Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial
Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial
复制标题
DOI：
10.1016/s0140-6736(15)61107-2
复制
发表时间：
2015-10-24
期刊：
影响因子：
168.9
通讯作者：
Bailey, Christine K.
中科院分区：
文献类型：
--
作者：
Grainger, John D.;Locatelli, Franco;Bailey, Christine K.
血小板生成素受体激动剂艾曲泊帕已被证明对慢性免疫性血小板减少症成人患者安全、耐受和有效。我们的目的是调查的安全性和有效性的儿童慢性免疫性血小板减少症。方法PETIT 2是一个两部分，随机，多中心，安慰剂对照研究在38个中心在12个国家（阿根廷，捷克共和国，德国，香港，以色列，意大利，俄罗斯，西班牙，台湾，泰国，英国和美国）。将患有慢性免疫性血小板减少症且血小板计数低于30 × 10（9）/L的1-17岁儿科患者随机分配（2：1）接受艾曲泊帕或安慰剂治疗。我们将患者按年龄分为三个队列（12-17岁、6-11岁和1-5岁的患者），然后随机进入13周的双盲期。通过葛兰素史克注册和药物订购系统进行随机化，患者和研究人员均对治疗分配设盲。分配至艾曲泊帕组的患者接受片剂（1-5岁患者接受口服混悬剂除外），每日一次，持续13周。6-17岁患者的起始剂量基于体重和种族，范围为50 mg/天至25 mg/天（1-5岁患者的起始剂量为1.2 mg/kg/天，东亚患者为0.8 mg/kg/天）。完成双盲期的患者进入24周开放标签治疗期，在此期间，所有患者均接受起始剂量（如果之前接受安慰剂治疗）或既定剂量的艾曲泊帕治疗。主要结果是在双盲期第5 - 12周，在没有补救治疗的情况下，血小板计数至少达到50 × 10（9）/L的患者比例，持续6周或更长时间。疗效评估中纳入的意向治疗人群包括随机分配至其中一个治疗组的所有患者，安全性人群包括接受至少一剂研究药物的所有患者。该试验在ClinicalTrials.gov注册，编号NCT 01520909。结果从2012年3月15日开始，92名患者入组，试验于2014年1月2日完成。63例患者被分配接受艾曲泊帕治疗，29例患者被分配接受安慰剂治疗。在双盲期，3例患者因不良事件停止治疗：艾曲泊帕组2例患者因肝转氨酶升高退出，安慰剂组1例患者因腹腔出血退出。25例（40%）接受艾曲泊帕治疗的患者和1例（3%）接受安慰剂治疗的患者在双盲期最后8周的6周内达到血小板计数至少50 x 10（9）/L的主要结局（比值比18.0，95% CI，2.3-140.9; p=0.0004）。所有队列的缓解相似（艾曲泊帕vs安慰剂：12-17岁患者为39% vs 10%，6-11岁患者为42% vs 0%，1-5岁患者为36% vs 0%）。在双盲期结束时，接受艾曲泊帕治疗的患者（63例患者中的23例[37%]）发生WHO 1-4级出血的患者比例低于接受安慰剂治疗的患者（29例患者中的16例[55%]）; 2-4级出血相似（接受艾曲泊帕治疗的3例[5%]患者vs接受安慰剂治疗的2例[7%]患者）。在24周的开放标签治疗期间，87例患者中有70例[80%]至少有一次血小板计数达到50 × 10（9）/L或更高。艾曲泊帕组发生频率高于安慰剂组的不良事件包括鼻咽炎（11例[17%]患者）、鼻炎（10例[16%]患者）、上呼吸道感染（7例[11%]患者）和咳嗽（7例[11%]患者）。艾曲泊帕组5例（8%）患者和安慰剂组4例（14%）患者发生严重不良事件。开放标签期和双盲期的安全性一致。试验期间未发生死亡、恶性肿瘤或血栓形成。解释艾曲泊帕可在40%的慢性免疫性血小板减少症患者中产生持续的血小板应答，是慢性症状性免疫性血小板减少症儿童的合适治疗选择。我们没有发现新的安全性问题，很少有患者因为不良事件而停止治疗。
Background The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia.Methods PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 x 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1.2 mg/kg/day or 0.8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 x 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909.Findings Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 x 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18.0, 95% CI, 2.3-140.9; p=0.0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 x 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial.Interpretation Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events.