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是一种以弥漫性动静脉为特征的遗传性疾病。 影响许多器官的畸形(动静脉畸形)和毛细血管扩张。高血压病最常见的临床表现 鼻出血和消化道出血；然而，涉及肺、脑或肝脏的动静脉畸形也可以导致毁灭性的 心血管并发症，包括充血性心力衰竭、肺出血和出血 卒中。据估计，美国有超过10万例HHT病例。除了……之外 出血和心血管症状，HHT的发病率导致焦虑和 严重影响社会功能的抑郁症。目前还没有被广泛接受的、有效的治疗HHT的方法。 通过介入方法消融HHT病变是常用的方法，但只能提供短暂的益处。 医学方法包括抗纤溶治疗、雌激素和奥曲肽等；然而， 这些药物对大多数患者都无效。最近的一项研究表明，含有氨甲环胺的鼻喷剂 酸、雌三醇或贝伐单抗在治疗HHT相关性鼻出血方面并不比安慰剂更有效。这个 目前的研究建立在几项小型研究的结果基础上，这些研究表明沙利度胺对HHT有效；然而， 沙利度胺在美国不能用于临床试验。因此，我们建议研究泊马度胺，一种 第三代沙利度胺类似物具有与沙利度胺相似的抗血管生成活性，但毒性更小。一个 由PI进行的小型、行业资助的初步研究已经证明了泊马度胺在HHT中的有效性和安全性，以及 FDA已经发布了IND来扩大这些观察结果。这份重新提交的报告提出了一种随机的安慰剂- 在NHLBI U34临床试验计划拨款和U24临床试验资助下开发的对照研究 血液疾病试验开发资源，由一组HHT专家、患者权益倡导者和 经验丰富的临床试验统计师。设计这项研究的同一团队将使用sirB在 克利夫兰诊所。我们建议(1)确定泊马度胺治疗慢性阻塞性肺疾病的疗效和安全性。 HHT和需要定期输铁或输血的鼻出血，(2)决定疗效 泊马度胺使用NIH PROMIS工具和HHT专属药物对HHT患者生活质量的影响 问卷调查，以及(3)创建研究患者样本的生物储存库，用于未来的生物标记物和 机械学研究。这项研究可能验证泊马度胺作为一种新的治疗选择并改变 HHT的治疗模式。

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.