Hydroxyurea Therapy for Neurological and Cognitive Protection in Pediatric Sickle Cell Anemia in Uganda: A Single Arm Open Label Trial, "BRAIN SAFE II"
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 270
- 试验地点
- 1
- 主要终点
- The frequency, age specific prevalence and severity of Sickle Cell Vasculopathy manifested by New stroke as assessed by the Pediatric NIH Stroke Scale (PedNIHSS) over the 3-year study while on hydroxyurea treatment, compared to baseline assessments.
研究概览
简要总结
Worldwide, an estimated 200,000 babies are born with Sickle Cell Anemia (SCA) annually. Affected children suffer chronic ill health with some having frequent hospitalization. The patients are also at a high risk of brain injury arising from small and large cerebral blood vessel damage in SCA, also called sickle cell vasculopathy (SCV). SCV is associated with the high risk of stroke. Such injury may manifest with neurological and cognitive impairment. An abnormal blood flow to the brain, as measured by a Doppler Ultrasound scan is a known risk factor for stroke.
The hypothesis is that hydroxyurea therapy will prevent, stabilize or improve SCV and its effects.
The study is an open label, single arm clinical trial to test the impact of hydroxyurea treatment in 270 children with SCA starting at ages 3-9 years.
Following baseline assessments, all participants will begin hydroxyurea therapy starting at about 20mg/kg/day. Changes in the frequency and severity of each test (neurological and cognitive tests and cerebral blood flow velocity) will be compared with their baseline tests (prior to hydroxyurea) by repeating these tests at 18 and 36 months. In a randomly selected subset of 90 participants, an evaluation of the impact of hydroxyurea on structural brain vascular injury using magnetic resonance brain imaging (MRI) and magnetic vessel imaging ,also called angiography (MRA) at baseline and at 36 months. Lastly, an assessment of changes to biomarkers of anemia, inflammation and malnutrition from before and during hydroxyurea therapy and determine their relationship to the outcomes. The proposed intervention with hydroxyurea is the first Africa-based trial to broadly prevent or ameliorate manifestations of SCV.
详细描述
Annually, an estimated 200,000 babies are born with Sickle Cell Anemia (SCA) worldwide. Affected children often suffer repeated acute illnesses and chronic ill health from vascular occlusive phenomenon. In particular, they are at a high risk of stroke due to the development of sickle cell cerebral vascular (SCV) injury. SCV can also cause neurocognitive impairment. Stroke risk may be predicted by abnormal cerebral arterial flow detected by transcutaneous Doppler ultrasound (TCD).
The specific aims are:
Aim 1: Determine the impact of hydroxyurea therapy on the frequency and severity of SCV in a cohort of children treated for three years, as measured by 3 distinct outcomes: abnormal TCD, neurocognitive impairment and primary stroke, compared with baseline.
Aim 2: Evaluate the impact of hydroxyurea on structural SCV using MRI and MRA in a randomly selected subset of this cohort.
Aim 3: Assess changes to anemia, malnutrition status, C-reactive protein and other inflammatory markers during hydroxyurea therapy, over time, compared with baseline levels.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 9 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented laboratory diagnosis of HbSS or HbS-B 0 thalassemia (both types are treated equally in SCA studies)
- •Ages 3 through 9 years (inclusive) at enrolment
- •To ensure clinic follow-up, child has attended Mulago Hospital Sickle Cell Anaemia (SCA)clinic 2 times in the prior 4 years, or at least once in the past 2 years if younger than < 4 years
- •No history of hydroxyurea use for longer than 6 months
- •Parent/legal guardian has provided a written consent (and if child is ≥8 years of age, has provided assent)
排除标准
- •History of neurological abnormality known before age 4 months (to avoid those with non SCA brain injury)
- •Child is currently enrolled in another clinical intervention trial
- •Prior stroke as detected by standard Pediatric NIH Stroke Scale (PedNIHSS) examination
- •Temporary exclusion criteria
- •Pre-existing hematological toxicity
- •Hemoglobin <4.0 gm/dL
- •Hemoglobin <6.0 gm/dL with Absolute Reticulocyte Count <100 x 10 9/L
- •Absolute Reticulocyte Count <80 x 109/L with Hemoglobin <7.0 gm/dL
- •Platelets <80 x 109/L
- •Absolute Neutrophil Count <1.0 x 109/L
- •Found to be with acute illness at enrolment with fever in last 1 week, respiratory infection, etc.
- •History of a sickle crisis within the prior 2 weeks, or blood transfusion within the past 90 days Participants with temporary exclusion can be enrolled later when stable or the excluding criteria has resolved
研究组 & 干预措施
single arm
Single arm, open label of hydroxyurea starting at 20mg/kg and increased to 30mg/kg depending on clinical need and according to standard guidelines
干预措施: Hydroxyurea (Drug)
结局指标
主要结局
The frequency, age specific prevalence and severity of Sickle Cell Vasculopathy manifested by New stroke as assessed by the Pediatric NIH Stroke Scale (PedNIHSS) over the 3-year study while on hydroxyurea treatment, compared to baseline assessments.
时间窗: 3 years
Baseline assessment will be completed for all study participants and over the 3-year study, scheduled outcome assessments will be performed at study months 18 and 36. These assessments will aim to document New (incident) stroke as assessed by the PedNIHSS
The frequency, age specific prevalence and severity of Sickle Cell Vasculopathy manifested by a change in transcranial doppler (TCD) velocity by 15cm/sec or more over the 3-year study while on hydroxyurea treatment, compared to baseline assessment.
时间窗: 3 years
Baseline assessment will be completed for all study participants and over the 3-year study, scheduled outcome assessments will be performed at study months 18 and 36.These assessments will aim to document a change in TCD velocity by 15cm/sec or more.
The frequency, age specific prevalence and severity of SCV manifested by New or worsening cognitive impairment, both quantitative and categorical over the 3-year study while on hydroxyurea treatment, compared to baseline assessments.
时间窗: 3 years
Baseline assessment will be completed for all study participants and over the 3-year study, scheduled outcome assessments will be performed at study months 18 and 36.These assessments will aim to document new or worsening cognitive impairment - both quantitative and categorical (by standardized criteria ≤-2 z-score) compared to established criteria
次要结局
- Stabilized or worsened structural changes on brain Magnetic Resonance Imaging(MRI) over the 3 years compared to baseline(3 years)
- Stabilized or worsened structural changes on brain Magnetic Resonance Angiography(MRA) over the 3 years compared to baseline(3 years)