Arginine Therapy for Pain in Sickle Cell Disease: A Phase-2 Randomized, Placebo-Controlled Trial

IF 10.1 1区 医学 Q1 HEMATOLOGY
Claudia R. Morris, Dunia Hatabah, Rawan Korman, Scott Gillespie, Nitya Bakshi, Lou Ann Brown, Frank Harris, Deborah Leake, Chris A. Rees, Kirshma Khemani, Elliott P. Vichinsky, Alexus Locke, Bridget Wynn, Mark A. Griffiths, Hagar Wilkinson, Polly Kumari, Lisa Sudmeier, Sruti Shiva, Carlton D. Dampier
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引用次数: 0

Abstract

We present a prospective randomized, placebo-controlled trial of intravenous arginine in patients 3–21 years hospitalized with sickle cell disease vaso-occlusive pain episodes (SCD-VOE) at two tertiary-care children's hospitals. Participants were randomized into 1 of 3 arms: Standard-dose (SD; 100 mg/kg/dose) every 8 h, Loading-dose (200 mg/kg followed by SD), or Placebo. The primary outcome was total parenteral opioid use (TPO). Secondary outcomes included time-to-crisis-resolution, pain scores, patient-reported outcomes (PROs), arginine bioavailability, and biomarkers of oxidative stress/mitochondrial function. Of 1548 patients screened, 108 were randomized (36 per study-arm; mean 12.6 ± 3.8 years, 52% female, and 65% hemoglobin-SS). This study did not meet its primary endpoint. TPO, time-to-crisis-resolution, pain scores, and PROs at discharge were similar across arms. Post hoc sensitivity analyses of children 5–16 years old demonstrated nearly double TPO utilization in those receiving placebo versus arginine (n = 87, p = 0.056), achieving significance in patients with plasma arginine < 60 μM. Arginine was low at presentation in 79% of patients (mean 50 ± 28 μM), and increased with arginine therapy (p < 0.001). Arginine bioavailability at VOE presentation inversely correlated with time-to-crisis-resolution (r = −0.39, p = 0.01) after placebo, an association eliminated by arginine supplementation (r = −0.04, p = 0.70). A dose-dependent increase in platelet-mitochondrial activity occurred after arginine versus no change after placebo (p < 0.001); plasma protein-carbonyl levels, a measure of oxidative stress, decreased after arginine therapy (p < 0.001) but increased in the placebo group (p = 0.02). SCD-VOE is associated with an acquired arginine deficiency that correlates with worse clinical outcomes. Arginine improved mitochondrial function and decreased oxidative stress compared to placebo, with clinically relevant opioid-sparing becoming significant in children with the lowest arginine concentration.

Trial Registration

Registered with ClinicalTrials.gov (NCT02536170) in August 2015

精氨酸治疗镰状细胞病疼痛:一项2期随机安慰剂对照试验
我们提出了一项前瞻性随机、安慰剂对照试验,静脉注射精氨酸治疗在两家三级儿童医院住院的3-21岁镰状细胞病血管闭塞性疼痛发作(SCD-VOE)患者。参与者随机分为3组中的1组:标准剂量组(SD);100mg /kg/剂量)每8 h,负荷剂量(200mg /kg后SD),或安慰剂。主要终点是总静脉注射阿片类药物使用(TPO)。次要结局包括危机解决时间、疼痛评分、患者报告结局(PROs)、精氨酸生物利用度和氧化应激/线粒体功能的生物标志物。在筛选的1548例患者中,108例被随机分组(每个研究组36例;平均12.6±3.8岁,女性52%,血红蛋白- ss 65%)。这项研究没有达到其主要终点。TPO、危机解决时间、疼痛评分和出院时的PROs在两组之间相似。对5-16岁儿童的事后敏感性分析显示,接受安慰剂组的TPO利用率几乎是接受精氨酸组的两倍(n = 87, p = 0.056),在血浆精氨酸浓度为60 μM的患者中具有显著性。79%的患者出现症状时精氨酸水平较低(平均50±28 μM),并随着精氨酸治疗而升高(p < 0.001)。安慰剂后,VOE表现时精氨酸的生物利用度与危机解决时间呈负相关(r = - 0.39, p = 0.01),补充精氨酸消除了这一关联(r = - 0.04, p = 0.70)。精氨酸治疗后血小板-线粒体活性呈剂量依赖性增加,而安慰剂治疗后无变化(p < 0.001);血浆蛋白羰基水平(一种氧化应激指标)在精氨酸治疗后降低(p < 0.001),而安慰剂组升高(p = 0.02)。SCD-VOE与获得性精氨酸缺乏相关,后者与较差的临床结果相关。与安慰剂相比,精氨酸改善了线粒体功能,降低了氧化应激,在精氨酸浓度最低的儿童中,临床相关的阿片类药物节约变得显著。
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来源期刊
CiteScore
15.70
自引率
3.90%
发文量
363
审稿时长
3-6 weeks
期刊介绍: The American Journal of Hematology offers extensive coverage of experimental and clinical aspects of blood diseases in humans and animal models. The journal publishes original contributions in both non-malignant and malignant hematological diseases, encompassing clinical and basic studies in areas such as hemostasis, thrombosis, immunology, blood banking, and stem cell biology. Clinical translational reports highlighting innovative therapeutic approaches for the diagnosis and treatment of hematological diseases are actively encouraged.The American Journal of Hematology features regular original laboratory and clinical research articles, brief research reports, critical reviews, images in hematology, as well as letters and correspondence.
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