1/2 Pomalidomide for Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia (HHT)

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最常见的表现是 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10万例HHT的患病率。除了出血和 心血管表现，HHT的发病率导致焦虑和抑郁的高发病率， 对社会功能影响很大。HHT尚无广泛接受的有效治疗方法。HHT病变消融 通过介入方法是常用的，但仅提供短暂的益处。医疗方法有 包括抗纤维蛋白溶解疗法、雌激素和奥曲肽等，然而，这些对 大多数病人最近的一项研究表明，含有氨甲环酸、雌三醇或贝伐单抗的鼻喷雾剂 在治疗HHT相关鼻出血方面并不比安慰剂更有效。目前的研究建立在结果的基础上， 几项小型研究表明沙利度胺在HHT中的疗效;然而，沙利度胺不适用于 因此，我们建议研究泊马度胺，第三代沙利度胺类似物， 类似于沙利度胺抗血管生成活性但毒性较低。一项由PI进行的小型、行业资助的试点研究 已经证明了泊马度胺在HHT中的有效性和安全性，FDA已经发布了IND来扩展这些 意见。本次重新提交的研究建议进行一项随机、安慰剂对照研究，该研究得到了以下研究的支持： NHLBI U34临床试验规划补助金和U24血液学临床试验开发资源 由HHT专家、患者倡导者和经验丰富的临床试验统计学家组成的团队进行疾病评估。相同的 设计该研究的团队将使用克利夫兰诊所的sIRB进行研究。我们建议：（1）确定 泊马度胺在需要定期铁剂输注的HHT和鼻出血患者中的疗效和安全性，或 输血，2）使用NIH确定泊马度胺对HHT患者生活质量的影响 PROMIS工具和HHT特定问卷，以及3）创建研究患者样本的生物储存库 用于未来的生物标志物和机制研究。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HHT的治疗模式。

ABSTRACT 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 US. 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 upon results of several small studies that suggest efficacy of thalidomide in HHT; however, thalidomide is not available for clinical trials in the U.S. Thus, we propose to study pomalidomide, a third generation thalidomide analogue with similar anti-angiogenic activity but less toxicity that thalidomide. A small, industry-funded pilot study by the PI has demonstrated efficacy and safety of pomalidomide in HHT, and the 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 a 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.