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增加有关。在美国，SCA儿童卒中的一级预防包括筛查经颅多普勒超声（TCD）速度升高，并对速度升高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输血治疗以预防中风，定期输血在非洲不可行。来自我们在尼日利亚卡诺进行的可行性试验（1 R21 NS 080639-NCE，NCT 01801423）的有希望的初步数据支持20 mg/kg/天中等剂量羟基脲（HU）治疗用于SCA儿童卒中一级预防的潜在用途。在可行性试验中，我们筛选了338名参与者; 92%（23/25） TCD测量值升高的参与者选择入组，66%（23名参与者中的15名;注意到2名参与者尚未达到他们的3个月里程碑），在HU治疗达到他们的第三个月的参与者中，他们的左和右大脑中动脉的TCD值升高到低于200 cm/sec; 89%（210/235）的TCD测量值未升高的筛选参与者同意随访3年，以评估发病率和死亡率的背景率。根据最近完成的NHLBI试验的结果，经颅多普勒（TCD）与输液改为羟基脲; NCT 01425307），表明TCD测量值升高的儿童在输血一年后可以转换为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，在3个月内，2/3的参与者的TCD速度下降，我们提出了一项双中心随机临床试验来测试以下假设：SCA儿童原发性卒中的相对风险降低66%，TCD测量值升高（n=220），随机分配至中等剂量与低剂量HU治疗（10与20 mg/kg/天），持续3年。为了准备这项申请，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）确定中剂量与低剂量HU治疗对一级预防卒中的疗效; 2）确定中剂量HU治疗降低全因住院发生率的疗效（疼痛、急性胸部综合征、感染或其他）;评估HU治疗的长期安全性在可行性试验中TCD测量值升高的受试者（n=25）中，与初始TCD正常的儿童相比，（n= 210，随访至少3年）。这项试验完成后，我们将确定中等剂量的HU疗法是否可以预防非洲高危儿童中数千例中风，同时在尼日利亚和加纳培训下一批医生科学家。

 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.