Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa

在非洲精准推广羟基脲的利用和安全

• 批准号: 10675756
• 负责人: Patrick Thomas McGann
• 金额: $ 34.04万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675756
• 关键词: 2 year old; 5 year old; Address; Adult; Adverse event; Affect; Africa; Africa South of the Sahara; African; Algorithms; Angola; Blood; Caring; Cessation of life; Child; Child Mortality; Childhood; Clinical; Clinical Trials; Computers; Country; Development; Dose; Drug Kinetics; Early Diagnosis; Family; Fetal Hemoglobin; Frequencies; Hematological Disease; Hematology; High Pressure Liquid Chromatography; Infant; Inherited; Knowledge; Laboratories; Life; Measurement; Measures; Mentored Patient-Oriented Research Career Development Award; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Newborn Infant; Oral; Participant; Patients; Pharmaceutical Preparations; Phase; Placebos; Quality of life; Resource-limited setting; Resources; Running; Safety; Sickle Cell; Sickle Cell Anemia; Symptoms; Tanzania; Therapeutic; Toxic effect; Weight; appropriate dose; arm; clinical research site; clinically significant; dose individualization; experience; health related quality of life; hydroxyurea; improved; interpatient variability; mortality; novel; novel therapeutics; open label; participant enrollment; precision medicine; prevent; prospective; randomized, clinical trials; research study; safety and feasibility; sickling; standard of care; treatment strategy

Project Summary/Abstract Sickle cell anemia (SCA) is among the world’s most common and devastating blood disorders, affecting more than 300,000 newborns per year. The majority of infants with SCA are born in the low-resource settings of sub- Saharan Africa, where an estimated 50-90% will die before 5 years of age due to lack of early diagnosis and appropriate care. Hydroxyurea is a once-daily oral medication that has become the standard of care for the treatment of children with SCA in high-resource settings. There is now a growing body of evidence to support the safety and clinical benefits of hydroxyurea for the treatment of SCA in sub-Saharan Africa. The requirement for frequent laboratory monitoring and the concern for hematologic laboratory toxicities, however, will limit widespread hydroxyurea utilization. We have recently developed and prospectively evaluated an individualized, pharmacokinetics-guided hydroxyurea dosing strategy for children with SCA that has demonstrated optimal clinical and laboratory benefits with minimal toxicity. In this proposal, we aim to extend this precision medicine approach to Africa. This proposal includes a prospective, randomized clinical trial of hydroxyurea for children with SCA at two clinical sites in sub-Saharan African (Luanda, Angola and Mwanza, Tanzania). The study will be the first to bring precision medicine to children with SCA through several novel features including measurement of hydroxyurea using a battery-powered HPLC machine and individualized dose calculations using an automated computer-based algorithm. The first phase of the study will compare dosing strategies and determine the optimal dosing strategy, and the second phase will importantly address the safety of hydroxyurea therapy with limited laboratory monitoring. The primary objectives are to establish the feasibility and evaluate the clinical benefits of PK-guided hydroxyurea for children with SCA in Africa and to provide evidence to support minimal laboratory monitoring with hydroxyurea therapy in these settings. We will accomplish these objectives through the following Specific Aims: Specific Aim 1: To compare the clinical benefits of two hydroxyurea dosing strategies for treatment of SCA in sub-Saharan Africa: a novel individualized, PK-guided initial dose without subsequent escalation and a weight-based dose with subsequent dose escalation. We hypothesize that the PK- guided arm will have a reduction in sickle-related adverse events compared to the weight-based arm. Specific Aim 2: To evaluate the safety of hydroxyurea for children with SCA in sub-Saharan Africa with limited laboratory monitoring. We hypothesize that there will be no difference in the frequency of adverse events (Grade ≥ 3) unrelated to SCA during the period of hydroxyurea treatment with limited monitoring compared to the no treatment run-in period. Exploratory Aim 3: To evaluate the utility and validity of two established measures of health-related quality of life (HRQoL) for patients and families affected by SCA in Angola and Tanzania before and after hydroxyurea treatment. We hypothesize that baseline HRQoL measures will be low for both measures and will improve significantly with hydroxyurea treatment.

项目概要/摘要 镰状细胞性贫血 (SCA) 是世界上最常见、最具破坏性的血液疾病之一，影响着更多人 每年有超过 300,000 名新生儿患有 SCA，大多数出生在资源贫乏的地区。 撒哈拉非洲地区，由于缺乏早期诊断和治疗，预计 50-90% 的人将在 5 岁之前死亡 羟基脲是一种每日一次的口服药物，已成为患者的护理标准。 现在有越来越多的证据支持在资源丰富的环境中治疗 SCA 儿童。 羟基脲在撒哈拉以南非洲地区治疗 SCA 的安全性和临床益处。 然而，由于频繁的实验室监测和对血液实验室毒性的担忧将限制 我们最近开发并前瞻性评估了一种个性化的、 药代动力学指导的 SCA 儿童羟基脲给药策略已得到最佳证明 在这项提案中，我们的目标是扩展这种精准医学。 该提案包括一项针对儿童的羟基脲前瞻性随机临床试验。 该研究将在撒哈拉以南非洲的两个临床地点（安哥拉罗安达和坦桑尼亚姆万扎）进行 SCA 合作。 成为第一个通过多项新颖功能为患有 SCA 的儿童提供精准医疗的公司，其中包括 使用电池供电的 HPLC 机器测量羟基脲，并使用 该研究的第一阶段将比较剂量策略和基于自动计算机的算法。 确定最佳给药策略，第二阶段将重点解决羟基脲的安全性问题 有限实验室监测的治疗的主要目标是确定可行性并评估。 PK 引导的羟基脲对非洲 SCA 儿童的临床益处，并提供证据支持 在这些情况下，通过羟基脲治疗进行最少的实验室监测，我们将实现这些目标。 通过以下具体目标： 具体目标 1：比较两种羟基脲给药的临床益处 撒哈拉以南非洲地区 SCA 的治疗策略：一种新颖的个体化、PK 指导的初始剂量，无需 随后的剂量递增和基于体重的剂量随后的剂量递增我们认为 PK-。 与基于重量的特定手臂相比，引导手臂将减少与镰刀相关的不良事件。 目标 2：利用有限的实验室评估羟基脲对撒哈拉以南非洲儿童 SCA 的安全性 我们监测到不良事件发生频率不会有差异（等级≥3） 与无羟基脲治疗期间的 SCA 无关，监测有限。 探索性目标 3：评估两种既定措施的实用性和有效性。 之前安哥拉和坦桑尼亚受 SCA 影响的患者和家庭的健康相关生活质量 (HRQoL) 在羟基脲治疗后，我们发现这两项指标的基线 HRQoL 指标都较低。 并且通过羟基脲治疗会显着改善。