Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa

项目总结/摘要 镰状细胞性贫血（SCA）是世界上最常见和最具破坏性的血液疾病之一， 每年超过30万新生儿。大多数患有SCA的婴儿出生在资源不足的环境中， 撒哈拉非洲，估计有50-90%的人由于缺乏早期诊断而在5岁前死亡， 适当的照顾。羟基脲是一种每日一次的口服药物，已成为 在高资源环境中治疗SCA儿童。现在有越来越多的证据支持 在撒哈拉以南非洲地区使用羟基脲治疗SCA的安全性和临床获益。的要求 然而，对于频繁的实验室监测和对血液学实验室毒性的关注， 广泛使用的羟基脲。我们最近开发了一种个性化的， 药代动力学指导的用于SCA儿童的羟基脲给药策略已被证明是最佳的 临床和实验室益处，毒性最小。在这个提案中，我们的目标是扩展这种精准医疗， 接近非洲。这项建议包括一项前瞻性，随机临床试验的羟基脲的儿童 在撒哈拉以南非洲的两个临床试验机构（安哥拉的罗安达和坦桑尼亚的姆万扎），这项研究将 成为第一个通过几个新功能为SCA儿童提供精准医疗的公司， 使用电池供电的HPLC仪测量羟基脲，并使用 一种基于计算机的自动算法研究的第一阶段将比较给药策略， 确定最佳的给药策略，第二阶段将重点关注羟基脲的安全性 有限的实验室监测。主要目标是确定可行性并评估 PK指导的羟基脲治疗非洲SCA儿童的临床获益，并提供证据支持 在这些情况下，最低限度的实验室监测与羟基脲治疗。我们将实现这些目标 具体目的1：比较两种羟基脲给药的临床获益 撒哈拉以南非洲SCA的治疗策略：一种新的个体化、PK指导的初始剂量， 随后的剂量递增和基于体重的剂量随后的剂量递增。我们假设PK- 与基于体重的臂相比，引导臂将减少镰刀相关的不良事件。 目的2：在实验室条件有限的情况下，评价羟基脲治疗撒哈拉以南非洲SCA儿童的安全性 监测.我们假设不良事件（≥ 3级）的频率没有差异 与对照组相比，在监测有限的情况下， 治疗导入期。探索性目标3：评价两种既定指标的效用和有效性， 之前在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） 和在羟基脲处理之后。我们假设基线HRQoL指标对于两种指标都较低 并将通过羟基脲治疗显著改善。

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.