Primary prevention of stroke in children with SCD in Sub-Saharan Africa II

 描述(由申请人提供)：镰状细胞性贫血(SCA)中的中风，特别是生活在非洲的儿童，与显著的发病率和过早死亡率的增加有关。在美国，SCA儿童中风的一级预防包括筛查经颅多普勒超声(TCD)血流速度升高，并对血流速度加快的儿童进行定期输血治疗。然而，由于安全血液供应不足以及父母不愿接受一级预防中风的输血治疗，常规输血在非洲是不可行的。来自我们在尼日利亚卡诺的可行性试验(1R21NS080639-NCE，NCT01801423)的可喜的初步数据支持使用20 mg/kg/天的中等剂量羟基脲(HU)疗法作为SCA儿童卒中的一级预防。在可行性试验中，我们筛选了338名参与者；92%(25人中的23人) 在选择登记的TCD测量升高的参与者中，66%(23人中有15人；注2中的参与者尚未达到他们的3个月里程碑)在接受HU治疗的第三个月的参与者中，左侧和右侧大脑中动脉的TCD升高值降至200厘米/秒以下；而在235名TCD未升高的筛查参与者中，89%(210人)同意接受为期三年的跟踪调查，以评估发病率和死亡率的背景发生率。根据最近完成的NHLBI试验的结果，输液改为羟基尿素的经颅多普勒(TCD)；(NCT01425307)，证明TCD检测升高的儿童在输血一年后可以切换到HU治疗，而TCD速度没有增加，再加上我们的初步试验结果表明3个月内参与者的TCD速度下降2/3，我们提议进行一项双中心随机临床试验以检验以下假设：患有SCA的儿童原发性中风的相对风险将降低66%，TCD检测升高(n=220)，随机分配到中剂量与低剂量HU治疗(10vs.20 mg/kg/天)，为期3年。为了准备这一申请，来自尼日利亚和加纳的两个团队都在范德比尔特大学医学院接受了为期1个月的以患者为导向的研究培训。其目的是：1)确定中剂量HU疗法与小剂量HU疗法在一级中风预防中的有效性；2)与小剂量HU疗法相比，确定中剂量HU疗法在降低因任何原因(疼痛、急性胸部综合征、感染或其他)而住院的所有原因的发生率方面的有效性；3)评估可行性试验(n=25)中TCD测量升高的参与者(n=25)与TCD最初正常的儿童(n=210)相比，HU疗法的长期安全性(6.5年)。在这项试验完成后，我们将确定中等剂量的HU疗法是否有可能预防非洲高危儿童的数千例中风，同时在尼日利亚和加纳培训下一批内科科学家。

 DESCRIPTION (provided by applicant): Strokes in sickle cell anemia (SCA), particularly in children living in Africa, are associated with significant morbidity and an increased rate of premature death. In the US, primary prevention of strokes in children with SCA involves screening for elevated transcranial Doppler ultrasound (TCD) velocity coupled with regular blood transfusion therapy for those with elevated velocities. However, regular blood transfusion is not feasible in Africa due to inadequate supply of safe blood and the reluctance of parents to accept blood transfusion therapy for primary stroke prevention. Promising preliminary data from our feasibility trial in Kano, Nigeria (1R21NS080639-NCE, NCT01801423) support the potential use of moderate dose hydroxyurea (HU) therapy of 20 mg/kg/day for primary prevention of stroke in children with SCA. In the feasibility trial, we screened 338 participants; 92% (23 of 25) of the participants with elevated TCD measurements elected to enroll, 66% (15 of 23; of note 2 participants have not reached their 3 month milestone) of the participants who reached their third month on HU therapy dropped their elevated TCD values to below 200 cm/sec in both left and right middle cerebral arteries; and 89% (210 of 235) of the screened participants with non-elevated TCD measurements agreed to be followed for three years for assessment of background rates of morbidity and mortality. Based on the results from the recently completed NHLBI trial, Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea; NCT01425307), demonstrating that children with an elevated TCD measurement can be switched to HU therapy after one year of blood transfusion without an increase in TCD velocities, coupled with our preliminary trial results indicating a decrease in TCD velocities in 2/3rds of the participants over 3 months, we propose a two center randomized clinical trial to test the following hypothesis: There will be a 66% relative risk reduction of primary strokes in children with SCA, and elevated TCD measurements (n=220), randomly allocated to moderate dose vs. low dose HU therapy (10 vs. 20 mg/kg/day) for 3 years. In preparation for this application, both teams from Nigeria and Ghana have received 1 month of patient-oriented research training at Vanderbilt University School of Medicine. The aims are to: 1) determine the efficacy of moderate vs. low dose HU therapy for primary stroke prevention; 2) determine the efficacy of moderate dose HU therapy for decreasing the incidence of all cause-hospitalization for any cause (pain, acute chest syndrome, infection, or other) when compared to low dose HU therapy; and 3) assess long-term safety of HU therapy (6.5 years) in participants from the feasibility trial with an elevated TCD measurement (n=25) when compared to children with an initial normal TCD (n= 210 followed for at least 3 years). After completion of this trial, we will determine whether moderate dose HU therapy can potentially prevent thousands of strokes in children at high risk in Africa, while simultaneously training the next cadre of physician scientiss in Nigeria and Ghana.