A Phase 3 Trial of L-Glutamine in Sickle Cell Disease
A Phase 3 Trial of L-Glutamine in Sickle Cell Disease
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DOI：
10.1056/nejmoa1715971
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发表时间：
2018-07-19
影响因子：
158.5
通讯作者：
Vichinsky, Elliott P.
中科院分区：
文献类型：
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作者：
Niihara, Yutaka;Miller, Scott T.;Vichinsky, Elliott P.
背景氧化应激导致镰状细胞病的复杂病理生理学。药物级 L-谷氨酰胺（USAN，谷氨酰胺）的口服治疗已被证明可以增加镰状细胞红细胞中还原型烟酰胺腺嘌呤二核苷酸的比例，这可能会减少氧化应激，并可能减少镰状细胞相关疼痛的发作。方法在一项多中心、随机、安慰剂对照、双盲、 在第 3 阶段试验中，我们测试了每天两次口服药物级 L-谷氨酰胺（每剂每公斤体重 0.3 克）与安慰剂相比，在降低镰状细胞性贫血或镰状地中海贫血以及上一年有两次或两次以上疼痛危机史的患者中疼痛危机发生率方面的功效。在筛选前接受羟基脲剂量稳定至少 3 个月的患者在 48 周的治疗期内继续该治疗。 结果 总共 230 名患者（年龄范围，5 至 58 岁；53.9% 女性）以 2:1 的比例随机分配接受 L-谷氨酰胺（152 名患者）或安慰剂（78 名患者）。 L-谷氨酰胺组患者的疼痛危象明显少于安慰剂组（P=0.005），L-谷氨酰胺组中位数为3.0，安慰剂组为4.0。 L-谷氨酰胺组的住院次数少于安慰剂组 (P=0.005)，L-谷氨酰胺组的中位数为 2.0，安慰剂组的中位数为 3.0。两个试验组中三分之二的患者同时接受羟基脲治疗。低度恶心、非心源性胸痛、疲劳和肌肉骨骼疼痛在 L-谷氨酰胺组中比安慰剂组更常见。 结论 在患有镰状细胞性贫血的儿童和成人中，接受 L-谷氨酰胺单独或与羟基脲口服治疗的患者 48 周内疼痛危象的中位数数量低于接受安慰剂（联合用药）的患者。 或不含羟基脲。
BACKGROUNDOxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade L-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain.METHODSIn a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade L-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle jr-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period.RESULTSA total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive L-glutamine (152 patients) or placebo (78 patients). The patients in the L-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the L-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the L-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the L-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the L-glutamine group than in the placebo group.CONCLUSIONSAmong children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with L-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea.