Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.
Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.
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DOI：
10.1016/s0140-6736(15)01041-7
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发表时间：
2016-02-13
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影响因子：
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通讯作者：
Adams RJ
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作者：
Ware RE;Davis BR;Schultz WH;Brown RC;Aygun B;Sarnaik S;Odame I;Fuh B;George A;Owen W;Luchtman-Jones L;Rogers ZR;Hilliard L;Gauger C;Piccone C;Lee MT;Kwiatkowski JL;Jackson S;Miller ST;Roberts C;Heeney MM;Kalfa TA;Nelson S;Imran H;Nottage K;Alvarez O;Rhodes M;Thompson AA;Rothman JA;Helton KJ;Roberts D;Coleman J;Bonner MJ;Kutlar A;Patel N;Wood J;Piller L;Wei P;Luden J;Mortier NA;Stuber SE;Luban NLC;Cohen AR;Pressel S;Adams RJ
对于患有镰状细胞贫血和经颅多普勒（TCD）血流速度升高的儿童，定期输血可有效预防原发性卒中，但必须无限期持续。在这种情况下，羟基脲的疗效尚不清楚。TWiTCH是一项多中心、III期、随机、开放标签、非劣效性试验，在TCD速度异常但无严重血管病变的儿童中比较标准治疗（输血）与替代治疗（羟基脲）。通过螯合（标准组）和连续静脉切开术（替代组）管理铁过载。主要研究终点是根据一般线性混合模型计算的24个月TCD流速，非劣效性界值= 15 cm/sec。在121名随机参与者中（61例输血，60例羟基脲），输血的儿童保持<30%的镰状血红蛋白，而服用羟基脲（平均27 mg/kg/天）的儿童平均胎儿血红蛋白为25%。第一次计划的中期分析证明了非劣效性，申办者终止了研究。标准组与替代组的最终基于模型的TCD速度（平均值±标准误）分别为143 ± 1.6和138 ± 1.6 cm/sec，差异（95% CI）= 4.54（0.10，8.98），非劣效性p=8.82 × 10−16，事后优效性p=0.023。在由设盲的审查者集中裁定的29例新发神经系统事件中，没有发生卒中，但每组有3例短暂性脑缺血发作。退出脑MRI/MRA显示，每组均没有新发脑梗死，但一名参与者（标准组）的血管病变加重。替代组的铁负荷下降更多，铁蛋白差异为−1047 ng/mL（−1524，−570），p<0.001，肝脏铁差异为−4.3 mg Fe/gm干重（−6.1，−2.5），p=0.001。对于患有镰状细胞贫血和TCD速度异常的高危儿童，在输血4年后且没有严重的MRA血管病变，羟基脲治疗可以替代慢性输血以维持TCD速度并有助于预防原发性卒中。
For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown. TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec. Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001. For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke.