Optimizing Hydroxyurea Therapy in Children With Sickle Cell Anemia In Malaria Endemic Areas: The NOHARM Maximum Tolerated Dose (MTD) Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 250
- 试验地点
- 1
- 主要终点
- Composite measure of organ damage
研究概览
简要总结
NOHARM MTD is an extension of a previous study for children with Sickle Cell Anemia (SCA) who were enrolled in the NOHARM study. All children enrolled in NOHARM received hydroxyurea treatment at a fixed daily dose of 20 mg/kg/day. This dose was selected as a likely safe dose, but does not escalate hydroxyurea to maximum tolerated dose "MTD" as is commonly done in the US. Without this information, we cannot know whether hydroxyurea treatment at the MTD would be feasible (since it requires closer monitoring to avoid hematological toxicities), safe (since adverse events may be greater with MTD, risk of malaria may be altered by MTD, and risk of infections as a result of neutropenia could also be greater with MTD) or beneficial (MTD is associated with higher hemoglobin and fetal hemoglobin concentration).
详细描述
The purpose of this study is to determine the long-term effects of hydroxyurea treatment on internal organs, the best dosing strategies for children with SCA in Africa, and to identify any genetic factors that affect how a child responds to the study medication. All children in this study will receive the research treatment, hydroxyurea. Hydroxyurea is used to prevent SCA pain episodes and is approved by the European Medicines Agency for adults, adolescents, and children over two-years-old with SCA. During quarterly visits, we will collect information about your child with the study medication, hydroxyurea. This study is being conducted by Dr. Russell Ware at Cincinnati Children's Hospital Medical Center (CCHMC) and his Co-Investigators including Professor Grace Ndeezi and Dr. Phillip Kasirye at the Mulago Hospital Sickle Cell Clinic, and the hydroxyurea medicine is supplied by the manufacturer.
The goal of this clinical trial is to assess the long-term risks and benefits of open-label dose-escalated oral hydroxyurea in a large cohort of Ugandan adolescents with sickle cell anemia (SCA). Additional objectives include investigation of hydroxyurea pharmacokinetics (PK) and pharmacodynamics (PD) in this population, and investigation of the drug's mechanisms of action through advanced genomics and multiomics analysis.
The main questions it aims to answer are:
Aim 1. To determine the safety and efficacy of maximum tolerated dose (MTD) vs. fixed dose (20 mg/kg/day) hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. For safety, we will compare adverse events and severe adverse events, including hematologic toxicities. For efficacy, we will assess hemoglobin level, fetal hemoglobin percentage (% HbF), and incidence of vaso-occlusive events such as pain crisis and acute chest syndrome.
Aim 2. To compare the clinical outcomes of MTD vs. fixed dose hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. Clinical outcomes assessed will include growth and malaria incidence over a 24-month follow-up period, and differences in renal, splenic, and cerebrovascular function between study entry and 24-month follow-up.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 11 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adolescents with confirmed SCA who are currently enrolled in the NOHARM MTD Study of hydroxyurea at the Mulago Hospital Sickle Cell Clinic (MHSCC), will be eligible for the NOHARM MTD LT version 2.0 extension study after completing re-consent. An age-matched untreated (hydroxyurea-naïve) group of adolescents will also be enrolled as a Comparator Cohort. This will comprise 75 children from Kampala and surrounding districts, ages 11 - 18 years of age, with confirmed SCA.
排除标准
- 未提供
结局指标
主要结局
Composite measure of organ damage
时间窗: From enrollment, after 24 months and again after 48 months of study treatment.
The primary study endpoint will be a composite measure of organ damage to the brain (defined as ≥2 silent cerebral infarcts on brain MRI or ≥170 cm/sec flow velocities by TCD) or the kidneys (confirmed micro- or macro-albuminuria), or bones (femoral head AVN, Mitchell Stage B or higher).
次要结局
未报告次要终点