2/2 Pomalidomide for Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia (HHT) Bleeding Data Coordinating Center

项目摘要 遗传性出血性毛细血管扩张症（HHT）是一种以弥漫性动静脉 畸形（AVM）和毛细血管扩张，影响许多器官。HHT最常见的表现 鼻出血和胃肠道出血;然而，累及肺、脑或肝脏的AVM也可能导致破坏性的 心血管并发症，包括充血性心力衰竭、肺出血和出血性 中风据估计，在美国有超过100，000例HHT病例。除了 出血和心血管表现，HHT的发病率导致焦虑的高发病率， 严重影响社会功能的抑郁症。HHT尚无广泛接受的有效治疗方法。 通过介入方法消融HHT病变是常用的，但仅提供短暂的受益。 医学方法包括抗纤维蛋白溶解疗法、雌激素和奥曲肽等;然而， 这些对大多数患者无效。最近的一项研究表明，含有氨甲环的鼻喷雾剂 酸、雌三醇或贝伐单抗在治疗HHT相关鼻出血方面并不比安慰剂更有效。的 目前的研究建立在几项小型研究的结果上，这些研究表明沙利度胺在HHT中的功效;然而， 沙利度胺在美国还不能用于临床试验。因此，我们建议研究泊马度胺， 第三代沙利度胺类似物，具有类似的抗血管生成活性，但毒性低于沙利度胺。一 PI进行的小型、行业资助的初步研究证明了泊马度胺在HHT中的疗效和安全性， FDA已发布IND以扩大这些观察结果。这次重新提交的建议是随机的，安慰剂- 在NHLBI U34临床试验计划资助和U24临床试验资助的支持下开发的对照研究 由HHT专家团队、患者倡导者和 经验丰富的临床试验统计学家。设计研究的同一团队将使用sIRB进行研究， 克利夫兰诊所我们建议（1）确定泊马度胺在以下患者中的疗效和安全性： HHT和鼻出血需要定期铁剂输注或输血，（2）确定 泊马度胺对HHT患者生活质量的影响，使用NIH PROMIS工具和HHT特异性 问卷，和（3）创建来自研究患者的样品的生物储存库，用于未来的生物标志物， 机械研究。这项研究可能会验证泊马度胺作为一种新的治疗选择，并改变 治疗HHT的范例。

Project Summary Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by diffuse arteriovenous malformations (AVMs) and telangiectasia that affect many organs. The most common manifestations of HHT are epistaxis and GI bleeding; however AVMs that involve the lungs, brain, or liver can also lead to devastating cardiovascular complications including congestive heart failure, pulmonary hemorrhage, and hemorrhagic stroke. Estimates suggest a prevalence of more than 100,000 cases of HHT in the United States. In addition to bleeding and cardiovascular manifestations, the morbidity of HHT leads to a high incidence of anxiety and depression that greatly affects social function. There is no broadly accepted, effective therapy for HHT. Ablation of HHT lesions via interventional approaches is commonly used but provides only transient benefit. Medical approaches have included anti-fibrinolytic therapy, estrogen, and octreotide, among others; however, these are not effective in most patients. A recent study demonstrated that nasal sprays containing tranexamic acid, estriol, or bevacizumab were no more effective than placebo in treating HHT-associated epistaxis. The current study builds on results of several small studies that suggest efficacy of thalidomide in HHT; however, thalidomide is not available for clinical trials in the United States. Thus, we propose to study pomalidomide, a third-generation thalidomide analog with similar anti-angiogenic activity but less toxicity than thalidomide. A small, industry-funded pilot study by the PI has demonstrated efficacy and safety of pomalidomide in HHT, and FDA has issued an IND to expand these observations. This resubmission proposes a randomized, placebo- controlled study developed with support from an NHLBI U34 Clinical Trial Planning Grant and U24 Clinical Trials Development Resource for Hematologic Disorders by a team of HHT experts, a patient advocate, and experienced clinical trial statisticians. The same team that designed the study will conduct it, using an sIRB at the Cleveland Clinic. We propose to (1) determine the efficacy and safety of pomalidomide in patients with HHT and epistaxis requiring periodic iron infusion or blood transfusion, (2) determine the effect of pomalidomide on quality of life in patients with HHT using NIH PROMIS tools and an HHT-specific questionnaire, and (3) create a biorepository of samples from study patients for future biomarker and mechanistic studies. This study may validate pomalidomide as a new therapeutic option and change the paradigm for treatment of HHT.