Antiangiogenic Therapy to Reduce Bleeding and Improve Health-Related Quality of Life in Hereditary Hemorrhagic Telangiectasia

抗血管生成疗法可减少遗传性出血性毛细血管扩张症的出血并改善健康相关的生活质量

• 批准号: 10448102
• 负责人: Hanny T Al-Samkari
• 金额: $ 19.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448102
• 关键词: Address; Adult; Affect; Anemia; Angiogenesis Inhibitors; Biological Markers; Blood Coagulation Disorders; Blood Transfusion; Caring; Characteristics; Chronic; Clinical; Clinical Investigator; Clinical Trials; Control Groups; Correlative Study; Data; Dependence; Development; Development Plans; Disease; Dose; Environment; Epistaxis; Erythrocytes; FDA approved; Functional disorder; Future; Gastrointestinal Hemorrhage; Goals; Gut Mucosa; Hematology; Hemoglobin; Hemorrhage; Hemostatic function; Hereditary hemorrhagic telangiectasia; Heterogeneity; Hour; Human; Information Systems; Infusion procedures; Inherited; International; Iron; Iron deficiency anemia; Knowledge; Label; Learning; Measurement; Measures; Mentors; Mentorship; Monoclonal Antibodies; Morbidity - disease rate; Observational Study; Oncology; Outcome; Patient Outcomes Assessments; Patients; Persons; Pharmaceutical Preparations; Phase II Clinical Trials; Physicians; Quality of life; Recurrence; Regimen; Research; Research Personnel; Research Project Grants; Residual state; Science; Scientist; Secondary to; Severities; Social isolation; Standardization; Structure of mucous membrane of nose; System; Systemic Therapy; Telangiectasis; Time; Transfusion; Travel; United States National Institutes of Health; VEGFA gene; Vascular Endothelial Growth Factors; Work; angiogenesis; arm; bevacizumab; career development; design; drug repurposing; health related quality of life; improved; innovation; instrument; mortality; neoplastic; novel; pharmacodynamic biomarker; primary endpoint; prospective; response biomarker; secondary endpoint; standard care; success; tool

Project Summary/Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant bleeding disorder affecting 1 in 5000 people in the US, is a devastating lifelong condition with no FDA-approved treatments. Accordingly, there is an urgent need for efficacious systemic therapies in HHT to reduce bleeding and improve health-related quality of life (HRQOL). Patients with HHT develop fragile telangiectasias along the gut and nasal mucosa secondary to elevated vascular endothelial growth factor (VEGF). This leads to recurrent severe epistaxis and chronic gastrointestinal bleeding, resulting in iron deficiency anemia (and dependence on blood transfusions and/or iron infusions) and severely diminished HRQOL. We and others have previously successfully used systemic bevacizumab, an anti-VEGF monoclonal antibody, as an off-label agent to treat chronic bleeding in HHT, documenting in multicenter observational studies a 70-80% reduction in red cell transfusions and iron infusions, a 3-4 g/dL mean hemoglobin rise, and 50% reduction in epistaxis severity compared to before bevacizumab treatment. However, this observational work is limited in generalizability given heterogeneity in patients, variable drug dosing, and non-standardized thresholds for administration of red cells and iron. Furthermore, the impact of bevacizumab on HRQOL and the angiogenic milieu is unknown. Therefore, we will perform a phase II clinical trial of systemic bevacizumab in adults with HHT dependent on iron infusions and/or blood transfusions to determine the impact of bevacizumab on bleeding and HRQOL. The primary endpoint will be a composite measurement of red cell transfusions and iron infusions, the Hematologic Support Score (HSS). We will evaluate the impact of bevacizumab on HRQOL in HHT as a secondary endpoint utilizing PROMIS instruments and a novel HHT-specific QOL tool. Finally, we will evaluate the effect of bevacizumab on angiogenic biomarkers in HHT, to better understand how it impacts the HHT angiogenic milieu. Our central hypothesis is that systemic bevacizumab significantly reduces chronic bleeding in HHT as measured by reductions in the HSS and improvements in hemoglobin and HRQOL. Success would pave the way for a larger definitive trial and establish a blueprint for conducting future studies repurposing other antiangiogenics for HHT. The applicant, Dr. Hanny Al-Samkari, is well-qualified to execute this research and is committed to becoming an independent hemostasis clinical investigator with a focus on drug repurposing and biomarker research in HHT. He will be mentored by Dr. David Kuter, with Dr. Neil Zakai, Dr. Karla Ballman and Dr. Dan Duda serving as co- mentors. Each mentor contributes unique expertise necessary for his transition to an independent HHT NIH physician scientist. To achieve his goals, he has proposed a comprehensive five-year career development plan of rigorous coursework that synergizes with the research plan aims. The MGH Division of Hematology Oncology is internationally-recognized for its tradition of clinical trial excellence, scientific discovery and mentorship, so is an ideal environment for completion of these scientific and career development objectives.

