Phase 2 Study: Intranasal Oxytocin vs. Placebo for the Treatment of Hyperphagia in Prader-Willi Syndrome [IND 121109 acknowledged 8/27/14]

项目摘要/摘要 Prader-Willi综合征(PWS)已被美国国立卫生研究院和 被美国国立卫生研究院罕见疾病研究办公室归类为此类疾病。[1]。要包含在此列表中，需要 在美国不到20万人的流行率。根据Prader-Willi综合征 美国癌症协会和文献回顾，目前对PWS患病率的估计从1： 8,000-1：30,000人，最有可能的患病率约为1：15,000人[2-8]。基于当前 美国人口普查数据美国有317,434,622人生活在美国。 PWS的患病率从10,581到39,679不等，最有可能的患病率约为21,000 美国人[9]。使用美国人口普查(2010)的最新数据，有74,181,467人 美国儿科人口(年龄18岁)[10]。假设PWS的患病率下降 在1：8,000到1：30,000之间，目前有2,473到9,273名18岁以下的人患有PWS。 PWS是一种罕见的神经发育障碍，由父系来源的印记缺乏表达所致 位于染色体15q11-q13上的材料。PWS的特点是轻度到中度的智力残疾， 重复/强迫行为和僵硬，社会认知缺陷和出生时严重的低眼压，其次是 晚年出现的吞噬过多症。肥胖是大多数发病率和死亡率的原因。 与PWS有关，强迫进食行为是导致生活质量下降的主要原因 给照顾者和家庭成员。催产素与PWS的病理生理学有关 在这一人群中对鼻腔内催产素(IN-OXT)进行了小型研究。然而，到目前为止，研究还没有 有足够的能力来检测吞噬过多的目标症状和相关症状的重要性 患有PWS的个体。这项建议的总体目标是研究IN-OXT在 从基线到第8周，用修订的Dykens过度吞噬问卷测量过度吞噬。 目前，还没有有效的治疗方法来控制PWS患者的吞噬功能亢进。 目标：这项2期试验的总体目标是比较从基线到第8周的变化 多肽IN-OXT对修订的Dykens高吞噬问卷在PWS儿童中的变化我们 已获得用于PWS的IN-OXT的IND(IND 121109)。我们已经获得了In-oxt和 配对安慰剂(由诺华公司生产，名为Syntocinon-见附录中的Letter和COA)。本阶段2 这项研究旨在为未来的3期试验生成初步数据，并针对这一症状 目前还没有有效治疗方法的人群。通过在儿科医生的生命早期治疗这些症状 对于PWS人群，我们可能会最大限度地发挥治疗效果。这项研究支持孤儿产品部门 确定和促进针对罕见疾病或疾病的治疗方法的发展的目标。 我们建议对50名儿童进行为期3年的平行、双盲、随机8周的IN-oxt与安慰剂对照试验。 (按性别分层；25名男性和25名女性)参加了PWS。患者将接受16IU/天的剂量- 牛肝素或安慰剂，疗程8周。为了优化不良事件或缺乏响应，我们允许 在第2周，一次向下滴定到12IU，一次向上滴定到24IU。 具体目标： 主要：比较in-oxt和安慰剂在修订后的Dykens吞噬问卷上的变化 PWS患儿从基线到第8周。我们假设IN-OXT将显著优于 安慰剂在改善吞噬过度方面的作用。 次要：比较IN-oxt与安慰剂从基线到第8周的变化： 1.重复行为量表修订版(RBS-R)。 2.通过生物电阻抗分析体重、BMI(z-Score)和身体成分 世界卫生组织生活质量调查问卷(WHO QOL) 4.唾液催产素浓度 5.安全分析 探索性： 1.使用ASA 24比较IN-oxt和安慰剂在饮食摄入量变化上的差异：自动、自我 管理，24小时回忆饮食日记系统，由国家癌症研究所(NCI)提供。 2.探讨医疗合并症对治疗结果的影响。 3.探讨吞噬功能亢进症患者体重给药与疗效的关系。 4.比较IN-oxt与安慰剂在基线和终点时激素水平的变化。测量的 激素将包括生长激素、胰多肽、YY肽、GLP-1、胰岛素、胰升糖素、睾酮和 雌激素。我们还将关注HbA1C的变化。

Project Summary/Abstract Prader-Willi Syndrome (PWS) has been designated as a rare disease by the National Institutes of Health and is categorized as such with the NIH Office of Rare Diseases Research. [1]. Inclusion on this list requires a prevalence of less than 200,000 people in the United States. According to the Prader-Willi Syndrome Association USA and a review of the literature, current estimates of the prevalence of PWS range from 1: 8,000 – 1: 30,000 with the most likely prevalence falling around 1 : 15,000 individuals [2-8]. Based on current U.S. Census data there are 317,434,622 people living in the U.S. Using the above prevalence estimates, the prevalence of PWS ranges from 10,581 to 39,679, and the most likely prevalence is approximately 21,000 Americans [9]. Using the most current available data from the U.S. Census (2010), there are 74,181,467 people in the pediatric population in the US (age < 18 years) [10]. Assuming that the prevalence of PWS falls between 1: 8,000 and 1: 30,000, there are currently between 2,473 and 9,273 people under age 18 with PWS. PWS is a rare neurodevelopmental disorder caused by lack of expression of paternally derived imprinted material on chromosome 15q11-q13. PWS is characterized by mild to moderate intellectual disabilities, repetitive/ compulsive behaviors and rigidity, social cognition deficits and severe hypotonia at birth, followed by the onset of hyperphagia later in life. Obesity is responsible for the majority of the morbidity