Sickle cell disease (SCD) is the most common hemoglobinopathy in the United States, and vaso-occlusive pain episodes (VOEs) are the leading cause of hospitalizations and emergency department (ED) visits.¹ There are limited therapies for the management of acute VOEs, which directly target the underlying etiology for sickle-related pain; therefore, treatment is largely symptomatic. Moderate to severe pain is typically treated with parenteral hydration, opioids, and hospitalization to achieve adequate pain control.

Arginine is a conditionally essential amino acid and the obligate substrate for nitric oxide (NO) synthesis. NO is a potent vasodilator, which is essential for vascular homeostasis; low NO bioavailability contributes to sickle cell vasculopathy. SCD is an “arginine-deficiency syndrome,” where low arginine bioavailability correlates with pulmonary hypertension risk, early mortality, and pain severity, predicting the need for pediatric hospitalization.^{2, 3} Arginine is also a precursor for kyotorphin (l-tyrosyl-l-arginine), an endogenous analgesic dipeptide.⁴ Intravenous (IV) arginine therapy was found to reduce opioid use by over 54% and significantly decrease pain scores in children hospitalized with SCD-VOEs compared to placebo in a phase-2 randomized, double-blinded, placebo-controlled trial (RCT).⁵ A recent RCT of oral arginine therapy in children hospitalized for SCD-VOEs in Nigeria similarly found a reduction in total analgesia, pain scores, time to crisis resolution, and the total length of hospital stay.⁴

IV arginine has an excellent safety profile, having received FDA approval for growth hormone stimulation testing in 1973, utilizing 500 mg/kg/dose (maximum 30 g/dose) over 30 min. IV arginine also has been used in the management of mitochondrial diseases and sepsis with few side effects.⁶ Adverse events (AEs) reported with IV arginine use include nausea, vomiting, headaches, flushing, dyspnea, and dose-dependent effects on blood pressure, electrolytes (e.g., potassium), and acid–base imbalance. Thus, it is important to determine whether IV arginine might increase the frequency or severity of these events during VOEs. A phase-2 RCT evaluating two IV arginine dosing regimens at Emory/Children's Healthcare of Atlanta has recently completed subject enrollment. The objective of the current report is to review the safety of IV arginine in this trial by examining the rates of AEs and serious adverse events (SAEs) after treatment across blinded study arms prior to locking the final data set for analysis of the primary and secondary end points.

This is a single-center, prospective, double-blind, RCT studying the effects of IV arginine therapy in children aged 3–21 years with SCD (any genotype) hospitalized for VOEs and requiring parenteral opioids. Patients with hepatic or renal dysfunction (ALT > 3 times normal upper limit, creatinine > 1.0 mg/dL, respectively), new SCD-specific therapy (e.g., hydroxyurea, voxelotor) in the last 3 months, Hgb < 5 g/dL, NO-based therapy in the last month, or those previously enrolled were excluded from study participation. Patients were randomized within 24 h of receiving their first dose of parenteral opioids in the ED into one of three IV arginine treatment arms: (a) standard dose (SD) (100 mg/kg/dose three times a day), (b) loading dose (200 mg/kg/dose) followed by SD, or (c) placebo (IV normal saline 1–2 mL/kg three times a day).

Demographics, clinical characteristics, time to crisis resolution, total parenteral opioid use, length of hospital stay, pain scores, blood biomarkers, and patient-reported outcomes were obtained before and after treatment. The primary outcome measure is the total parenteral opioid use between study arms. Lab values above the upper limit of normal range were considered elevated and reported as AEs if present after enrollment.

The sample size calculated for this study was 108 patients (36 per arm), based on Morris et al.⁵ Chi-squared/Fisher exact tests were utilized as indicated to compare development of AEs and SAEs across the randomization arms; a p-value < .05 was considered significant. The study protocol is approved by Emory University and Children's Healthcare of Atlanta Institutional Review Boards, conducted under an active Investigational New Drug (IND) #66943 (Sponsor-C.R.M.), registered with ClinicalTrials.gov (NCT02536170) and funded in part by FDA-R01FD004814-01A2 and NCCIH K24AT009893-01 (to C.R.M.).

A total of 1548 patients were screened, of which 266 were eligible with a guardian present; 114 were consented, 108 were randomized, and 6 were categorized as screen failures (Figure S1). The majority of patients (74%) were enrolled in the ED. The first patient was enrolled in March 2016; enrollment is now complete.

