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

精氨酸疗法治疗镰状细胞病儿童的疼痛

• 批准号: 9059771
• 负责人: Claudia R Morris
• 金额: $ 19.73万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059771
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute Pain; Admission activity; Affect; Amino Acids; Applied Research; Arginine; Biological Availability; Blood; Blood Cells; Blood Vessels; Bolus Infusion; Cell Adhesion Molecules; Child; Childhood; Clinical; Clinical Investigator; Clinical Trials; Complex; Continuous Infusion; Crete; Data; Data Collection; Data Coordinating Center; Death Rate; Dose; Down-Regulation; Drug Kinetics; Electrons; Emergency Care; Emergency Medicine; Emergency department visit; Erythrocytes; Event; Funding; Future; Grant; Health; Healthcare; Hematologist; Hospitalization; Hour; Hydration status; Individual; Infusion procedures; Intervention; Intracellular Transport; Intravenous; Length; Length of Stay; Lung; Magnesium; Measures; Multicenter Trials; Narcotics; Nitric Oxide; Opioid; Outcome; Pain; Pain management; Pathway interactions; Patients; Pharmacodynamics; Phase; Phase III Clinical Trials; Placebos; Plasma; Platelet Aggregation Inhibition; Production; Protocols documentation; Randomized; Reperfusion Injury; Research; Research Infrastructure; Resolution; Safety; Schools; Sickle Cell Anemia; Site; Specialist; Supplementation; Time; United States National Institutes of Health; Urine; Vasodilator Agents; analog; arginase; arginine treatment; base; clinical practice; clinically relevant; design; double-blind placebo controlled trial; experience; improved; laboratory facility; metabolome; mortality; novel; novel therapeutics; opioid use; oxidation; pleiotropism; protocol development; study population; success; trend; urinary; vaso-occlusive pain

 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.

 描述（由申请人提供）：镰状细胞病（SCD）的血管闭塞性疼痛发作（VOE）是住院、急诊（艾德）就诊的主要原因，并与死亡率增加相关。治疗选择有限。由于我们发现SCD和VOE患儿精氨酸水平较低，我们对54例需要住院治疗的VOE患儿进行了精氨酸治疗的随机、双盲、安慰剂对照试验。我们观察到，与安慰剂相比，接受5天100 mg/kg/剂TID IV精氨酸治疗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，住院时间缩短近17小时的临床相关趋势。精氨酸是一种安全、廉价的干预措施，对伴有VOE的儿童SCD患者具有麻醉保护作用。本申请将开发基础设施，以设计使用精氨酸作为SCD儿童VOE新治疗的关键临床试验，这可能会改变临床实践。目标1将进行目前缺乏的关键药代动力学（PK）和药效学研究，以评价精氨酸治疗的推注给药与连续输注， 最佳剂量，以达到和维持血浆精氨酸水平足以细胞内精氨酸转运和最大的一氧化氮（NO）的生产。基线和每日血浆精氨酸及其代谢产物、精氨酸酶、红细胞内精氨酸浓度、尿精氨酸、精氨酸 类似物和NO代谢物将与在21名住院患者中获得的8小时pK数据一起测量。将获得临床结局，如疼痛危机解决时间、艾德和住院时间、阿片类药物总使用量和疼痛评分。Aim 2A将根据国家标准创建一个标准化的基于ED的疼痛治疗方案，该方案将与所有潜在的研究中心共享，其中包括17个高容量的儿科急救应用研究网络（PECARN）和非PECARN ED。将通过对每个研究中心的20个连续图表进行图表审查，前瞻性地识别本标准实践的研究中心变异性。目标2B将收集 评估12个月内潜在研究中心急诊室对所有符合条件的SCD和VOE患者的容量和入院率的可行性数据，以证明可以充分接触拟议网络内的目标研究人群。目标3将建立一个在SCD-VOE临床试验设计和成功完成方面经验丰富的临床研究者网络。我们已经组建了一个经验丰富的方案指导委员会，具有SCD临床试验方面的专业知识，并获得了美国唯一一个联邦资助的儿科艾德网络PECARN的认可。PECARN的参与将确保获得大量儿科ED，并在基于ED的多中心试验中获得良好的研究记录和成功。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，基于艾德的疼痛方案和L-精氨酸治疗SCD儿童血管闭塞性疼痛的III期临床试验的完整方案，以提交NIH资助。