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

孟鲁司特治疗镰状细胞性贫血的 2 期研究

• 批准号: 8568575
• 负责人: Michael R. DeBaun
• 金额: $ 39.66万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8568575
• 关键词: Phase; Study; Montelukast; Treatment; Sickle

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.

抽象的 羟基脲（HU）是食品药品监督管理局（FDA）批准的唯一一种用于预防的药物 镰状细胞疾病（SCD）中的血管胶质性疼痛发作。该建议支持随机，双盲， Montelukast（Cysteinyl Leukotriene受体1拮抗剂）的安慰剂对照II期试验结合 HU可预防青少年和成年人的血管胶质疼痛发作。我们的调查 团队已经产生了大量的临床和临床前数据，这意味着白细胞三烯（Cyslts） 血管封闭的发病机理。在具有SCD的儿童和成人的单独同类中，基线水平为 CYSLT与疼痛的住院率有关。此外，经过处理的SCD的鼠模型 蒙特卢卡斯特（Montelukast 与未处理的SCD小鼠相比，血管细胞粘附分子1（SVCAM-1）。 Montelukast是FDA- 批准的疗法耐受性良好，并且已经在患有哮喘的SCD患者中广泛使用。 我们已经组建了一个多学科团队来检验该假设[Montelukast增添了HU功效 与单独使用HU相比，用于改善血管封闭的治疗]。在此提案中，我们将比较 接受了蒙特鲁卡斯特和胡治疗的参与者对接受安慰剂和HU治疗的参与者总共8周。这 在具有SCD的青少年和成年人中，将测试以下特定目标：AIM 1。 在HU中添加的Montelukast与安慰剂将改善与嵌入相关组织的标记 青少年和SCD成年人的伤害]和目标2。[评估Montelukast的生理影响 与安慰剂相比，在患有SCD的青少年和成年人中添加了HU]； （subaim 2a）[确定是否 在HU中添加的Montelukast和安慰剂将改善青少年和成年人的肺功能 SCD]; （subaim 2b）[确定蒙特鲁克斯特和安慰剂是否添加到胡前卫将改善前臂 SCD的青少年和成年人的微血管血流]。预计[20％]辍学 费率，我们将注册63名参与者，并预计50名参与者将接受Montelukast或安慰剂治疗 8周。如果这项研究提供了初步证据，表明与HU结合使用的Montelukast具有功效 为了治疗血管咬合，我们将提出一项更大的多中心III期试验。