Patient demographics randomized by treatment group are provided in Table S1, which also includes a summary of the cumulative 372 AEs in 91 of 108 (84.3%) unique patients and 28 SAEs in 19 (17.6%) unique patients; these are classified by system and per treatment arm. There was a median of two AEs in patients who experienced them. Headache and gastrointestinal complaints including abdominal pain, nausea, and vomiting were the most commonly reported symptoms and often occurred before administration of the study drug; however, there were no significant differences across treatment arms in either the total AEs or in the AEs that occurred after initiation of treatment (Table S1).

Multiple parameters were monitored during the study, as documented in Table 1. Serum bilirubin, AST, and ALT (markers of liver function and hemolysis) were elevated at the time of randomization in some patients and increased after treatment, but there were no significant differences across treatment arms in total liver function AEs or in those that occurred after treatment. Although statistically significant differences among study arms were noted in serum blood urea nitrogen (BUN), serum bicarbonate, and serum potassium, they were not clinically relevant (Table 1).

A cumulative total of 28 SAEs occurred in 19 of 108 unique subjects (17.6%) (2 SAEs occurred during a single prolonged hospitalization and 26 involved re-hospitalizations within 30 days). There was a median of one SAE per patient with any SAE, with a maximum of five SAEs occurring in one patient. There were no SAEs “definitely related” to the study drug administration, nine SAEs were “possibly related” (re-hospitalization within 7 days), and the rest were “unlikely related” or “not related” to the study.

No differences in the seriousness (p = .208), severity (p = .165), or relatedness (p = .493) for all events (SAEs and AEs) or those that occurred after treatment were identified across treatment arms.

This interim report on the safety of IV arginine in children with SCD hospitalized with VOEs reaffirms prior reports on the safety of IV arginine therapy in this patient population.^4-6 IV arginine therapy has been successfully used in the treatment of multiple medical conditions including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), acute metabolic strokes in primary mitochondrial disease (e.g., Kearns Sayre syndrome), and hyperammonemia crises due to urea cycle defects and improves mitochondrial function in SCD.⁶ IV arginine is administered as an arginine hydrochloride infusion and is generally well tolerated with minimal side effects. AEs reported in the literature with IV arginine include changes in blood pressure, potassium, phosphate, acid–base status, and blood glucose, with pharmacokinetic studies reporting AEs related to the dose and rate of IV arginine infusion.

As expected in a study of hospitalized patients with SCD, AEs were common, with a cumulative 372 AEs documented in 91 unique patients. Headaches and gastrointestinal complaints are established AEs associated with IV arginine, which were also observed in this study. These symptoms, which may be side effects of opioid use or may be features of VOE for some patients, were frequently present before patients received the study drug, and there were no differences in AEs that occurred after treatment. No new AEs emerged compared to what have previously been reported with arginine therapy. All SAEs were associated with re-hospitalization mainly for pain or acute chest syndrome (ACS), or prolonged hospitalization. Less than 10% of patients were re-hospitalized at least once within 7 days of discharge, which is lower than published readmission rates of up to 20%.⁵ No statistically significant differences in SAEs were found across study arms.

The results of this study are congruent with the available literature demonstrating no significant or clinically relevant changes in renal or liver function or changes in electrolytes or acid–base status with the administration of IV arginine. The observed mild decrease in serum bicarbonate did not result in acidosis, nor did any increase in serum potassium result in hyperkalemia. These findings are of clinical relevance since they could allow for less intensive lab monitoring during therapy and therefore reduce the need for multiple blood draws. Additionally, patients hospitalized for VOEs typically receive NSAIDs as part of their analgesia regimen; the observation of a stable creatinine level from admission to the time of discharge likely means that IV arginine will be well tolerated in patients receiving NSAID therapy.

Of particular interest in this study was the finding of elevated serum ALT levels in some patients before randomization, which continued to rise during the course of the study. This was unlikely to be related to IV arginine administration since it was observed in all three arms and might represent the course of liver dysfunction during VOEs not previously described. Although this observation may not warrant any medical intervention, the presence of abnormal liver function tests may be of clinical importance in some patients hospitalized with VOEs who often receive potentially hepatotoxic drugs like acetaminophen as part of their analgesia regimen.

To conclude, in this RCT of IV arginine administration for the treatment of SCD patients hospitalized with VOEs, no unexpected SAEs occurred and SAE/AE rates were similar across study arms. IV arginine was generally well tolerated without the observation of new clinical or biochemical AEs compared to other arginine studies. This study provides further support for the safety of IV arginine therapy in children with SCD.

