Arginine therapy for the treatment of pain in children with sickle cell disease

 描述(由申请人提供)：镰状细胞病(SCD)中的血管闭塞性疼痛发作(VOE)是住院、急诊科(ED)就诊的主要原因，与死亡率增加有关。治疗选择有限。自从我们发现SCD和VOE的儿童精氨酸水平低后，我们对54名需要住院的VOE儿童进行了一项随机、双盲、安慰剂对照的精氨酸治疗试验。我们观察到，与安慰剂相比，接受100 mg/kg/剂量TID IV精氨酸治疗5天的儿童的阿片类药物总使用量减少了54%，出院时疼痛评分显著降低，住院时间减少了近17小时，这一趋势与临床相关。对于伴有VOE的儿童SCD患者，精氨酸是一种安全而廉价的干预措施，具有节省麻醉药物的效果。这一应用将开发基础设施，以设计一种关键的临床试验，使用精氨酸作为治疗SCD儿童VOE的新疗法，这可能会改变临床实践。目的1将进行目前缺乏的关键药代动力学(PK)和药效学研究，以评估团注和持续滴注精氨酸疗法，以确定 达到和维持精氨酸水平的最佳剂量，足以在细胞内转运精氨酸和最大限度地产生一氧化氮(NO)。基线及每日血浆精氨酸及其代谢物、精氨酸酶、红细胞内精氨酸浓度、尿精氨酸、精氨酸 类似物，没有代谢物将与21名住院患者获得的8小时PK数据一起测量。临床结果，如疼痛危象缓解时间、急诊和住院时间、阿片类药物总使用量和疼痛评分将被获得。AIM 2A将根据国家标准创建基于ED的标准化疼痛治疗方案，该方案将与所有潜在站点共享，其中包括17个大容量儿科急救应用研究网络(PECARN)和非PECARN ED。通过对每个站点的20个连续图表进行图表检查，将前瞻性地确定与此标准做法不同的站点变异性。Aim 2B将收集 对所有符合条件的SCD和VOE患者的潜在地点急诊室的容量和入院率的可行性数据进行了为期12个月的评估，以证明在建议的网络中有足够的机会接触到目标研究人群。AIM 3将建立一个在设计和成功完成SCD-VOE临床试验方面经验丰富的临床研究人员网络。我们组建了一个在SCD临床试验方面经验丰富的方案指导委员会，并获得了PECARN的认可，PECARN是美国唯一一个由联邦政府资助的儿科ED网络。PECARN的参与将确保获得具有良好研究记录的大量儿科ED，并在基于ED的多中心试验中取得成功。这些目标的完成将提供必要的数据，以确定精氨酸治疗的最佳剂量策略，建立临床网络、数据协调计划、基于ED的止痛方案以及L-精氨酸治疗SCD儿童血管闭塞性疼痛的第三阶段临床试验的完整方案，该方案将向美国国立卫生研究院提交资金申请。

 DESCRIPTION (provided by applicant): Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency department (ED) visits & are associated with increased mortality. Treatment options are limited. Since we discovered that children with SCD & VOE have low arginine levels, we performed a randomize, double-blinded, placebo-controlled trial of arginine therapy in 54 children with VOE requiring hospitalization. We observed a 54% reduction in total opioid use & significantly lower pain scores at discharge in children who received 5 days of 100 mg/kg/dose TID IV arginine therapy compared to placebo, as well as a clinically relevant trend in reduced length of hospital stay of nearly 17 hours. Arginine is a safe & inexpensive intervention with narcotic-sparing effects in pediatric SCD patients with VOE. This application will develop the infrastructure to design a pivotal clinical tral using arginine as a novel treatment of VOE in children with SCD that may change clinical practice. Aim 1 will perform critical pharmacokinetics (pK) and pharmacodynamics studies currently lacking, to evaluate bolus dosing vs. continuous infusion of arginine therapy to identify the optimal dose to achieve and maintain plasma arginine levels sufficient for intracellular arginine transport & maximal nitric oxide (NO) production. Baseline & daily plasma arginine & its metabolites, arginase, intracellular erythrocyte arginine concentration, urinary arginine, arginine analogs, & NO metabolites will be measured together with 8-hour pK data obtained in 21 hospitalized patients. Clinical outcomes such as time-to-pain- crisis-resolution, length of ED & hospital stay, total opioid use, & pain scores will be obtained. Aim 2A will create a standardized ED-based pain therapy protocol based on national standards that will be shared with all potential sites, which include 17 high-volume Pediatric Emergency Care Applied Research Network (PECARN) & non-PECARN EDs. Site variability from this standard practice will be prospectively identified by chart review of 20 consecutive charts at each site. Aim 2B will collect feasibility data on volume & admission rates from the EDs of potential sites on all eligible patients with SCD & VOE evaluated over a 12-month period in order to demonstrate sufficient access to the targeted study population within the proposed network. Aim 3 will establish a network of clinical investigators highly experienced in the design & successful completion of clinical trials in SCD-VOE. We have assembled a highly experienced Protocol Steering Committee with expertise in SCD clinical trials, & obtained the endorsement of PECARN, the only federally-funded pediatric ED network in the U.S. PECARN participation will insure access to high-volume pediatric EDs with a strong research track record & success in ED-based multi-center trials. Completion of these aims will provide data necessary to identify optimal dosing strategy for arginine therapy, establish a clinical network, data coordinating plan, an ED- based pain protocol and a completed protocol for a phase III clinical trial of L-arginine for the treatmet of vaso- occlusive pain in children with SCD to be submitted for NIH funding.