Crossover Study of an Oral Treatment for Sickle Cell Disease

摘要 镰状细胞病（SCD）影响美国约10万人， 全球数百万。症状在出生后不久出现，在欠发达国家， 大多数患有SCD的儿童在五岁之前死亡。在美国，SCD患者患有慢性 疼痛和疲劳，需要住院治疗的严重急性疼痛危象和阿片类药物，中风， 多器官损伤，平均死亡率在40多岁。FDA唯一批准的药物 治疗成人SCD的药物是抗癌药羟基脲。迫切需要新的治疗方法 对于患有SCD的儿童和成人。 SCD-101是一种植物药，在体外和体内都显示出直接的抗镰状化作用， 活动我们的目标是开发SCD-101作为一种安全有效的口服治疗药物， 镰状细胞病在儿童和成人中不可阻挡的发展。在撒哈拉以南非洲和 在印度，数百万人患有镰状细胞病，80%的人口依赖于 用于初级卫生保健的传统药物（植物药）。因此，SCD-101作为一种植物药， 药物，是全球数百万镰状细胞病患者的解决方案。 我们最近完成了一项28天的SCD-101重复口服剂量，剂量递增研究， 23名患有镰状细胞病的成年人。1b期试验结果表明，SCD-101是安全的， 耐受性良好，并确定了用于II期研究的剂量和时间表。在两 最高剂量，对减少疲劳和疼痛有深远的影响，这两个最常见的 SCD的症状基于我们1b期研究的结果，我们提出了一个双盲， 在18名纯合型（S/S）镰状细胞病患者中进行的安慰剂对照2x 2交叉研究 确定用于II期和III期研究的临床相关终点。 一项交叉研究，每个受试者都是他或她自己的对照， 样本量，因此交叉研究具有36例患者平行设计的等效功效。 拟定的交叉研究有足够的把握度显示统计学显著性， 基于我们的1b期研究结果，疲劳的临床相关改善， 统计学显著和临床相关的疼痛改善。交叉研究还将 测量SCD-101对睡眠、红细胞（RBC）溶血标志物、炎性 细胞因子和静脉全血中的循环镰状细胞。

ABSTRACT Sickle cell disease (SCD) affects approximately 100,000 people in the United States and millions worldwide. Symptoms appear shortly after birth, and in less developed countries the majority of children with SCD die before the age of five. In the U.S., SCD patients suffer chronic pain and fatigue, severe acute painful crises requiring hospitalization and opiates, strokes, and multi-organ damage, and have an average mortality in their 40s. The only FDA approved drug for adults with SCD is the anticancer drug hydroxyurea. New treatments are desperately needed for both children and adults with SCD. SCD-101 is a botanical drug that has shown direct in vitro and in vivo anti-sickling activity. Our goal is to develop SCD-101 as a safe and effective oral treatment that prevents the inexorable progression of sickle cell disease in children and adults. In sub-Saharan Africa and India, where many millions suffer with sickle cell disease, 80% of the population depends on Traditional Medicine (botanicals) for primary health care. Therefore, SCD-101, as a botanical drug, is the solution for the millions with sickle cell disease worldwide. We recently completed a 28-day repeat oral dose, dose-escalation study of SCD-101 in 23 adults with sickle cell disease. The Phase 1b results showed that SCD-101 was safe and well tolerated and established the dose and schedule to be used in a Phase 2 study. At the two highest doses, there was a profound effect on reducing fatigue and pain, the two most common symptoms of SCD. Building on the results of our Phase 1b study, we propose a double-blind, placebo controlled 2x2 crossover study in 18 patients with homozygous (S/S) sickle cell disease to establish the clinically relevant endpoints to be used in a Phase 2 and Phase 3 study. A crossover study, where each subject is his or her own control, doubles the effective sample size, so the crossover study has the equivalent power of a 36 patient parallel design. The proposed crossover study has sufficient power to show a statistically significant and clinically relevant improvement in fatigue based our Phase 1b results, and may show a statistically significant and clinically relevant improvement in pain. The crossover study will also measure the effect of SCD-101 on sleep, red blood cell (RBC) hemolysis markers, inflammatory cytokines, and circulating sickled cells in venous whole blood.