镰状细胞病 (SCD) 是美国最常见的血红蛋白病，血管闭塞性疼痛发作 (VOE) 是住院和急诊 (ED) 就诊的主要原因。¹急性 VOE 的治疗方法有限，直接针对镰刀相关疼痛的潜在病因；因此，治疗主要是对症治疗。中度至重度疼痛通常通过肠胃外水化、阿片类药物和住院治疗来实现充分的疼痛控制。

精氨酸是一种条件必需氨基酸，是一氧化氮 (NO) 合成的必需底物。NO 是一种有效的血管扩张剂，对血管稳态至关重要；低 NO 生物利用度会导致镰状细胞血管病变。SCD 是一种“精氨酸缺乏综合征”，其中低精氨酸生物利用度与肺动脉高压风险、早期死亡率和疼痛严重程度相关，预示着需要儿科住院治疗。^{2, 3}精氨酸也是 kyotorphin（l -酪氨酰 - l -精氨酸）的前体，kyotorphin是一种内源性镇痛二肽。^4个在一项 2 期随机、双盲、安慰剂对照试验 (RCT) 中，与安慰剂相比，静脉 (IV) 精氨酸疗法可减少超过 54% 的阿片类药物使用，并显着降低因 SCD-VOE 住院的儿童的疼痛评分。⁵最近一项对尼日利亚因 SCD-VOE 住院的儿童进行口服精氨酸治疗的随机对照试验同样发现，总体镇痛、疼痛评分、危机解决时间和总住院时间均有所减少。^4个

IV 精氨酸具有出色的安全性，已于 1973 年获得 FDA 批准用于生长激素刺激测试，在 30 分钟内使用 500 mg/kg/剂量（最大 30 g/剂量）。IV 精氨酸也已用于治疗线粒体疾病和败血症，几乎没有副作用。^6个IV 精氨酸报告的不良事件 (AE) 包括恶心、呕吐、头痛、潮红、呼吸困难，以及对血压、电解质（如钾）和酸碱失衡的剂量依赖性影响。因此，重要的是要确定 IV 精氨酸是否会增加 VOE 期间这些事件的频率或严重程度。一项评估亚特兰大埃默里/儿童保健中心的两种 IV 精氨酸给药方案的 2 期 RCT 最近完成了受试者注册。本报告的目的是在锁定最终数据集以分析主要和次要数据之前，通过检查盲法研究组治疗后 AE 和严重不良事件 (SAE) 的发生率来审查 IV 精氨酸的安全性终点。

这是一项单中心、前瞻性、双盲、随机对照试验，研究 IV 精氨酸治疗对因 VOE 住院并需要肠外阿片类药物的 3-21 岁 SCD（任何基因型）儿童的影响。肝或肾功能不全患者（ALT > 正常上限的 3 倍，肌酐分别 > 1.0 mg/dL），最近 3 个月内新的 SCD 特异性治疗（例如，羟基脲，voxelotor），Hgb < 5 g/dL，上个月进行过基于 NO 的治疗，或之前入组的患者被排除在研究参与之外。患者在 ED 中接受第一剂肠外阿片类药物后 24 小时内被随机分配到三个 IV 精氨酸治疗组之一：(a) 标准剂量 (SD)（100 mg/kg/剂量，每天三次），(b)负荷剂量（200 mg/kg/剂量），然后是 SD，或 (c) 安慰剂（IV 生理盐水 1–2 mL/kg，每天三次）。

在治疗前后获得人口统计学、临床特征、危机解决时间、肠外阿片类药物使用总量、住院时间、疼痛评分、血液生物标志物和患者报告的结果。主要结果指标是研究组之间的总肠外阿片类药物使用情况。高于正常范围上限的 Lab 值被认为升高，如果在注册后出现，则报告为 AE。

根据 Morris 等人的数据，为本研究计算的样本量为 108 名患者（每组 36 名）。⁵卡方/Fisher 精确检验被用于比较随机分组中 AE 和 SAE 的发展；p值 < .05 被认为是显着的。该研究方案经埃默里大学和亚特兰大儿童保健机构审查委员会批准，根据有效的新药研究 (IND) #66943（赞助商-CRM）进行，已在 ClinicalTrials.gov ( NCT02536170 ) 注册，部分资金由FDA- R01FD004814-01A2 和 NCCIH K24AT009893-01（至 CRM）。

共筛选了1548名患者，其中266名符合条件且有监护人在场；114 人获得同意，108 人被随机分配，6 人被归类为筛选失败（图 S1）。大多数患者 (74%) 被纳入 ED。第一位患者于 2016 年 3 月入组；注册现已完成。

