Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa

项目摘要/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，影响更多的是 每年有300,000个新生儿。大多数患有SCA的婴儿出生在低资源环境下 撒哈拉非洲，估计有50%-90%的人将在5岁前死亡，原因是缺乏早期诊断和 适当的照顾。羟基脲是一种每日一次的口服药物，已成为治疗糖尿病的标准药物。 在高资源环境下对患有SCA儿童的治疗。现在有越来越多的证据支持 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。这一要求 然而，对于频繁的实验室监测和对血液学实验室毒性的担忧，将限制 羟基尿素的广泛利用。我们最近开发并前瞻性评估了一种个性化的、 药代动力学指导的羟基尿素给药策略对儿童SCA的治疗效果最佳 临床和实验室受益，毒性最小。在这项提案中，我们的目标是扩大这一精准医疗 对非洲的态度。该提案包括一项儿童羟基脲的前瞻性随机临床试验。 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)与SCA合作。这项研究将 是第一个通过几个新颖的功能为患有SCA的儿童带来精准医疗的公司，包括 使用电池供电的高效液相色谱仪测量羟基尿素，并使用 一种基于计算机的自动算法。这项研究的第一阶段将比较给药策略和 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 在有限的实验室监测下进行治疗。主要目标是确定可行性并评估 PK引导下羟基脲治疗非洲儿童SCA的临床疗效及证据支持 在这些环境下，使用羟基脲治疗进行最低限度的实验室监测。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效果 撒哈拉以南非洲SCA的治疗策略：一种新的个体化、PK引导的初始剂量 随后的剂量升级和基于体重的剂量以及随后的剂量升级。我们假设PK- 与基于重量的手臂相比，引导手臂将减少与镰刀相关的不良事件。特定的 目的2：在实验室有限的情况下，评价羟基脲治疗撒哈拉以南非洲儿童SCA的安全性 监控。我们假设不良事件的发生频率没有差别(≥3级) 监测有限的羟基脲治疗期间与SCA无关，与NO 治疗磨合期。探索性目标3：评估两种已建立的测量方法的实用性和有效性 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) 羟基脲治疗后。我们假设基线的HRQOL测量对于这两个测量都是低的 羟基脲治疗后可明显改善。

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.