Stroke Prevention in Nigeria: SPRING 2

尼日利亚的中风预防：春季 2

• 批准号: 10741173
• 负责人: SHEHU UMAR ABDULLAHI
• 金额: $ 61.76万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741173
• 关键词: Acute Pain; Adoption; American Society of Hematology; Anemia; Area; Assessment tool; Blood Cell Count; Blood Flow Velocity; Brain; Cephalic; Child; Childhood; Clinic Visits; Clinical; Clinical Trials; Cost Effectiveness Analysis; Data Coordinating Center; Dimensions; Dose; Double-Blind Method; Effectiveness; Event; Fogarty International Center; Funding; Goals; Guidelines; Hospitalization; Incidence; Intervention; Judgment; Literature; Low income; Maintenance; Measures; Methods; National Institute of Neurological Disorders and Stroke; Neurology; Nigeria; Nigerian; Nurses; Outpatients; Pain; Participant; Persons; Phase; Physicians; Population; Prevention program; Principal Investigator; Publishing; Quality-Adjusted Life Years; Randomized, Controlled Trials; Reach, Effectiveness, Adoption, Implementation, and Maintenance; Recommendation; Relative Risks; Research; Risk Reduction; Sample Size; Sickle Cell Anemia; Stroke; Stroke prevention; Testing; Time; Visit; arm; cost; cost effectiveness; cost-effectiveness evaluation; cost-effectiveness ratio; effectiveness evaluation; effectiveness testing; evidence based guidelines; follow-up; health care model; health care service utilization; high risk; hybrid type 1 trial; hydroxyurea; implementation evaluation; incremental cost-effectiveness; member; multidisciplinary; neuroimaging; open label; pediatrician; phase III trial; phase IV trial; prevent; preventive intervention; primary outcome; relative cost; routine care; screening; secondary outcome; sickling; skills; standard care; stroke incidence; stroke risk; treatment group; trial comparing

SUMMARY: We propose a multicenter open-label, single-arm type I hybrid trial to assess the effectiveness of hydroxyurea therapy for primary stroke prevention in children with sickle cell anemia (SCA) living in Nigeria. Our team just completed a double-blind, parallel-group phase III randomized controlled trial (SPRING), where we compared low-dose to moderate-dose hydroxyurea for primary stroke prevention in children with SCA and abnormal transcranial Doppler (TCD) velocities (>200 cm/sec). Children with abnormal TCD velocities have a high stroke risk of approximately 10.7 events per 100 person-years (observation arm in the STOP trial). In the low- (n=109) and moderate-dose (n=111) hydroxyurea groups, the stroke incidence rates were 1.2 and 1.9 per 100 person- years, respectively, p=0.77 (combined incidence rate 1.5 per 100 person-year). Despite equal efficacy for stroke prevention in both treatment groups, moderate- when compared to low-dose hydroxyurea, was more effective in preventing severe acute pain and all-cause hospitalizations. Our findings supported the American Society of Hematology's evidence-based guidelines for hydroxyurea therapy for primary stroke prevention in low-income settings. Our hypothesis to be tested: in a multicenter single-arm type I hybrid trial, for children with abnormal TCD velocities treated with hydroxyurea, the stroke incidence rate will be non-inferior to the SPRING trial results, with an upper non-inferiority margin of 4 strokes per 100-person-years. The point estimate method was used to determine the non-inferiority margin based on the Nigerian pediatrician's judgment of what maximum stroke rate would be clinically meaningful to demonstrate the effectiveness and justify treatment for the high-risk stroke group. A non-inferiority test with an overall sample size of 220 participants will achieve 91% power at a 0.050 significance level to detect non-inferiority when the expected proportion of strokes is 0.035, a minimum follow-up period of 2.5 years and a loss to follow-up of 10% per year. Participants will be followed as per standard care, including clinic visits every 3 months and complete blood cell counts every 6 months. We will conduct the following aims:1) Determine the incidence of the first stroke and TIA in children with abnormal TCD velocities treated with hydroxyurea for 2.5 years in the type 1 hybrid trial; 2) Evaluate the implementation and sustainability of the intervention within the extended RE-AIM framework; 3) Evaluate the cost-effectiveness of low- compared to a higher dose of hydroxyurea for primary stroke prevention in children with abnormal TCD velocities. Capacity building for the three Nigerian Multiple Principal Investigators, the statisticians, and nurses will be focused on three areas- a) developing a Nigerian data coordinating center and the required skills to support a clinical trial; b) developing a regional TCD course for nurses, enhancing task shifting and reach, and c) performing cost-effective analysis for the type I hybrid trial comparing low-and moderate dose hydroxyurea.

总结： 我们建议进行一项多中心、开放标签、单臂I型混合试验，以评估羟基脲的有效性 治疗生活在尼日利亚的镰状细胞性贫血（SCA）儿童的一级卒中预防。我们的团队刚刚 完成了一项双盲、平行组III期随机对照试验（SPRING）， 低剂量至中剂量羟基脲用于SCA和异常 经颅多普勒（TCD）速度（>200 cm/sec）。TCD速度异常的儿童脑卒中发生率高 风险约为每100人-年10.7起事件（STOP试验中的观察组）。在低-（n=109） 和中等剂量（n=111）的羟基脲组，脑卒中发生率分别为1.2和1.9/100人- 年，p=0.77（合并发病率为1.5/100人-年）。尽管对于 两个治疗组的卒中预防，中度-与低剂量羟基脲相比， 有效预防严重急性疼痛和全因住院。我们的发现支持了美国人 血液学学会的循证指南，用于一级预防卒中的羟基脲治疗， 低收入环境。我们的假设有待检验：在一项多中心单臂I型混合试验中， 如果TCD速度异常，经羟基脲治疗，中风发生率将不劣于SPRING 试验结果，非劣效性界值上限为每100人年4次卒中。点估计法 用于确定非劣效性界值，基于尼日利亚儿科医生对以下内容的判断： 最大卒中发生率在证明有效性和证明治疗合理性方面具有临床意义， 中风高危人群总体样本量为220名受试者的非劣效性检验将达到91% 当预期卒中比例为0.035时，在0.050显著性水平下检测非劣效性的把握度，a 最短随访期为2.5年，每年失访率为10%。与会者将被跟踪， 每标准治疗，包括每3个月一次的诊所访视和每6个月一次的全血细胞计数。我们 将进行以下目的：1）确定首次中风和TIA的发生率在儿童异常 在1型杂交试验中，使用羟基脲治疗2.5年的TCD速度; 2）评价实施情况 在扩展的RE-AIM框架内进行干预的可持续性; 3）评估成本效益 与较高剂量的羟基脲相比，低剂量的羟基脲用于TCD异常儿童的一级预防卒中 速度尼日利亚三名多重主要研究者、统计学家和护士的能力建设 将侧重于三个领域- a）开发尼日利亚数据协调中心和所需的技能， 支持临床试验; B）为护士开发区域TCD课程，增强任务转移和覆盖范围，以及 c）对I型混合试验进行成本效益分析，比较低剂量和中等剂量的羟基脲。