Phase 2 Study of Montelukast for the Treatment of Sickle Cell Anemia

描述(由申请人提供)： 这项建议是关于孟鲁司特(一种半胱氨酰白三烯受体1拮抗剂)与羟基脲(HU)联合用于预防患有镰状细胞病(SCD)的青少年和成人的血管闭塞性疼痛发作的随机、双盲、安慰剂对照的第2阶段试验。研究小组已经产生了半胱氨酰白三烯(CysLts)在血管闭塞发病机制中的临床和临床前数据。在儿童和成人SCD患者的不同队列中，CysLTs的基线水平与因疼痛而住院的比率有关。此外，与未治疗的SCD小鼠相比，经孟鲁司特治疗的SCD小鼠模型显示血管充血减少，炎症标记物可溶性血管细胞黏附分子-1(sVCAM-1)水平降低。孟鲁司特是FDA批准的一种疗法，已经用于同时患有哮喘的SCD患者。需要检验的假设是，与单独使用HU相比，孟鲁司特增加了HU治疗改善血管闭塞的疗效。在这项提案中，接受孟鲁司特和HU治疗的参与者将与接受安慰剂和HU治疗的参与者进行总计8周的比较。将在青少年和成人SCD患者中测试以下特定目标：目的1.确定孟鲁司特与安慰剂加用HU是否会改善青少年和成人SCD患者血管闭塞相关组织损伤的标记物，并目的2.评估孟鲁司特与安慰剂加用HU对青少年和成人SCD患者的生理效应，特别是(Subaim 2A)，以确定孟鲁司特与安慰剂加HU是否会改善青少年和成人SCD患者的肺功能；(Subaim 2B)确定孟鲁司特与安慰剂加用HU是否会分别改善青少年和成人SCD患者的前臂微血管血流。预计20%的辍学率，63名参与者将被登记，预计50名参与者将接受为期8周的孟鲁司特或安慰剂治疗。

DESCRIPTION (provided by applicant): This proposal is for a randomized, double-blind, placebo-controlled Phase 2 trial of montelukast (a cysteinyl leukotriene receptor 1 antagonist) combined with hydroxyurea (HU) for the prevention of vaso-occlusive pain episodes in adolescents and adults with sickle cell disease (SCD). The investigative team has generated clinical and pre-clinical data implicating cysteinyl leukotrienes (CysLTs) in the pathogenesis of vaso-occlusion. In separate cohorts of children and adults with SCD, baseline levels of CysLTs were associated with the rate of hospitalizations for pain. Further, murine models of SCD treated with montelukast showed decreased vascular congestion and lower levels of the inflammatory marker soluble vascular cell adhesion molecule-1 (sVCAM-1) compared to untreated SCD mice. Montelukast is an FDA-approved therapy that is already used in individuals with SCD who also have asthma. The hypothesis to be tested is that montelukast adds efficacy to HU therapy for improving vaso-occlusion when compared to HU alone. In this proposal, participants treated with montelukast and HU will be compared to those treated with placebo and HU for a total of 8 weeks. The following specific aims will be tested in adolescents and adults with SCD: Aim 1. To determine whether montelukast versus placebo added to HU will improve markers of vaso-occlusion-associated tissue injury in adolescents and adults with SCD, and Aim 2. To evaluate physiologic effects of montelukast versus placebo added to HU in adolescents and adults with SCD, specifically (Subaim 2A) to determine if montelukast versus placebo added to HU will improve lung function in adolescents and adults with SC; (Subaim 2B) to determine if montelukast versus placebo added to HU will improve forearm microvascular blood flow in adolescents and adults with SCD, respectively. Anticipating a 20 percent dropout rate, 63 participants will be enrolled with the expectation that 50 participants will receive montelukast or placebo therapy for 8 weeks.