表 S1 提供了按治疗组随机分组的患者人口统计数据，其中还包括 108 名 (84.3%) 独特患者中 91 名的累积 372 次 AE 和 19 名 (17.6%) 独特患者中的 28 次 SAE 的总结；这些按系统和每个治疗组分类。经历过 AE 的患者中有两个 AE 的中位数。头痛和胃肠道不适，包括腹痛、恶心和呕吐，是最常报告的症状，通常发生在研究药物给药之前；然而，在总 AE 或治疗开始后发生的 AE 方面，治疗组之间没有显着差异（表 S1）。

研究期间监测了多项参数，如表 1 所示。一些患者的血清胆红素、AST 和 ALT（肝功能和溶血标志物）在随机分组时升高，治疗后升高，但无显着差异在总肝功能 AE 或治疗后发生的 AE 中跨治疗组。尽管研究组之间在血清血尿素氮 (BUN)、血清碳酸氢盐和血清钾方面存在统计学显着差异，但它们在临床上并不相关（表 1）。

108 名独立受试者中有 19 名 (17.6%) 累计发生 28 起 SAE（2 起 SAE 发生在单次长期住院期间，26 起涉及 30 天内再次住院）。每名患者有一次 SAE 的中位数，其中一名患者最多发生五次 SAE。没有与研究药物管理“明确相关”的 SAE，9 个 SAE 与研究“可能相关”（7 天内再次住院），其余与研究“不太可能相关”或“不相关”。

 所有事件（SAE 和 AE）或治疗后发生的事件在治疗组之间的严重性 ( p = .208)  、严重性 ( p =  .165) 或相关性 ( p = .493)没有差异。

这份关于因 VOE 住院的 SCD 患儿静脉注射精氨酸安全性的中期报告重申了之前关于静脉注射精氨酸治疗在该患者群体中的安全性的报告。^4-6 IV 精氨酸疗法已成功用于治疗多种疾病，包括线粒体脑病伴乳酸性酸中毒和中风样发作 (MELAS)、原发性线粒体疾病引起的急性代谢性中风（例如 Kearns Sayre 综合征）和高氨血症危象由于尿素循环缺陷并改善 SCD 中的线粒体功能。^6个IV精氨酸作为精氨酸盐酸盐输注给药，通常耐受性良好，副作用最小。文献中报告的静脉注射精氨酸的不良事件包括血压、钾、磷酸盐、酸碱状态和血糖的变化，药代动力学研究报告了与静脉注射精氨酸的剂量和速率相关的不良事件。

正如在一项针对 SCD 住院患者的研究中预期的那样，AE 很常见，在 91 名独特患者中记录了累计 372 起 AE。头痛和胃肠道不适是与 IV 精氨酸相关的既定 AE，在本研究中也观察到了这些 AE。这些症状可能是阿片类药物使用的副作用，也可能是一些患者的 VOE 特征，在患者接受研究药物之前经常出现，并且治疗后发生的 AE 没有差异。与之前报道的精氨酸疗法相比，没有出现新的 AE。所有 SAE 都与主要因疼痛或急性胸部综合征 (ACS) 或住院时间延长而再次住院有关。不到 10% 的患者在出院后 7 天内至少再次住院一次，⁵在研究组中未发现 SAE 存在统计学上的显着差异。

这项研究的结果与现有文献一致，表明静脉注射精氨酸后肾功能或肝功能或电解质或酸碱状态没有显着或临床相关的变化。观察到的血清碳酸氢盐轻度下降并未导致酸中毒，血清钾的任何增加也未导致高钾血症。这些发现具有临床相关性，因为它们可以在治疗期间减少密集的实验室监测，从而减少多次抽血的需要。此外，因 VOE 住院的患者通常会接受非甾体抗炎药作为其镇痛方案的一部分；观察到从入院到出院时肌酐水平稳定可能意味着接受 NSAID 治疗的患者对静脉注射精氨酸的耐受性良好。

这项研究特别令人感兴趣的是，一些患者在随机分组前发现血清 ALT 水平升高，并在研究过程中持续升高。这不太可能与 IV 精氨酸给药有关，因为在所有三个组中都观察到它，并且可能代表之前未描述的 VOE 期间的肝功能障碍过程。尽管这一观察结果可能不需要任何医疗干预，但肝功能检查异常的存在对于一些因 VOE 住院的患者可能具有临床重要性，这些患者经常接受对乙酰氨基酚等潜在肝毒性药物作为其镇痛方案的一部分。

总之，在这项 IV 精氨酸给药治疗因 VOE 住院的 SCD 患者的随机对照试验中，没有发生意外的 SAE，并且 SAE/AE 率在研究组之间相似。与其他精氨酸研究相比，IV 精氨酸通常耐受性良好，没有观察到新的临床或生化 AE。该研究进一步支持静脉注射精氨酸治疗 SCD 儿童的安全性。