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

1/2 Pomalidomide 用于治疗遗传性出血性毛细血管扩张症 (HHT) 患者的出血

• 批准号: 10581634
• 负责人: Keith R. McCrae
• 金额: $ 61.81万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581634
• 关键词: ACVRL1 gene; Ablation; Advocate; Affect; Angiogenesis Inhibitors; Antifibrinolytic Agents; Anxiety; Arteriovenous malformation; Biological Markers; Biopsy; Blood Platelets; Blood Transfusion; Blood Vessels; Brain; Brain hemorrhage; Cardiovascular Manifestation; Cardiovascular system; Clinic; Clinical; Clinical Trials; Collaborations; Congestive Heart Failure; Data; Data Coordinating Center; Databases; Diagnosis; Diffuse; Disease; Double-Blind Method; Epistaxis; Estriol; Estrogens; Funding; Future; Gastroenterologist; Gastrointestinal Hemorrhage; Generations; Genes; Grant; Hematological Disease; Hematologist; Hemorrhage; Hereditary Disease; Hereditary hemorrhagic telangiectasia; Incidence; Individual; Industry; Infusion procedures; Intervention; Iron; Legal patent; Lesion; Leukocytes; Liver; Lung; MADH4 gene; Measures; Medical; Mental Depression; Molecular Analysis; Morbidity - disease rate; Mutate; Mutation; National Heart, Lung, and Blood Institute; Nose; Octreotide; Organ; Outcome; Parents; Patients; Periodicals; Physicians; Pilot Projects; Placebos; Plasma; Prevalence; Quality of life; Questionnaires; Randomized; Recurrence; Reporting; Research; Research Personnel; Resource Development; Resources; Safety; Sampling; Sampling Studies; Schedule; Scientist; Serum; Severities; Signal Transduction; Social Functioning; System; Telangiectasis; Thalidomide; Thrombolytic Therapy; Toxic effect; Tranexamic Acid; Translating; United States National Institutes of Health; analog; bevacizumab; biobank; clinically relevant; cohort; design; effective therapy; efficacy evaluation; experience; improved; mortality; multidisciplinary; novel therapeutics; patient advocacy group; placebo controlled study; pomalidomide; radiologist; randomized placebo controlled study; recruit; response; statistics; tool; trial planning

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.

抽象的 遗传性出血性毛细血管扩张症（HHT）是一种以弥漫性动静脉血管扩张为特征的遗传性疾病。 影响许多器官的畸形（AVM）和毛细血管扩张。 HHT 最常见的表现是 鼻衄和胃肠道出血；然而，累及肺、脑或肝的 AVM 也可能导致毁灭性的后果。 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 100,000 例 HHT 病例。除了出血和 心血管表现，HHT 的发病率导致焦虑和抑郁的高发生率， 极大地影响社会功能。 HHT 尚无被广泛接受的有效疗法。 HHT 病变消融 通过介入方法是常用的，但只能提供短暂的益处。医疗方法有 包括抗纤溶疗法、雌激素和奥曲肽等，但这些疗法对治疗无效 大多数患者。最近的一项研究表明，含有氨甲环酸、雌三醇或贝伐珠单抗的鼻喷雾剂 在治疗 HHT 相关鼻出血方面并不比安慰剂更有效。当前的研究建立在结果的基础上 多项小型研究表明沙利度胺对 HHT 有效；然而，沙利度胺不适用于 在美国进行的临床试验因此，我们建议研究泊马度胺，一种第三代沙利度胺类似物 与沙利度胺相似的抗血管生成活性，但毒性较小。 PI 进行的一项由行业资助的小型试点研究 已证明泊马度胺在 HHT 中的有效性和安全性，FDA 已发布 IND 来扩大这些范围 观察。这次重新提交提出了一项在以下机构的支持下开发的随机、安慰剂对照研究： NHLBI U34 临床试验计划拨款和 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负责治疗疾病。相同 设计该研究的团队将使用克利夫兰诊所的 sIRB 来进行该研究。我们建议 1) 确定 泊马度胺对需要定期输注铁剂或鼻出血的 HHT 患者的疗效和安全性 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。这项研究可能验证泊马度胺作为一种新的治疗选择 并改变 HHT 的治疗范式。