Naloxone Lotion for the Treatment of Pruritus in Mycosis Fungoides

7.项目摘要/摘要 该项目是这项拨款申请的主题，是一项第三阶段临床研究，旨在证明安全性和 0.5%盐酸纳洛酮洗剂缓解霉菌病相关瘙痒的疗效观察 真菌样(MF)[以及S艾扎里综合征(SS)，都是]型[S]皮肤T细胞淋巴瘤。 伴随着皮肤疾病的严重瘙痒(瘙痒)，如MF，最常见的亚型 CTCL，常常被低估。严重的慢性瘙痒症在临床上对发病率和 死亡率影响疾病的临床管理及其成本。作为一种症状，瘙痒是不舒服的 烦人、干扰和干扰日常生活的活动，干扰睡眠，并可能影响社交互动 行为。此外，慢性瘙痒与相当大的生活质量损害有关。 相当于慢性疼痛。1据估计，MF患者的死亡率是其他患者的两倍。 目前的药物并不能完全解决与瘙痒相关的瘙痒。 患上了多发性硬化症，这会导致来自鞭挞的感染。纳洛酮0.5%盐酸洗剂将填补这一未得到满足的医疗需求。 传统的止痒药物，即抗组胺药、三环类抗抑郁药和皮质类固醇类药物，通常不是 有效地控制与MF.11相关的瘙痒目前的证据表明，与MF相关的瘙痒可能是 并为治疗MF相关的瘙痒症提供了科学依据 阿片类拮抗剂。纳洛酮在药理学上被归类为阿片类拮抗剂，其活性为 包括Mu、Delta、Kappa1和Kappa3.3在内的多种阿片受体治疗皮肤瘙痒 使用纳洛酮局部制剂的MF代表了一种新的治疗方法[作为全身给药 由于纳洛酮在血液中的半衰期很短，因此不切实际。] 这是一项为期6-9周的双盲、车辆控制、交叉研究，涉及大约160名成年受试者， 有与MF[或SS]相关的中到重度瘙痒(0-10分最低5分)。 这项研究包括一周的非治疗筛查期，在此期间，受试者将被要求 完成每日一份评估全身瘙痒的日记。一周的筛选期之后是两周的筛选 疗程4~28天，疗程2周。主题将是 随机1：1在第一个疗程中接受0.5%盐酸纳洛酮洗剂或赋形剂洗剂，以及 另一组在第二个疗程。主要疗效变量将是与基线相比的变化 在每次治疗的第14天评估瘙痒症的11分数字评定量表(NRS)的每周平均值 句号。 第三阶段研究的计划持续时间约为两年。在这项第三阶段研究之后，Elorac，Inc. 将进行6个月的安全性研究，以完成并向美国FDA提交NDA。六项第一阶段研究4、5、6、7、8、9 在15名患有MF或SS10的受试者中进行的第二阶段安全性和有效性试验已经完成。纳洛酮 用于局部治疗与MF相关的瘙痒的洗剂于8月1日被FDA授予孤儿地位 2010年11月23日和2013年4月11日被指定为快车道。

7. Project Summary/Abstract The project which is the subject of this grant application is a Phase 3 clinical study to demonstrate safety and efficacy of Naloxone 0.5% Hydrochloride (HCl) Lotion for the relief of pruritus associated with [the] mycosis fungoides (MF) [as well as Sèzary syndrome (SS), both being] form[s] of cutaneous t-cell lymphoma (CTCL). The seriousness of pruritus (itch) that accompanies skin disorders such as MF, the most prevalent subtype of CTCL, is often underestimated. Severe chronic pruritus has clinically significant effects on morbidity and mortality that impact clinical management of the disease its costs. As a symptom, itch is uncomfortable and annoying, distracts and disrupts activities of daily life, interferes with sleep, and may affect social interactive behavior. Moreover, chronic pruritus has been associated with considerable impairment of quality of life comparable to chronic pain.1 The mortality rate in patients with MF is estimated to be twice as frequent in patients with itching than in those without itching.2 Current medications do not completely address the pruritus associated with MF which leads to infections from excoriations. Naloxone 0.5% HCl Lotion will fill this unmet medical need. Traditional anti-pruritic drugs, i.e. antihistamines, tricyclic antidepressants, and corticosteroids, are not generally effective in managing the itch associated with MF.11 Current evidence suggests that MF related pruritus may be mediated by a peripheral opinergic pathway and provides the scientific rationale for treating MF related pruritus with the opioid antagonist. Naloxone is classified pharmacologically as an opioid antagonist with activity at multiple opioid receptors including Mu, Delta, Kappa1 and Kappa3.3 The treatment of pruritus associated with MF using a topical formulation of naloxone represents a novel therapeutic approach [as systemic administration is not practical due to the short half life of naloxone in blood.] This is a 6 – 9 week, double-blind, vehicle-controlled, crossover study of approximately 160 adult subjects that have moderate to severe pruritus (a minimum score of 5 on the 0 – 10 point scale) associated with MF [or SS]. The study is composed of a 1 week non-treatment Screening Period during which subjects will be required to complete a daily diary assessing overall pruritus. The 1 week Screening Period is followed by a two week Treatment Period, 4 – 28 day Washout Period, and another two week Treatment Period. Subjects will be randomized 1:1 to receive either Naloxone 0.5% HCl Lotion or Vehicle Lotion in the first Treatment Period, and the other in the second Treatment Period. The primary efficacy variable will be the change from Baseline in the weekly average of the 11-point Numeric Rating Scale (NRS) for Pruritus assessed at Day 14 of each Treatment Period. The planned duration of the Phase 3 study is approximately 2 years. Following this Phase 3 study, Elorac, Inc. will conduct a 6 month safety study to complete and submit a NDA to the US FDA. Six Phase 1 studies4,5,6,7,8,9 and a Phase 2 safety and efficacy trial in 15 subjects with MF or SS10 have already been completed. Naloxone Lotion for the topical treatment of pruritus associated with MF was granted orphan status by the FDA on November 23, 2010 and fast track designation on April 11, 2013.