Stroke Prevention with Hydroxyurea Enabled through Research and Education: A Phase 2 Primary Stroke Prevention Trial in Sub-Saharan Africa.

IF 1.7 4区医学 Q3 HEMATOLOGY Acta Haematologica Pub Date : 2023-01-01 Epub Date: 2022-08-17 DOI:10.1159/000526322

Luke R Smart, Emmanuela E Ambrose, Georgina Balyorugulu, Primrose Songoro, Idd Shabani, Protas Komba, Mwesige Charles, Thad A Howard, Kathryn E McElhinney, Sara M O'Hara, Jodie Odame, Maria Nakafeero, Janet Adams, Susan E Stuber, Adam Lane, Teresa S Latham, Abel N Makubi, Russell E Ware

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Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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通过研究和教育促进羟基脲预防中风：撒哈拉以南非洲地区的中风初级预防 2 期试验。

导言：中风是镰状细胞性贫血（SCA）的一种严重并发症，具有毁灭性的后遗症。经颅多普勒（TCD）超声波检查可预测中风风险，但在资源匮乏的环境中，实施TCD筛查和适当的治疗以预防中风的发生仍具有挑战性。SPHERE（NCT03948867）是一项在坦桑尼亚进行的前瞻性羟基脲治疗 SCA 的 2 期开放标签试验：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；时间平均流速（TAMVs）有条件（170-199 cm/s）或异常（≥200 cm/s）的儿童接受羟基脲治疗，剂量为 20 mg/kg/天，剂量递增至最大耐受剂量（MTD）。主要研究终点为服用羟基脲 12 个月后 TAMV 的变化；次要终点包括 SCA 相关临床事件、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，202 名儿童（平均 6.8 ± 3.5 岁，53% 为女性）加入并接受了 TCD 筛查；196 名儿童通过 DNA 检测被认为符合条件。大多数儿童曾多次住院和输血，基线血红蛋白（7.7 ± 1.1 g/dL）和%HbF（9.3 ± 5.4%）较低。49例（25%）患者在入院时可触及脾脏肿大；平均声像图脾脏体积为103 mL（范围为8-1,045 mL）。TCD筛查发现了22%的有条件异常速度和2%的异常速度，96%（45/47）符合条件的儿童开始接受羟基脲治疗：SPHERE为坦桑尼亚建立了高质量的研究基础设施和TCD筛查SCA的地方能力。完全入组的参与者中，基线 TCD 速度升高和脾脏肿大的发病率较高。SPHERE 将前瞻性地确定羟基脲在 MTD 阶段对中风一级预防的益处，预计将在坦桑尼亚全国范围内推广羟基脲治疗。

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来源期刊

Acta Haematologica 医学-血液学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： ''Acta Haematologica'' is a well-established and internationally recognized clinically-oriented journal featuring balanced, wide-ranging coverage of current hematology research. A wealth of information on such problems as anemia, leukemia, lymphoma, multiple myeloma, hereditary disorders, blood coagulation, growth factors, hematopoiesis and differentiation is contained in first-rate basic and clinical papers some of which are accompanied by editorial comments by eminent experts. These are supplemented by short state-of-the-art communications, reviews and correspondence as well as occasional special issues devoted to ‘hot topics’ in hematology. These will keep the practicing hematologist well informed of the new developments in the field.