中华皮肤科杂志 ›› 2019, Vol. 52 ›› Issue (8): 519-524.doi: 10.3760/cma.j.issn.0412-4030.2019.08.001

• 论著 •    下一篇

0.03%他克莫司软膏长期间歇维持治疗儿童特应性皮炎的多中心随机对照临床研究

梁源1    刘玲玲2    王珊1    赵作涛2    马琳1    向欣1    顾恒3    陈崑3    王华4    易红4    陈瑾萍5    张金桃5    姚志荣6    郭一峰6    陈戟7    程颖7    朱学骏2   

  1. 1首都医科大学附属北京儿童医院皮肤科  国家儿童医学中心  100045； 2北京大学第一医院皮肤科  皮肤病分子诊断北京市重点实验室  100034； 3中国医学科学院  北京协和医学院  皮肤病医院，南京  210042； 4重庆医科大学附属儿童医院皮肤科  400014； 5广州市儿童医院皮肤科  510120； 6上海交通大学医学院附属新华医院皮肤科  200092； 7上海儿童医学中心皮肤科  200127
  • 收稿日期:2018-12-28 修回日期:2019-05-26 出版日期:2019-08-15 发布日期:2019-07-30
  • 通讯作者: 刘玲玲 E-mail:liulingling2000@163.com

Efficacy and safety of 0.03% tacrolimus ointment in the long-term intermittent maintenance treatment of atopic dermatitis in children: a multicenter randomized controlled clinical trial

Liang Yuan1, Liu Lingling2, Wang Shan1, Zhao Zuotao2, Ma Lin1, Xiang Xin1, Gu Heng3, Chen Kun3, Wang Hua4, Yi Hong4, Chen Jinping5, Zhang Jintao5, Yao Zhirong6, Guo Yifeng6, Chen Ji7, Cheng Ying7, Zhu Xuejun2   

  1. 1Department of Dermatology, Beijing Children′s Hospital, Capital Medical University, National Center for Children′s Health, Beijing 100045, China;  2Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis of Dermatoses, Beijing 100034, China;  3Hospital for Skin Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; 4Department of Dermatology, Children′s Hospital of Chongqing Medical University, Chongqing 400014, China;  5Department of Dermatology, Guangzhou Children′s Hospital, Guangzhou 510120, China;  6Department of Dermatology, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China;  7Department of Dermatology, Shanghai Children′s Medical Center, Shanghai 200127, China
  • Received:2018-12-28 Revised:2019-05-26 Online:2019-08-15 Published:2019-07-30
  • Contact: Liu Lingling E-mail:liulingling2000@163.com

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摘要： 【摘要】 目的 比较0.03%他克莫司软膏长期间歇维持治疗与传统治疗对减少儿童中重度特应性皮炎复发次数、延长复发间隔的有效性及安全性。方法 采用随机、开放、对照临床试验方法，于2012年9月至2013年11月在7家医院进行试验。共分两个阶段，第一阶段：从全国7家医院纳入2 ~ 15岁中重度特应性皮炎患儿171例，均接受0.03%他克莫司软膏每日2次共2 ~ 6周的常规治疗，结束时，达到研究者总体评估（IGA） ≤ 2分的患者进入第二阶段，随机分配至试验组（62例）和对照组（63例），其中试验组接受每周2次（周一和周四）0.03%他克莫司软膏的间歇维持治疗，对照组不治疗。疾病复发时，两组患儿均接受0.03%他克莫司软膏每日2次的常规治疗，整体观察期为6个月。主要疗效指标为首次复发时间（从第一阶段治疗结束至发生第1次复发的天数），次要疗效指标包括第二阶段时复发次数、复发时疾病严重程度、复发持续时间、复发时瘙痒评分、他克莫司使用总量、总有效率，以及不良事件发生率等。结果 125例AD患儿进入第二阶段，121例完成随访，其中试验组60例中25例（41.7%）复发，对照组61例中46例（75.4%）复发，试验组的复发率显著低于对照组（χ2 = 14.20，P < 0.001）。试验组首次复发时间（46.9 ± 37.7） d较对照组（28.8 ± 32.3） d显著延长（Z = 1 093.50，P = 0.020）。试验组总复发次数为31次，每例复发（0.52 ± 0.68）次，对照组总复发86次，每例复发（1.41 ± 1.23）次，差异有统计学意义（t = 4.96，P < 0.001），两组之间在复发期间的疾病严重程度（湿疹面积和严重程度指数：Z = 971.50，P = 0.393）、复发持续时间（Z = 747.00，P = 0.066）和瘙痒评分（Z = 894.00，P = 0.947）差异均无统计学意义。全部患儿对治疗药物均耐受良好，未发生与他克莫司软膏相关的严重不良事件。结论 每周2次使用0.03％他克莫司软膏间歇维持治疗6个月，可以有效预防和减少儿童中重度特应性皮炎的复发，延长复发间期，并且耐受性良好。

