Johns Hopkins University School of Medicine, Baltimore, Maryland.
University of Massachusetts Medical School, Worcester.
JAMA. 2021 Apr 20;325(15):1513-1523. doi: 10.1001/jama.2021.3414.
Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea.
To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes.
DESIGN, SETTING, AND PARTICIPANTS: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-β0 thalassemia, or S-β+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included.
A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194).
Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup.
Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%).
Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes.
ClinicalTrials.gov Identifier: NCT01737814.
虽然有有效的药物可预防镰状细胞病（SCD）的疼痛性血管阻塞发作，但对于正在进行的疼痛性血管阻塞发作，没有疾病修正治疗方法；治疗仍然是支持性的。先前对聚氧丙烯 188 的 3 期试验报告称，SCD 中疼痛性血管阻塞发作的持续时间缩短，尤其是在儿童和接受羟基脲治疗的参与者中。
重新评估聚氧丙烯 188 对血管阻塞发作的疗效。
设计、地点和参与者：这是一项 3 期、随机、双盲、安慰剂对照、多中心、国际试验，于 2013 年 5 月至 2016 年 2 月进行，包括 12 个国家的 66 家医院和 60 个城市；纳入 388 名年龄在 4 至 65 岁之间的 SCD（血红蛋白 SS、SC、S-β0 地中海贫血或 S-β+ 地中海贫血疾病）患者，他们患有需要住院治疗的急性中度至重度疼痛，这是疼痛性血管阻塞发作的典型表现。
1 小时内静脉注射 100mg/kg 的负荷剂量聚氧丙烯 188，然后连续 12 至 48 小时输注 30mg/kg/h 的持续输注（n=194）或安慰剂（n=194）。
所有参与者和年龄小于 16 岁的参与者（作为单独的亚组）从随机分组到最后一次使用肠外阿片类药物的时间（小时）。
在 437 名符合条件的参与者中，有 388 名被随机分组（平均年龄 15.2 岁；176 [45.4%] 为女性），384 名（99.0%）参与者的主要结局可用，357 名（92.0%）参与者的 15 天随访可用，368 名（94.8%）参与者的 30 天随访可用。两组之间最后一次使用肠外阿片类药物的平均时间无显著差异（聚氧丙烯 188 组为 81.8 小时，安慰剂组为 77.8 小时；差异为 4.0 小时[95%CI，-7.8 至 15.7]；几何均数比为 1.2[95%CI，1.0-1.5]；P=0.09）。基于年龄和治疗的显著交互作用（P=0.01），年龄小于 16 岁的参与者从随机分组到最后一次使用肠外阿片类药物的时间存在治疗差异（聚氧丙烯 188 组为 88.7 小时，安慰剂组为 71.9 小时；差异为 16.8 小时[95%CI，1.7-32.0]；几何均数比为 1.4[95%CI，1.1-1.8]；P=0.008）。聚氧丙烯 188 组比安慰剂组更常见的不良事件包括高胆红素血症（12.7%比 5.2%）；安慰剂组更常见的不良事件包括缺氧（12.0%比 5.3%）。
在儿童和成人 SCD 患者中，聚氧丙烯 188 并未显著缩短血管阻塞发作期间最后一次使用肠外阿片类药物的时间。这些发现不支持使用聚氧丙烯 188 治疗血管阻塞发作。
ClinicalTrials.gov 标识符：NCT01737814。
