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

摘要 羟基脲（HU）是唯一一种经美国食品药品监督管理局（FDA）批准用于预防 镰状细胞病（SCD）中的血管闭塞性疼痛发作。该提案支持随机、双盲、 孟鲁司特（一种半胱氨酰白三烯受体1拮抗剂）与 HU用于预防青少年和成人SCD患者的血管闭塞性疼痛发作。我们的调查 研究小组已经产生了大量的临床和临床前数据，表明半胱氨酰白三烯（CysLTs）在 血管闭塞的发病机制。在患有SCD的儿童和成人的单独队列中， CysLT与疼痛住院率相关。此外，用以下药物治疗的SCD鼠模型 孟鲁司特显示血管充血减少，可溶性炎症标记物水平降低， 血管细胞粘附分子-1（sVCAM-1）与未治疗的SCD小鼠相比。孟鲁司特是FDA- 已批准的治疗耐受性良好，并已广泛用于患有SCD的哮喘患者。 我们已经组建了一个多学科的团队来验证孟鲁司特增加HU疗效的假设 与单独HU相比，用于改善血管闭塞的治疗]。在本提案中，我们将比较 用孟鲁司特和HU治疗的参与者与用安慰剂和HU治疗的参与者总共8周。的 将在患有SCD的青少年和成人中测试以下具体目标：目标1。[To确定是否 与安慰剂相比，孟鲁司特加到HU中将改善血管闭塞相关组织的标志物 青少年和成人SCD损伤]，目的2。[To评价孟鲁司特的生理作用 与在患有SCD的青少年和成人中HU中添加安慰剂相比];（Subaim 2A）[为了确定 与安慰剂相比，将孟鲁司特添加到HU中将改善青少年和成人的肺功能， SCD];（Subaim 2B）[确定与安慰剂相比，将孟鲁司特添加至HU是否会改善前臂 青少年和成人SCD患者的微血管血流]。预计[20%]辍学 率，我们将招募63名参与者，预计50名参与者将接受孟鲁司特或安慰剂治疗 8周。如果这项研究提供了孟鲁司特与HU联合使用的初步证据， 对于血管阻塞的治疗，我们将提出一项更大规模的多中心III期试验。

Abstract Hydroxyurea (HU) is the only drug approved by the Food and Drug Administration (FDA) for the prevention of vaso-occlusive pain episodes in sickle cell disease (SCD). This proposal supports a randomized, double-blind, placebo-controlled phase II trial of montelukast (a cysteinyl leukotriene receptor 1 antagonist) combined with HU for the prevention of vaso-occlusive pain episodes in adolescents and adults with SCD. Our investigative team has generated abundant 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 well tolerated and already widely used in individuals with SCD who also have asthma. We have assembled a multi-disciplinary team to test the hypothesis [that montelukast adds efficacy to HU therapy for improving vaso-occlusion when compared to HU alone]. In this proposal, we will compare participants treated with montelukast and HU 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]; (Subaim 2A) [To determine if montelukast versus placebo added to HU will improve lung function in adolescents and adults with SCD]; (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%] dropout rate, we will enroll 63 participants and expect that 50 participants will receive montelukast or placebo therapy for 8 weeks. If this study provides preliminary evidence that montelukast when combined with HU has efficacy for the treatment of vaso-occlusion, we will propose a larger multi-center phase III trial.