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

描述（由申请人提供）： 该提案是一项随机、双盲、安慰剂对照的2期试验，孟鲁司特（一种半胱氨酰白三烯受体1拮抗剂）联合羟基脲（HU）预防青少年和成人镰状细胞病（SCD）患者的血管闭塞性疼痛发作。研究小组已经产生了临床和临床前数据，表明半胱氨酰白三烯（CysLTs）在血管闭塞的发病机制中。在患有SCD的儿童和成人的单独队列中，CysLT的基线水平与疼痛住院率相关。此外，与未治疗的SCD小鼠相比，用孟鲁司特治疗的SCD小鼠模型显示血管充血减少和炎性标志物可溶性血管细胞粘附分子-1（sVCAM-1）水平降低。孟鲁司特是一种FDA批准的治疗方法，已经用于患有SCD的哮喘患者。 待检验的假设是，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功效。 在该提案中，将用孟鲁司特和HU治疗的参与者与用安慰剂和HU治疗的参与者进行总共8周的比较。将在患有SCD的青少年和成人中测试以下特定目标：目标1。确定与安慰剂相比，将孟鲁司特添加到HU中是否会改善患有SCD的青少年和成人的血管闭塞相关组织损伤的标志物，目的2。评价在HU中添加孟鲁司特与安慰剂对患有SCD的青少年和成人的生理作用，特别是（Subaim 2A），以确定在HU中添加孟鲁司特与安慰剂是否会改善患有SC的青少年和成人的肺功能;（Subaim 2B）以确定在HU中添加孟鲁司特与安慰剂是否会分别改善患有SCD的青少年和成人的前臂微血管血流。预计20%的脱落率，63名参与者将被招募，预计50名参与者将接受孟鲁司特或安慰剂治疗8周。

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.