈 李萍 王华 马琳. 克立硼罗软膏早期缓解儿童特应性皮炎临床症状及改善缓解期临床症状的多中心临床研究[J]. 中华皮肤科杂志, 2023,56(9):815-821. doi:10.35541/cjd.20230255

Wang Shan, Wang Xingyu, Shu Hong, Zhang Bin, Shi Hang, Yang Huan, Qian Qiufang, Ma Hongyan, Liang Yuan, Zhao Mutong, Shen Chunping, Jiao Lei, Tian Jing, Wang Yang, Gu Ying, Sun Jing, Liu Ying, Li Ping, Wang Hua, Ma Lin. Efficacy of crisaborole ointment in clinical symptom relief in the early stage of childhood atopic dermatitis and in symptom improvement in the remission stage: a multicenter clinical study[J]. Chinese Journal of Dermatology, 2023, 56(9): 815-821.doi:10.35541/cjd.20230255