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

2/2 泊马度胺治疗遗传性出血性毛细血管扩张症 (HHT) 患者的出血 出血数据协调中心

• 批准号: 10385835
• 负责人: Sonia M Thomas
• 金额: $ 39.53万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385835
• 关键词: Ablation; Adverse event; Advocate; Affect; Agreement; Antifibrinolytic Agents; Anxiety; Arteriovenous malformation; Authorization documentation; Biological Markers; Biometry; Blood Transfusion; Blood Vessels; Brain; Brain hemorrhage; Cardiovascular Manifestation; Cardiovascular system; Case Report Form; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Collaborations; Collection; Communication; Companions; Congestive Heart Failure; Consent; Custom; Data; Data Collection; Data Coordinating Center; Development; Diffuse; Double-Blind Method; Eligibility Determination; Enrollment; Ensure; Epistaxis; Erythrocytes; Estriol; Estrogens; Funding; Future; Gastrointestinal Hemorrhage; Generations; Grant; Guidelines; Hematological Disease; Hemorrhage; Hereditary Disease; Hereditary hemorrhagic telangiectasia; Incidence; Industry; Infrastructure; Infusion procedures; Institution; Institutional Review Boards; International; Intervention; Investigation; Iron; Lead; Lesion; Liver; Lung; Manuals; Medical; Mental Depression; Monitor; Morbidity - disease rate; Motivation; Mucous Membrane; Multi-Institutional Clinical Trial; National Heart, Lung, and Blood Institute; Nature; Nose; Octreotide; Oral; Organ; Patient Schedules; Patients; Periodicity; Pilot Projects; Placebos; Positioning Attribute; Prevalence; Principal Investigator; Procedures; Protocols documentation; Publications; Quality of life; Questionnaires; Randomized; Refractory; Reporting; Research Personnel; Resource Development; Risk; Safety; Sampling Studies; Severities; Site; Social Functioning; System; Telangiectasis; Testing; Thalidomide; TimeLine; Toxic effect; Tranexamic Acid; Travel; United States; United States National Institutes of Health; analog; base; bevacizumab; biobank; clinical center; data integrity; data management; data quality; data repository; design; effective therapy; efficacy evaluation; experience; investigator training; meetings; novel therapeutics; pomalidomide; prevent; randomized placebo controlled study; randomized placebo-controlled clinical trial; recruit; response; symposium; tool; treatment choice; web platform

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.

项目摘要 遗传性出血性毛道症（HHT）是一种遗传性疾病，其特征是弥漫性动脉静脉 影响许多器官的畸形（AVM）和毛细血管扩张。 HHT最常见的表现 是脑力和胃肠道出血；但是涉及肺，大脑或肝脏的AVM也可能导致毁灭性 心血管并发症，包括充血性心力衰竭，肺出血和出血 中风。估计表明，美国有超过100,000例HHT的患病率。此外 出血和心血管表现，HHT的发病率很高，焦虑率很高 极大地影响社会功能的抑郁症。 HHT没有广泛接受的有效疗法。 通常使用通过介入方法消融HHT病变，但仅提供瞬态益处。 医学方法包括抗纤维蛋白疗法，雌激素和奥曲肽等。然而， 这些在大多数患者中都不有效。最近的一项研究表明，含有tranexamic的鼻喷雾剂 酸，雌二醇或贝伐单抗比安慰剂在治疗HHT相关的脑症方面更有效。这 当前的研究基于几项小型研究的结果，这些研究表明沙利度胺在HHT中的功效。然而， 在美国，沙利度胺不可用于临床试验。因此，我们建议研究pomalidomide，a 第三代沙利度胺类似物具有相似的抗血管生成活性，但毒性比沙利度胺较少。一个 PI由行业资助的小型试点研究表明，HHT中的Pomalidomide的功效和安全性，以及 FDA已发出IND来扩大这些观察结果。该重新提出提出了一个随机的安慰剂 - 在NHLBI U34临床试验计划赠款和U24临床的支持下开发的对照研究 由HHT专家团队，患者拥护者和 经验丰富的临床试验统计学家。设计研究的同一支团队将使用SIRB在 克利夫兰诊所。我们建议（1）确定pomalidomide在患者患者中的功效和安全性 HHT和需要定期输注或输血的HHT和EPISTAXIS（2）确定 NIH Promis工具和HHT特异 问卷和（3）从研究患者的未来生物标志物和 机械研究。这项研究可能会验证Pomalidomide作为一种新的治疗选择，并改变 用于治疗HHT的范例。