Reitamo S, Rustin M, Harper J, Kalimo K, Rubins A, Cambazard F, Brenninkmeijer E E A, Smith C, Berth-Jones J, Ruzicka T, Sharpe G, Taieb A
Department of Dermatology, Helsinki University Central Hospital, Meilahdentie 2, 00250 Helsinki, Finland.
Br J Dermatol. 2008 Sep;159(4):942-51. doi: 10.1111/j.1365-2133.2008.08747.x. Epub 2008 Jul 15.
For the treatment of a chronic disease like atopic dermatitis, sustained tolerability and efficacy of the applied medication are essential.
The present open-label, noncomparative study was conducted to obtain information on the long-term safety and efficacy of 0.1% tacrolimus ointment.
Patients aged 2 years or older with an affected body surface area of more than 5%, who previously participated in a clinical trial on tacrolimus ointment, were eligible for this study. The treatment area was defined by the investigator at study entry. Both children and adults applied continuously or intermittently 0.1% tacrolimus ointment twice daily during episodes of active disease plus an additional week after remission over a follow-up period of up to 4 years.
The intent-to-treat population comprised 782 patients, with a median age of 22 years (range 2-72). Patients remained in the study for up to 4 years. Approximately half of the patients discontinued the study prematurely; the median follow-up was 1422 days. Median tacrolimus ointment use was 31.2 g during the first week; ointment use decreased during the first year and then remained stable for the remainder of the study. The median cumulative tacrolimus use was 271.5 g at month 6, 462.5 g at month 12, 739.9 g at month 24, 1029.3 g at month 36 and 1320.8 g at month 48. Altogether 51.8% of patients discontinued the study prematurely; the main reasons were withdrawal of consent (13.3%), loss to follow-up (11.3%) and lack of efficacy (9.4%). Adverse events led to study discontinuation in 3.7% of the patients. The most frequent application site events were skin burning and pruritus. These events were most often reported in adult patients during the initial treatment period; prevalence decreased after the first week and remained at a low level throughout the study. Nonapplication site events occurred with stable incidences throughout the study period. In general, calculated daily hazard rates did not indicate an increased risk of adverse events with prolonged treatment. The total affected body surface area decreased substantially upon onset of treatment and efficacy of treatment was maintained until the end of the study with smaller but continuous improvements throughout the follow-up period. Overall, 75% of the patients and 76% of the investigators rated their satisfaction with the treatment as excellent, very good or good at the end of the study or at the time of premature discontinuation.
The safety profile of intermittent or continuous long-term application of 0.1% tacrolimus ointment for up to 4 years was consistent with that which has been established from shorter studies and gave no reason for concern. In addition, 0.1% tacrolimus ointment demonstrated sustained efficacy as reflected by the expression of high satisfaction with treatment by both patients and investigators.
对于特应性皮炎等慢性疾病的治疗，所用药物的持续耐受性和疗效至关重要。
开展本项开放标签、非对照研究，以获取有关0.1%他克莫司软膏长期安全性和疗效的信息。
年龄在2岁及以上、体表面积受累超过5%且此前参加过他克莫司软膏临床试验的患者符合本研究条件。治疗区域由研究者在研究入组时确定。儿童和成人在疾病活动期每天两次连续或间歇应用0.1%他克莫司软膏，缓解后再加用一周，随访期长达4年。
意向性治疗人群包括782例患者，中位年龄为22岁（范围2 - 72岁）。患者在研究中最长持续4年。约一半患者过早退出研究；中位随访时间为1422天。第一周他克莫司软膏的中位用量为31.2克；软膏用量在第一年减少，之后在研究剩余时间保持稳定。第6个月他克莫司的累积中位用量为271.5克，第12个月为462.5克，第24个月为739.9克，第36个月为1029.3克，第48个月为1320.8克。共有51.8%的患者过早退出研究；主要原因是撤回同意（13.3%）、失访（11.3%）和缺乏疗效（9.4%）。不良事件导致3.7%的患者退出研究。最常见的用药部位事件是皮肤烧灼感和瘙痒。这些事件在成年患者初始治疗期间报告最多；第一周后患病率下降，且在整个研究期间维持在低水平。非用药部位事件在整个研究期间发生率稳定。总体而言，计算得出的每日风险率未表明长期治疗会增加不良事件风险。治疗开始后受累体表面积大幅下降，治疗效果一直维持到研究结束，在整个随访期间虽有较小但持续的改善。总体而言，75%的患者和76%的研究者在研究结束时或过早停药时将他们对治疗的满意度评为优秀、非常好或良好。
间歇性或连续性长期应用0.1%他克莫司软膏长达4年的安全性与短期研究结果一致，无需担忧。此外，0.1%他克莫司软膏显示出持续疗效，这体现在患者和研究者对治疗的高度满意度上。
