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; 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 epit骨和胃肠道出血；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，肺出血和出血性中风。 估计表明，美国有超过100,000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 极大地影响社会功能。 HHT没有广泛接受的有效疗法。消融HHT病变 通常使用介入方法，但仅提供瞬态益处。医疗方法有 包括抗纤维蛋白水解疗法，雌激素和奥曲肽等，但是这些在 大多数患者。最近的一项研究表明，含有tranexamic酸，雌二醇或贝伐单抗的鼻喷雾剂 在治疗与HHT相关的脑epip骨治疗方面的有效性更高。当前的研究基于结果 在几项暗示沙利度胺在HHT中的功效的小型研究中；但是，沙利度胺不可用 因此 类似的抗血管生成活性，但毒性比沙利度胺较少。 PI的一项小型，行业资助的试点研究 已经证明了pomalidomide在HHT中的功效和安全性，FDA发出了IND来扩展这些 观察。该重新提出提出了一项随机，安慰剂控制的研究，并在 NHLBI U34临床试验计划补助金和U24血液学的临床试验发展资源 HHT专家，患者拥护者和经验丰富的临床试验统计学家的疾病。相同 设计研究的团队将使用克利夫兰诊所的SIRB进行进行。我们建议1）确定 Pomalidomide在HHT和脑力症患者中的疗效和安全性，需要定期输注或 输血，2）确定使用NIH的HHT患者的Pomalidomide对生活质量的影响 Promis工具和HHT特异性问卷，以及3）从研究患者中创建样本的生物座 用于未来的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 并更改范式以治疗HHT。