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

撒哈拉以南非洲地区 SCD 儿童卒中的一级预防 II

• 批准号: 9750007
• 负责人: SHEHU UMAR ABDULLAHI
• 金额: $ 102.22万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750007
• 关键词: Adherence; Africa; Africa South of the Sahara; Age; Biological; Birth; Blood; Blood Transfusion; Cessation of life; Child; Childhood; Clinic; Clinical; Clinical Research; Country; Coupled; Data; Doppler Ultrasound; Dose; Dropout; Drops; Eligibility Determination; Enrollment; Event; Funding; Ghana; Goals; Hospitalization; Incidence; Income; Infection; Laboratories; Left; Measurement; Mentors; Morbidity - disease rate; Myelosuppression; National Heart, Lung, and Blood Institute; Nigeria; Pain; Parents; Participant; Patients; Phase III Clinical Trials; Physicians; Positioning Attribute; Preparation; Primary Prevention; Randomized; Randomized Clinical Trials; Relative Risks; Research; Research Training; Risk; Risk Reduction; Safety; Scientist; Serious Adverse Event; Sickle Cell Anemia; Stroke; Stroke prevention; Teaching Hospitals; Testing; Training; Transfusion; United States National Institutes of Health; Universities; acute chest syndrome; base; cohort; cost; eligible participant; feasibility trial; high risk; hospitalization rates; hydroxyurea; mean corpuscular volume observed; medical schools; medication compliance; meetings; middle cerebral artery; mortality; multidisciplinary; patient oriented research; phase III trial; premature; prevent; public health relevance; screening; stroke clinical trials; stroke risk; treatment group

 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.

 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，与显着的发病率和过早死亡率增加相关。在美国，SCA 儿童中风的一级预防包括筛查。对于经颅多普勒超声 (TCD) 速度升高的患者，定期输血治疗是可行的。然而，由于安全血液供应不足和血液供应不足，定期输血在非洲并不可行。父母不愿意接受输血疗法来预防中风 我们在尼日利亚卡诺进行的可行性试验（1R21NS080639-NCE，NCT01801423）提供了有希望的初步数据，支持可能使用 20 毫克/公斤/天的中等剂量羟基脲 (HU) 疗法。在可行性试验中，我们筛选了 92% 的参与者（其中 23 名）。二十五) 在选择加入的 TCD 测量值升高的参与者中，66%（23 人中的 15 人；值得注意的是 2 名参与者尚未达到 3 个月的里程碑）在 HU 治疗达到第三个月的参与者中，66% 将其升高的 TCD 值降至以下水平左、右大脑中动脉均为 200 厘米/秒；89%（235 名中的 210 名）TCD 测量值未升高的筛选参与者同意随访三年以评估背景率根据最近完成的 NHLBI 试验（输血改为羟基脲的经颅多普勒 (TCD)）的结果，表明 TCD 测量值升高的儿童可以在不输血一年后转为 HU 治疗。 TCD 速度增加，加上我们的初步试验结果表明 2/3 的参与者在 3 个月内 TCD 速度下降，我们提出了一项两中心随机临床试验来检验以下假设：患有 SCA 的儿童原发性中风的相对风险将降低 66%，且 TCD 测量值升高 (n=220)，随机分配至中等剂量与低剂量HU 疗法（10 与 20 毫克/公斤/天）为期 3 年。为了准备这项应用，来自尼日利亚和加纳的两个团队在范德比尔特大学医学院接受了 1 个月的以患者为导向的研究培训。 : 1) 确定中剂量 HU 治疗与低剂量 HU 治疗对于初级卒中预防的疗效； 2) 确定中剂量 HU 治疗对于降低因任何原因（疼痛、急性胸部综合征、感染或感染）而住院的发生率的疗效；其他）与低剂量 HU 治疗相比；3）与初始 TCD 正常的升高儿童相比，通过 TCD 测量（n = 25）评估可行性试验参与者的 HU 治疗（6.5 年）的长期安全性(n= 210 次随访至少 3 年）。完成这项试验后，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，同时培训尼日利亚和加纳的下一批医师科学家。 。

项目成果

Hydroxycarbamide and white matter integrity in paediatric sickle cell disease: Commentary to accompany: hydroxycarbamide treatment in children with sickle cell anaemia is associated with more intact white matter integrity: a quantitative MRI study.

儿童镰状细胞病中的羟基脲和白质完整性：附注评论：镰状细胞性贫血儿童的羟基脲治疗与更完整的白质完整性相关：一项定量 MRI 研究。

• 发表时间: 2019-10-01
• 影响因子: 6.5
• 作者: Lance, Eboni I;Jordan, Lori C
• 通讯作者: Jordan, Lori C

World Health Organization's Growth Reference Overestimates the Prevalence of Severe Malnutrition in Children with Sickle Cell Anemia in Africa.

世界卫生组织的生长参考高估了非洲镰状细胞性贫血儿童严重营养不良的患病率。

• 发表时间: 2020-01-02
• 作者: Ghafuri, Djamila L;Abdullahi, Shehu U;Jibir, Binta W;Gambo, Safiya;Bello;Haliru, Lawal;Bulama, Khadija;Usman, Fahd M;Gambo, Awwal;Aliyu, Muktar H;Greene, Brittany C;Kassim, Adetola A;Slaughter, Chris;Rodeghier, Mark;DeBaun, Mic
• 通讯作者: DeBaun, Mic

Moderate fixed-dose hydroxyurea for primary prevention of strokes in Nigerian children with sickle cell disease: Final results of the SPIN trial.

中等固定剂量羟基脲用于尼日利亚镰状细胞病儿童中风的一级预防：SPIN 试验的最终结果。

• 发表时间: 2020
• 影响因子: 12.8
• 作者: Galadanci, Najibah A;Abdullahi, Shehu U;Ali Abubakar, Shehi;Wudil Jibir, Binta;Aminu, Hauwa;Tijjani, Aliyu;Abba, Muhammad S;Tabari, Musa A;Galadanci, Aisha;Borodo, Awwal Musa;Belonwu, Raymond;Salihu, Auwal S;Rodeghier, Mark;Ghafuri, Djamila L
• 通讯作者: Ghafuri, Djamila L

Neurologic complications in children under five years with sickle cell disease.

五岁以下镰状细胞病儿童的神经系统并发症。

• 发表时间: 2019
• 影响因子: 2.5
• 作者: Galadanci, Aisha A;DeBaun, Michael R;Galadanci, Najibah A
• 通讯作者: Galadanci, Najibah A

Establishing Sickle Cell Disease Stroke Prevention Teams in Africa is Feasible: Program Evaluation Using the RE-AIM Framework.

在非洲建立镰状细胞病中风预防小组是可行的：使用 RE-AIM 框架进行项目评估。

• 发表时间: 2022-01-01
• 作者: Ghafuri, Djamila L;Abdullahi, Shehu U;Dambatta, Abdu H;Galadanci, Jamil;Tabari, Musa A;Bello;Idris, Nura;Inuwa, Hauwa;Tijjani, Aliyu;Suleiman, Aisha A;Jibir, Binta W;Gambo, Safiya;Gambo, Awwal I;Khalifa, Yusuf;Haliru, Lawal;Ab
• 通讯作者: Ab