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）：在一项具有里程碑意义的临床试验中，口服羟基脲（HU）降低了纯合子SS疾病（HbSS）成人患者的血管闭塞性危象和急性胸部综合征的频率，并减少了输血和住院治疗的需求。 虽然本研究和其他研究的共识是HU在HbSS中具有多效性作用模式，对HbF、致密细胞、网织红细胞、白色细胞和红细胞-内皮相互作用有影响，但这些单独作用模式对疾病改善的相对优点尚不清楚。 NHLBI将开展一项儿科羟基脲III期临床试验（BABY HUG），其中将在一项随机、双盲、安慰剂对照试验中检测HU，以预防200名HbSS婴儿的慢性器官损伤。 作为主要研究的前奏，2003年，将对40名婴儿（进入研究时年龄为12至17个月）进行为期两年的婴儿HUG随机安慰剂对照试验，以确定更大提案的可行性。 将确定主要和次要终点（即脾和肾功能以及CNS受累）的有效性，并评估HU对该年轻队列的生长、身体和认知发育的影响。 器官评价将包括脾动脉造影和凹陷红细胞计数;肾小球滤过率，以及微量白蛋白尿和尿液浓缩能力的评价;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是否调节血液循环细胞成分的活化和细胞-细胞相互作用，从而改善HbSS婴儿的血管病理学和临床病程。 待评价的生物标志物将包括红细胞与内皮细胞和固定化细胞外基质蛋白粘附的功能评估、F细胞数量、红细胞标志物（包括CD 71（应激网织红细胞））、各种红细胞粘附分子和磷脂酰丝氨酸（PS）阳性。 凝血激活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。 将通过血浆sol VCAM-1和循环内皮微粒的定量和定性评估来评估内皮活化。 将分别通过溶胶P-选择素和L-选择素水平评价血小板和白色细胞活化。 我们预测，HU治疗与安慰剂相比，将导致生物标志物变化模式提示治疗效果。 我们的评估也将提供信息描绘的机制，胡调节这些细胞间的相互作用。 BABY HUG试验方案中临床病程和器官功能障碍的两年随访评价也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早于特定器官功能障碍或血管病理学或与特定器官功能障碍或血管病理学相关。 在这些比较中可以检测到较大的差异，而较小的差异将为随后进入III期临床试验的另外160名儿童的进一步标本采集和分析提供基础。 由于我们中心在HbSS婴儿生物标志物评价方面拥有丰富的既往经验，因此纳入这些适当选择的生物标志物以评估疾病进展将补充本试验方案。 我们的辅助建议应该提高长期利益和科学生产力的重要多机构NHLBI赞助的研究。 此外，这项研究的结果可能对与血管病变相关的其他疾病状态具有重要意义。