and mortality associated with PWS, and compulsive eating behaviors are most responsible for diminishing the quality of life for caregivers and family members. Oxytocin has been implicated in the pathophysiology of PWS and there have been small studies of intranasal oxytocin (IN-OXT) in this population. To date, however, studies have not been adequately powered to detect significance in target symptoms of hyperphagia and associated symptoms of individuals with PWS. The overall goal of this proposal is to study the safety and efficacy of IN-OXT on hyperphagia as measured by the Revised Dykens Hyperphagia Questionnaire from baseline to week 8. Currently, there are no effective treatments available to manage hyperphagia in patients with PWS. Objective: The overall objective of this Phase 2 trial is to compare the change from baseline to week 8 of the peptide IN-OXT on changes on the Revised Dykens Hyperphagia Questionnaire in children with PWS. We have obtained an IND for the use of IN-OXT for PWS (IND 121109). We have acquired the IN-OXT and matching placebo (Manufactured by Novartis as Syntocinon - see letter and COA in appendix). This Phase 2 study is designed to generate preliminary data for future Phase 3 trials, and targets symptoms in this population that currently have no effective treatments. By treating these symptoms earlier in life in a pediatric PWS population, we may maximize the treatment impact. This study supports the Orphan Product Divisions goal of identifying and promoting the development of treatments indicated for a rare disease or condition. We propose a 3 year parallel, double-blind, randomized 8 week trial of IN-OXT vs. placebo in 50 children (stratified by gender; 25 male and 25 female) enrolled with PWS. Patients will receive a dose of 16 IU/day IN- OXT or placebo for 8 weeks. To allow for optimization for adverse events or lack of response, we allow for one downward titration to 12 IU, and one upward titration to 24 IU at week 2, respectively. Specific Aims: Primary: To compare IN-OXT vs. placebo on changes on the Revised-Dykens Hyperphagia Questionnaire from baseline to week 8 in children with PWS. We hypothesize that IN-OXT will be significantly superior to placebo in improving hyperphagia. Secondary: To compare the change from baseline to week-8 of IN-OXT vs. placebo on: 1. Repetitive Behavior Scale-Revised (RBS-R). 2. Weight, BMI (z-score) and Body composition via bioelectrical impedance analysis 3. World Health Organization Quality of Life Questionnaire (WHOQOL) 4. Salivary Oxytocin Concentration 5. Safety Analyses Exploratory: 1. To compare IN-OXT vs. placebo on changes in dietary intake using the ASA 24: Automated, Self- Administered, 24 hour Recall diet diary system, as provided by the National Cancer Institute (NCI). 2. To examine the impact of medical co-morbidities on treatment outcome. 3. To examine the relationship between weight-based dosing and treatment response on hyperphagia. 4. To compare IN-OXT vs. placebo on changes in hormone levels at baseline and endpoint. Measured hormones will include ghrelin, pancreatic polypeptide, peptide YY, GLP-1, insulin, glucagon, testosterone and estrogen. We will also look at changes in HbA1C.