Hydroxyurea with dose escalation for primary stroke risk reduction in children with sickle cell anaemia in Tanzania (SPHERE): an open-label, phase 2 trial.
Hydroxyurea with dose escalation for primary stroke risk reduction in children with sickle cell anaemia in Tanzania (SPHERE): an open-label, phase 2 trial.
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羟基脲通过剂量递增降低坦桑尼亚镰状细胞性贫血儿童的原发性中风风险（SPHERE）：一项开放标签的 2 期试验。
DOI：
10.1016/s2352-3026(22)00405-7
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Smart,LukeR
中科院分区：
文献类型：
--
作者：
Ambrose,EmmanuelaE;Latham,TeresaS;Songoro,Primrose;Charles,Mwesige;Lane,AdamC;Stuber,SusanE;Makubi,AbelN;Ware,RussellE;Smart,LukeR
经颅多普勒筛查联合长期输血可降低镰状细胞贫血儿童的卒中风险，但在资源匮乏的环境中并不可行。羟基脲是降低中风风险的替代治疗。我们的目的是估计在坦桑尼亚的镰状细胞贫血的儿童中风的风险，并确定疗效的羟基脲，以减少和预防stroke.MethodsWe做了一个开放标签，2期试验（球）在布甘多医疗中心，姆万扎，坦桑尼亚。经血红蛋白电泳确诊为镰状细胞贫血的2-16岁儿童有资格入组。参与者由当地检查员进行经颅多普勒超声筛查。多普勒速度升高的受试者，无论是条件性（170-199 cm/s）还是异常（≥200 cm/s），均接受口服羟基脲，起始剂量为20 mg/kg，每日一次，每8周一次，剂量递增至5 mg/kg/天，直至最大耐受剂量。多普勒速度正常（<170 cm/s）的参与者接受镰状细胞贫血诊所的常规护理，并在12个月后重新筛选，以确定他们是否符合试验治疗的条件。主要终点是从基线访视到12个月的羟基脲治疗后经颅多普勒血流速度的变化，在所有具有配对基线和12个月治疗后随访测量值的患者中进行分析。在符合方案人群（所有接受研究治疗的受试者）中分析安全性。这项研究在ClinicalTrials.gov注册，NCT 03948867。结果在2019年4月24日至2020年4月9日期间，202名儿童入组并接受了经颅多普勒筛查。196名参与者（平均年龄6.8岁[SD 3.5]，103名[53%]为女性，93名[47%]为男性）通过基于DNA的检测证实了镰状细胞贫血。在基线筛选时，196名参与者中有47名（24%）经颅多普勒速度升高（43名[22%]条件性，4名[2%]异常）; 45名开始使用平均剂量为20.2 mg/kg/d（SD 1.4）的羟基脲，12个月后平均剂量递增至27.4 mg/kg/d（5.1）。在12个月（± 1个月;中位数11个月，IQR 11-12）和24个月（±3个月;中位数22个月，22-22）后分析治疗反应。经颅多普勒血流速度从基线时的182 cm/s（12）下降到平均149 cm/s（SD 27），显著低于基线（p<0·0001），42名参与者在治疗12个月后平均下降35 cm/s（SD 23），基线和12个月的配对结果可用。没有发生临床中风，42名参与者中有35名（83%）恢复到正常的经颅多普勒速度。临床不良反应轻微，剂量限制性毒性不常见。最常见的3级不良事件是疟疾（45例患者中12例[29%]发作）和败血症（13例[32%]发作）。有三个严重的不良事件，其中没有一个是治疗相关的，没有治疗相关的死亡happened.InterpretationChildren与镰状细胞贫血在坦桑尼亚有一个高基线中风的风险。最大耐受剂量的羟基脲可显著降低经颅多普勒血流速度并降低原发性卒中风险。经颅多普勒筛查加最大耐受剂量的羟基脲是一种有效的卒中预防策略，支持撒哈拉以南非洲地区镰状细胞贫血患者更广泛地使用羟基脲。
BackgroundTranscranial Doppler screening with chronic transfusions reduces stroke risk in children with sickle cell anaemia but is not feasible in low-resource settings. Hydroxyurea is an alternative treatment to decrease stroke risk. We aimed to estimate stroke risk in children with sickle cell anaemia in Tanzania and to determine the efficacy of hydroxyurea to decrease and prevent stroke.MethodsWe did an open-label, phase 2 trial (SPHERE) at Bugando Medical Centre, Mwanza, Tanzania. Children aged 2–16 years with a diagnosis of sickle cell anaemia confirmed by haemoglobin electrophoresis were eligible for enrolment. Participants had transcranial Doppler ultrasound screening by a local examiner. Participants with elevated Doppler velocities, either conditional (170–199 cm/s) or abnormal (≥200 cm/s), received oral hydroxyurea starting at 20 mg/kg once daily and escalated every 8 weeks by 5 mg/kg per day to the maximum tolerated dose. Participants with normal Doppler velocities (<170 cm/s) received usual care from the sickle cell anaemia clinic and were rescreened after 12 months to determine whether they qualified for treatment on trial. The primary endpoint was change in transcranial Doppler velocity from the baseline visit to after 12 months of hydroxyurea treatment, analysed in all patients who had paired baseline and follow-up measurements collected after 12 months of treatment. Safety was analysed in the per-protocol population (all participants who received study treatment). This study is registered with ClinicalTrials.gov, NCT03948867.FindingsBetween April 24, 2019, and April 9, 2020, 202 children were enrolled and had transcranial Doppler screening. Sickle cell anaemia was confirmed by DNA-based testing in 196 participants (mean age 6·8 years [SD 3·5], 103 [53%] were female, and 93 [47%] were male). At the baseline screening, 47 (24%) of 196 participants had elevated transcranial Doppler velocities (43 [22%] conditional, four [2%] abnormal); 45 initiated hydroxyurea at a mean dose of 20·2 mg/kg per day (SD 1·4) with escalation to a mean dose of 27·4 mg/kg per day (5·1) after 12 months. Treatment response was analysed after 12 months (± 1 month; median 11 months, IQR 11–12) and 24 months (±3 months; median 22 months, 22–22). Transcranial Doppler velocities decreased to a mean of 149 cm/s (SD 27) compared with 182 cm/s (12) at baseline, which was significantly lower than baseline (p<0·0001), with an average decline of 35 cm/s (SD 23) after 12 months of treatment in 42 participants with paired results available at baseline and 12 months. No clinical strokes occurred, and 35 (83%) of 42 participants reverted to normal transcranial Doppler velocities. Clinical adverse events were mild, and dose-limiting toxicities were uncommon. The most common grade 3 adverse events were malaria (12 [29%] episodes in 45 patients) and sepsis (13 [32%] episodes). There were three serious adverse events, none of which were treatment-related, and no treatment-related deaths occurred.InterpretationChildren with sickle cell anaemia in Tanzania have a high baseline stroke risk. Hydroxyurea at the maximum tolerated dose significantly lowers transcranial Doppler velocities and reduces primary stroke risk. Transcranial Doppler screening plus hydroxyurea at the maximum tolerated dose is an effective stroke prevention strategy, supporting wider hydroxyurea access for patients with sickle cell anaemia across sub-Saharan Africa.FundingAmerican Society of Hematology, National Institutes of Health, Cincinnati Children's Research Foundation.
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