关键词: 皮炎, 特应性； 儿童； 随机对照试验； 治疗结果； 药物毒性； 他克莫司

Abstract: 【Abstract】 Objective To compare the efficacy and safety of the long-term intermittent maintenance treatment with tacrolimus 0.03% ointment versus traditional treatment in reducing relapses and prolonging the recurrence interval in children with moderate to severe atopic dermatitis （AD）. Methods A two-phase randomized, open-labelled, controlled clinical trial was conducted from September 2012 to November 2013. In the first phase, a total of 171 children aged 2 - 15 years with moderate to severe AD were enrolled from 7 hospitals in China, and received conventional treatment with tacrolimus 0.03% ointment twice a day for 2 - 6 weeks. At the end of the treatment, the patients who achieved an investigator′s global assessment （IGA） score ≤ 2 （n = 125） were randomly classified into 2 groups to receive the second-phase treatment: test group （n = 62） receiving intermittent maintenance treatment with tacrolimus 0.03% ointment twice a week （Monday and Thursday）, and control group （n = 63） receiving no treatment. If the patients in the 2 groups experienced relapse, they received conventional treatment with tacrolimus 0.03% ointment twice a day. The overall observation period was 6 months. The primary endpoint was the time to the first relapse, which was defined as the number of days from the end of the first-phase treatment to the first relapse. The secondary endpoints included the number of relapses at the second-phase trial, the disease severity at the time of relapse, the duration of relapse, the pruritus score at the time of relapse, the total amount of tacrolimus ointment used, the total response rate at the second-phase trial, and the incidence of adverse events. Results A total of 125 children with AD were enrolled into the second-phase trial, and 121 of them completed the follow-up. Among the 121 patients, the recurrence rate was significantly lower in the test group （25/60, 41.7%） than in the control group （46/61, 75.4%; χ2 = 14.20, P < 0.001）. The time to the first relapse was significantly longer in the test group （46.9 ± 37.7 d） than in the control group （28.8 ± 32.3 d; Z = 1 093.50, P = 0.020）. The total number of recurrence was 31 and 86 in the test group and control group respectively, and the mean number of recurrence in each patient was significantly lower in the test group （0.52 ± 0.68） than in the control group （1.41 ± 1.23, t = 4.96, P < 0.001）. There were no significant differences between the two groups regarding disease severity during relapse （eczema area and severity index: Z = 971.50, P = 0.39）, duration of relapse （Z = 747.00, P = 0.07）, and pruritus score during relapse （Z = 894.00, P = 0.95）. The therapeutic drug was tolerated well in all the children, and no tacrolimus-related serious adverse events occurred. Conclusion The intermittent maintenance treatment with tacrolimus 0.03% ointment twice a week for 6 months can effectively and safely prevent and reduce relapses, and prolong the recurrence interval in children with moderate to severe AD.

Key words: Dermatitis, atopic, Child, Randomized controlled trial, Treatment outcome, Drug toxicity, Tacrolimus