项目概要/摘要 遗传性出血性毛细血管扩张症 (HHT)，一种常染色体显性遗传性出血性疾病，影响五千分之一的人 对于美国人来说，这是一种毁灭性的终生疾病，且尚无 FDA 批准的治疗方法。据此，有一个 迫切需要有效的 HHT 全身治疗，以减少出血并改善与健康相关的质量 生活（HRQOL）。 HHT 患者继发于肠道和鼻粘膜的脆弱毛细血管扩张。 血管内皮生长因子（VEGF）升高。这会导致反复严重鼻出血和慢性 胃肠道出血，导致缺铁性贫血（以及依赖输血和/或铁剂 输液）并严重降低 HRQOL。我们和其他人之前已经成功地使用了系统 贝伐单抗，一种抗 VEGF 单克隆抗体，作为治疗 HHT 慢性出血的标签外药物， 多中心观察研究记录了红细胞输注和铁输注减少了 70-80%， 与贝伐珠单抗使用前相比，平均血红蛋白升高 3-4 g/dL，鼻出血严重程度降低 50% 治疗。然而，鉴于患者的异质性、可变性，这项观察工作的普遍性受到限制。 药物剂量以及红细胞和铁给药的非标准化阈值。此外，影响 贝伐珠单抗对 HRQOL 和血管生成环境的影响尚不清楚。因此，我们将进行II期临床 对依赖铁剂输注和/或输血的成人 HHT 进行全身贝伐珠单抗试验 确定贝伐珠单抗对出血和 HRQOL 的影响。主要终点将是一个复合终点 红细胞输注和铁输注的测量，血液支持评分（HSS）。我们将评估 贝伐珠单抗对 HHT 中 HRQOL 的影响作为次要终点，利用 PROMIS 仪器和 新颖的 HHT 特定 QOL 工具。最后，我们将评估贝伐珠单抗对血管生成生物标志物的影响 HHT，更好地了解它如何影响 HHT 血管生成环境。我们的中心假设是系统性的 贝伐珠单抗可显着减少 HHT 的慢性出血（通过 HSS 和 HSS 的减少来衡量） 血红蛋白和 HRQOL 的改善。成功将为更大规模的最终试验铺平道路，并建立 未来研究重新利用其他抗血管生成药物治疗 HHT 的蓝图。 申请人 Hanny Al-Samkari 博士完全有资格执行这项研究，并致力于成为一名 独立止血临床研究者，专注于 HHT 的药物再利用和生物标志物研究。 他将得到 David Kuter 博士的指导，Neil Zakai 博士、Karla Ballman 博士和 Dan Duda 博士将担任联合导师。 导师。每位导师都贡献了他过渡到独立 HHT NIH 所需的独特专业知识 医师科学家。为了实现自己的目标，他提出了全面的五年职业发展计划 与研究计划目标相协同的严格课程作业。麻省总医院血液肿瘤科 因其卓越的临床试验、科学发现和指导的传统而受到国际认可， 完成这些科学和职业发展目标的理想环境。