Sirolimus (Rapamycin) for Slow-Flow Malformations in Children The Observational-Phase Randomized Clinical PERFORMUS Trial
Sirolimus (Rapamycin) for Slow-Flow Malformations in Children The Observational-Phase Randomized Clinical PERFORMUS Trial
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DOI：
10.1001/jamadermatol.2021.3459
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发表时间：
2021-09-15
期刊：
影响因子：
10.9
通讯作者：
Morel, Baptiste
中科院分区：
文献类型：
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作者：
Maruani, Annabel;Tavernier, Elsa;Morel, Baptiste
重要西罗莫司越来越多地被用于治疗各种血管异常，虽然其疗效的证据是lacked.Objective评估西罗莫司的疗效和安全性的儿童慢血流血管畸形，以更好地描绘治疗的适应症。设计、设置和参与者这项多中心、开放标签、观察期随机临床试验包括59名6至18岁的慢流血管畸形儿童，他们于2015年9月28日至2018年3月22日在11家法国三级医院中心招募。从2019年12月4日至2020年11月10日，在意向治疗的基础上进行统计分析。干预患者经历了一个观察期，然后在接受口服西罗莫司（目标血清水平，4-12 ng/mL）时转换为干预期。切换时间随机从第4个月至第8个月，整个研究期间持续12个月，为每个patient.MAIN结局和措施的主要结果是在磁共振成像扫描（集中解释）每单位时间（即干预期间和观察期间）检测到的血管畸形的体积变化。次要结果包括主观终点：疼痛、出血、渗血、生活质量和安全性。（35名女孩[59.3%];平均[SD]年龄，11.6 [3.8]岁），22单纯静脉畸形18例（37.3%），囊性淋巴管畸形18例（30.5%），合并畸形19例（32.2%）。与持续时间相关的磁共振成像扫描检测到的血管畸形体积变化在干预期和观察期之间总体上没有显著差异（所有血管畸形：平均[SD]差异，-0.001 [0.007];静脉畸形：平均[SD]差异，0.001 [0.004];合并畸形：平均值[SD]差异，0.001 [0.009]）。然而，观察到纯淋巴管畸形儿童的体积显著减少（平均值[SD]差异，-0.005 [0.005]）。总体而言，西罗莫司对疼痛（尤其是合并畸形）、出血、渗血、自我评估疗效和生活质量有积极影响。在西罗莫司治疗期间，56例患者发生了231起不良事件（5起严重不良事件，无危及生命）。最常见的不良事件是口腔溃疡（29例[49.2%]）。结论和相关性这一观察期随机临床试验允许澄清的目标时，开始西罗莫司治疗6岁以上的儿童患者和家庭。单纯淋巴管畸形似乎是西罗莫司治疗的最佳适应症，因为有证据表明，每单位时间内淋巴管畸形的体积减少，渗出和出血，生活质量提高。同样基于症状，单纯静脉畸形的获益似乎低于其他2个亚组。
IMPORTANCE Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking.OBJECTIVE To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment. Design, Setting and Participants This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020.INTERVENTIONS Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient.MAIN OUTCOMES AND MEASURES The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety.RESULTS Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]).CONCLUSIONS AND RELEVANCE This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms.