Biomakers in Sickle Cell Anemia: Response to Hydroxyurea

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病（HbSS）成人患者血管闭塞危象和急性胸综合征的频率，减少了输血和住院的需要。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、白细胞和红细胞内皮相互作用有影响，但这些个体作用模式对疾病改善的相对优点尚不清楚。NHLBI将开展一项儿童羟基脲III期临床试验（BABY HUG），其中HU将在一项随机双盲、安慰剂对照试验中进行测试，以预防200名HbSS婴儿的慢性器官损伤。作为主要研究的前奏，在2003年，将对40名婴儿（研究开始时年龄为12至17个月）进行为期两年的随机安慰剂对照试验，以确定更大规模建议的可行性。将确定主要和次要终点（即脾和肾功能以及中枢神经系统受累）的有效性，并评估HU对这一年轻队列的生长、身体和认知发展的影响。器官评估包括脾显像和凹点红细胞计数；肾小球滤过率，微量白蛋白尿和尿浓缩能力评估；脑MRI/MRA和经颅多普勒（TCD）测量。这项研究为我们提供了一个独特的机会来评估各种生物标志物，以评估HU是否调节血液循环细胞成分的激活，以及细胞间的相互作用，从而改善HbSS婴儿的血管病理和临床过程。待评估的生物标志物将包括红细胞粘附内皮和固定化细胞外基质蛋白的功能评估、F细胞数量、红细胞标志物包括CD71（应激网织细胞）、各种红细胞粘附分子和磷脂酰丝氨酸（PS）阳性。凝血激活的标志物包括全血组织因子活性（WBTF）和凝血酶原片段F1.2水平。内皮活化将通过血浆溶胶VCAM-1和循环内皮微粒的定量和定性评估来评估。血小板和白细胞的活化将分别通过p -选择素和l -选择素的水平来评估。我们预测，与安慰剂相比，HU治疗将导致提示治疗效果的生物标志物变化模式。我们的评估也将提供描述HU调节这些细胞-细胞相互作用机制的信息。在BABY HUG试点方案中，对临床过程和器官功能障碍的两年随访评估也将为我们提供独特的机会来评估特定生物标志物的异常值是否会先于或与特定器官功能障碍或血管病理一起发生。在这些比较中可以发现较大的差异，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收集和分析提供基础。由于本中心过去在HbSS婴儿生物标志物评估方面拥有丰富的经验，因此纳入这些适当选择的生物标志物来评估疾病进展将补充该试点方案。我们的辅助建议应提高这项重要的多机构nhlbi赞助研究的长期效益和科学生产力。此外，这项研究的发现可能对与血管病变相关的其他疾病状态具有重要意义。

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.