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。HHT最常见的表现是 鼻出血和消化道出血；然而，累及肺、脑或肝脏的动静脉畸形也可导致毁灭性的 心血管并发症包括充血性心力衰竭、肺出血和出血性中风。 据估计，美国有超过10万例高血压病患者。除了流血和 心血管症状，HHT的发病率导致焦虑和抑郁的高发 极大地影响了社会功能。目前还没有被广泛接受的、有效的治疗HHT的方法。HHT病变的消融治疗 通过介入方法是常用的方法，但只提供短暂的好处。医学方法有 包括抗纤溶治疗、雌激素和奥曲肽等，但这些药物对 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相关性鼻出血方面并不比安慰剂有效。目前的研究建立在结果的基础上 几项表明沙利度胺对HHT有效的小型研究；然而，沙利度胺不适用于 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 抗血管生成活性与沙利度胺相似，但毒性较小。由PI进行的一项由行业资助的小型试点研究 已经证明泊马度胺在HHT中的有效性和安全性，FDA已经发布了IND来扩大这些药物的范围 观察。这项重新提交的研究提出了一项随机的、安慰剂对照的研究，该研究得到了来自 NHLBI血液学U34临床试验计划资助和U24临床试验开发资源 由HHT专家、患者权益倡导者和经验丰富的临床试验统计学家组成的团队。相同 设计这项研究的团队将在克利夫兰诊所使用sirB进行研究。我们建议1)确定 泊马度胺治疗高血压伴鼻出血需定期补铁或补铁的疗效和安全性 输血，2)用美国国立卫生研究院测定泊马度胺对HHT患者生活质量的影响 PROMIS工具和特定于HHT的调查问卷，以及3)创建研究患者样本的生物信息库 用于未来的生物标记物和机制研究。这项研究可能会验证泊马度胺作为一种新的治疗选择 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.