Biomakers in Sickle Cell Anemia: Response to Hydroxyurea

镰状细胞性贫血的生物制造者：对羟基脲的反应

• 批准号: 6671113
• 负责人: MARIE J. STUART
• 金额: $ 39.25万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-04 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6671113
• 关键词: biomarker; cell cell interaction; clinical research; erythrocytes; hemoglobin F; human subject; human therapy evaluation; hydroxyurea; patient oriented research; pediatric pharmacology; placebos; preschool child (1-5); sickle cell anemia

DESCRIPTION (provided by applicant): In a landmark clinical trial, oral hydroxyurea (HU) decreased the frequency of vaso-occlusive crises and acute chest syndrome, and reduced the need for transfusions and hospitalizations in adult patients with homozygous SS disease (HbSS). While the consensus from this study, and others is that HU has pleotropic modes of action in HbSS with effects on HbF, dense cells, reticulocytes, white cells and red cell-endothelial interactions, the relative merits of these individual modes of action on disease amelioration are not known. The NHLBI will be conducting a pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) in which HU will be tested in a randomized double-blinded, placebo-controlled trial for the prevention of chronic organ damage in 200 infants with HbSS. As a prelude to the major study, in 2003, a pilot Baby HUG randomized placebo-controlled, two-year trial of 40 infants (ages 12 to 17 months at study entry) will be conducted to ascertain the feasibility of the larger proposal. The validity of primary and secondary end points, i.e. splenic and renal function, and CNS involvement will be ascertained, and the effects of HU on growth, physical and cognitive development in this young cohort will be assessed. Organ evaluations will include splenic scintigraphy and pitted red cell counts; glomerular filtration rate, and evaluation for microalbuminuria and urine concentrating ability; brain MRI/MRA and transcranial doppler (TCD) measurements. This study provides us the unique opportunity for an evaluation of various biomarkers to assess whether HU modulates activation of the circulating cellular elements of blood, and cell-cell interactions, with resulting ameliorative effects on the HbSS infant's vascular pathology and clinical course. Biomarkers to be evaluated will include functional assessment of erythrocyte adhesion to endothelium and to immobilized extra-cellular matrix proteins, F cell numbers, erythrocyte markers including CD71 (stress reticulocyte), various red cell adhesion molecules and phosphatidylserine (PS) positivity. Markers of coagulation activation will include whole blood tissue factor activity (WBTF) and prothrombin fragment F1.2 levels. Endothelial activation will be assessed by plasma sol VCAM-1 and a quantitative and qualitative assessment of circulating endothelial microparticles. Platelet and white cell activation will be evaluated by sol P-selectin and L-selectin levels respectively. We predict that HU therapy, when compared to placebo will result in a pattern of biomarker changes suggestive of a treatment effect. Our evaluations will also provide information delineating the mechanisms by which HU modulates these cell-cell interactions. The two-year follow-up evaluations of clinical course and organ dysfunction in the BABY HUG pilot protocol will also provide us the unique opportunity to assess whether abnormal values of a specific biomarker(s) will predate or occur in conjunction with specific organ dysfunction, or vascular pathology. Large differences will be detectable in these comparisons, while smaller differences will provide the basis for further specimen collection and analysis in the additional 160 children to be later entered in the Phase III Clinical trial. Since our Center possesses significant past experience in biomarker evaluations in infants with HbSS, the incorporation of these appropriately chosen biologic markers to assess disease progression will complement this pilot protocol. Our ancillary proposal should enhance the long-term benefits and scientific productivity of this important multiinstitutional NHLBI-sponsored research. In addition, findings from this study could have significant implications for other disease states associated with vasculopathy.

描述（由申请人提供）：在具有里程碑意义的临床试验中，口服羟基脲（HU）降低了血管熟悉的危机和急性胸部综合征的频率，并减少了成人肉体疾病（HBS）（HBS）的成人患者输血和住院的需求。 尽管这项研究的共识以及其他人的共识是在HBSS中具有对HBF，密集细胞，网状细胞，白细胞，白细胞和红色细胞内皮相互作用的影响的多余作用模式，但这些单个作用方式对疾病降低的相对优点，尚不清楚。 NHLBI将进行一项小儿羟基脲III期临床试验（婴儿拥抱），其中将在一项随机的双盲，安慰剂对照试验中对HU进行测试，以预防200名HBSS婴儿的慢性器官损害。 作为主要研究的前奏，2003年，将进行一项试验婴儿拥抱随机安慰剂对照，为期两年的40名婴儿（研究入学时12至17个月）的试验，以确定较大建议的可行性。 将确定原发点和次要终点，即脾和肾功能以及中枢神经系统的参与的有效性，并将评估HU对这种年轻队列中生长，物理和认知发展的影响。 器官评估将包括脾脏闪烁显像和红细胞计数；肾小球滤过率，以及微珠尿和尿液浓缩能力的评估；脑MRI/MRA和经颅多普勒（TCD）测量。 这项研究为我们提供了评估各种生物标志物的独特机会，以评估HU是否调节了血液的循环细胞元素和细胞 - 细胞相互作用的激活，从而对HBSS婴儿的血管病理学和临床过程产生改善作用。 待评估的生物标志物将包括对内皮细胞粘附和固定的细胞外基质蛋白的功能评估，F细胞数，红细胞标记物，包括CD71（胁迫网状细胞），各种红细胞粘附分子和磷脂基二酰胺（PS）。 凝血激活的标志物将包括全血组织因子活性（WBTF）和凝血酶原片段F1.2水平。 内皮激活将通过血浆溶胶VCAM-1评估，并对循环内皮微粒的定量和定性评估进行评估。 血小板和白细胞活化将分别通过溶胶P-选择素和L-选择素水平评估。 我们预测，与安慰剂相比，HU治疗将导致生物标志物变化的模式，暗示了治疗效果。 我们的评估还将提供信息，以描绘HU调节这些细胞相互作用的机制。 婴儿拥抱试验方案中临床过程和器官功能障碍的两年随访评估还将为我们提供独特的机会，以评估特定生物标志物的异常值是否会段或与特定器官功能障碍或血管病理学结合使用。 在这些比较中将可以检测到很大的差异，而较小的差异将为进一步的标本收集和分析的基础提供基础，以稍后将在III期临床试验中输入。 由于我们的中心在患有HBSS的婴儿的生物标志物评估中具有丰富的过去经验，因此将这些适当选择的生物学标志物纳入评估疾病进展将补充该试验方案。 我们的辅助建议应提高这项重要的NHLBI赞助研究的长期利益和科学生产力。 此外，这项研究的发现可能对与血管病相关的其他疾病状态产生重大影响。