Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Global Health Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Acta Haematol. 2023;146(2):95-105. doi: 10.1159/000526322. Epub 2022 Aug 17.
Stroke is a severe complication of sickle cell anemia (SCA), with devastating sequelae. Transcranial Doppler (TCD) ultrasonography predicts stroke risk, but implementing TCD screening with suitable treatment for primary stroke prevention in low-resource environments remains challenging. SPHERE (NCT03948867) is a prospective phase 2 open-label hydroxyurea trial for SCA in Tanzania.
After formal training and certification, local personnel screened children 2-16 years old; those with conditional (170-199 cm/s) or abnormal (≥200 cm/s) time-averaged mean velocities (TAMVs) received hydroxyurea at 20 mg/kg/day with dose escalation to maximum tolerated dose (MTD). The primary study endpoint is change in TAMV after 12 months of hydroxyurea; secondary endpoints include SCA-related clinical events, splenic volume and function, renal function, infections, hydroxyurea pharmacokinetics, and genetic modifiers.
Between April 2019 and April 2020, 202 children (average 6.8 ± 3.5 years, 53% female) enrolled and underwent TCD screening; 196 were deemed eligible by DNA testing. Most had numerous previous hospitalizations and transfusions, with low baseline hemoglobin (7.7 ± 1.1 g/dL) and %HbF (9.3 ± 5.4%). Palpable splenomegaly was present at enrollment in 49 (25%); average sonographic splenic volume was 103 mL (range 8-1,045 mL). TCD screening identified 22% conditional and 2% abnormal velocities, with hydroxyurea treatment initiated in 96% (45/47) eligible children.
SPHERE has built local capacity with high-quality research infrastructure and TCD screening for SCA in Tanzania. Fully enrolled participants have a high prevalence of elevated baseline TCD velocities and splenomegaly. SPHERE will prospectively determine the benefits of hydroxyurea at MTD for primary stroke prevention, anticipating expanded access to hydroxyurea treatment across Tanzania.
中风是镰状细胞贫血症（SCA）的严重并发症，会带来毁灭性的后果。经颅多普勒（TCD）超声检查可预测中风风险，但在资源匮乏的环境中，实施 TCD 筛查并进行适当的治疗以预防原发性中风仍然具有挑战性。SPHERE（NCT03948867）是坦桑尼亚一项针对 SCA 的前瞻性 2 期开放性羟基脲试验。
在经过正式培训和认证后，当地人员对 2-16 岁的儿童进行筛查；那些 TAMV 处于临界状态（170-199cm/s）或异常（≥200cm/s）的儿童接受 20mg/kg/天的羟基脲治疗，并逐步增加剂量至最大耐受剂量（MTD）。主要研究终点是羟基脲治疗 12 个月后 TAMV 的变化；次要终点包括与 SCA 相关的临床事件、脾脏体积和功能、肾功能、感染、羟基脲药代动力学和遗传修饰因子。
2019 年 4 月至 2020 年 4 月期间，共有 202 名儿童（平均年龄 6.8±3.5 岁，53%为女性）入组并接受了 TCD 筛查；196 名儿童通过 DNA 检测被认为符合条件。大多数儿童之前有多次住院和输血经历，基线血红蛋白（7.7±1.1g/dL）和 %HbF（9.3±5.4%）水平较低。49 名（25%）儿童在入组时即存在可触及的脾肿大；平均超声脾脏体积为 103mL（范围 8-1045mL）。TCD 筛查发现 22%的儿童存在临界 TCD 速度，2%的儿童存在异常 TCD 速度，96%（45/47）符合条件的儿童开始接受羟基脲治疗。
SPHERE 在坦桑尼亚建立了具有高质量研究基础设施和 TCD 筛查能力的当地能力。已完全入组的参与者基线 TCD 速度升高和脾肿大的患病率较高。SPHERE 将前瞻性地确定 MTD 下羟基脲治疗对原发性中风预防的益处，预计将在整个坦桑尼亚扩大羟基脲治疗的应用。
