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.

摘要 羟基脲(HU)是美国食品和药物管理局(FDA)批准的唯一一种预防高血压的药物。 镰状细胞病(SCD)的血管闭塞性疼痛发作。这一建议支持随机、双盲、 孟鲁司特(一种半胱氨酰白三烯受体1拮抗剂)联合孟鲁司特的安慰剂对照II期试验 HU用于预防患有SCD的青少年和成年人的血管闭塞性疼痛发作。我们的调查人员 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。在不同的SCD儿童和成人队列中，基线水平 CysLT与疼痛住院率有关。此外，对SCD的小鼠模型进行了治疗 孟鲁司特显示血管充血减少，炎症标志物可溶性水平降低 血管细胞黏附分子-1(sVCAM-1)与未经治疗的SCD小鼠的比较。孟鲁司特是FDA- 经批准的治疗方法，耐受性良好，已广泛用于同时患有哮喘的SCD患者。 我们已经组建了一个多学科的团队来验证这一假设[孟鲁司特对HU有疗效 与单独使用HU相比，用于改善血管闭塞的治疗]。在这份提案中，我们将比较 接受孟鲁司特和HU治疗的患者与接受安慰剂和HU治疗的患者相比，总共为期8周。这个 以下具体目标将在患有SCD的青少年和成人中进行测试：目标1。[确定是否 孟鲁司特与安慰剂相比，加入HU将改善血管闭塞相关组织的标志物 青少年和成人SCD的伤害]，以及目标2。[评估孟鲁司特的生理作用 与HU在患有SCD的青少年和成人中添加安慰剂的对比]；(Subaim 2A)[确定是否 孟鲁司特与安慰剂相比，加入HU将改善青少年和成人的肺功能 [以确定加用孟鲁司特与安慰剂是否会改善前臂 青少年和成年SCD患者的微血管血流情况]。预计会有[20%]的辍学 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 持续8周。如果这项研究提供了孟鲁司特与HU联合治疗有效的初步证据 对于血管闭塞的治疗，我们将提出一项更大规模的多中心III期试验。