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.

项目摘要/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，5000人中有1人患病 在美国，这是一种毁灭性的终生疾病，没有FDA批准的治疗方法。相应地，有一种 HHT急需有效的系统治疗，以减少出血，提高与健康相关的质量 生活质量(HRQOL)。HHT患者继发于肠道和鼻黏膜的脆性毛细血管扩张 血管内皮生长因子(VEGF)升高。这会导致反复的严重鼻出血和慢性 胃肠道出血，导致缺铁性贫血(并依赖输血和/或铁 输液)，并严重降低了HRQOL。我们和其他人之前已经成功地使用系统 贝伐单抗是一种抗血管内皮生长因子的单抗，作为一种非标签剂治疗HHT中的慢性出血， 多中心观察性研究证明，红细胞输注和铁质输注减少了70%-80%， 与贝伐单抗治疗前相比，平均血红蛋白升高3-4g/dL，鼻出血严重程度降低50% 治疗。然而，考虑到患者的异质性，这项观察工作在概括性上是有限的，变量 药物剂量，以及红血球和铁的非标准化给药阈值。此外，它的影响 贝伐单抗对HRQOL和血管生成环境的影响尚不清楚。因此，我们将进行二期临床 全身性贝伐单抗在成人HHT患者中的试验 确定贝伐单抗对出血和HRQOL的影响。主端点将是一个复合端点 红细胞输注和铁输注的测量，血液学支持评分(HSS)。我们将评估 贝伐单抗对HHT患者HRQOL的影响 新的HHT特定的生活质量工具。最后，我们将评估贝伐单抗对血管生成生物标志物的影响。 为了更好地了解它是如何影响HHT血管生成环境的。我们的中心假设是系统性的 贝伐单抗显著减少HHT的慢性出血，通过HSS和HSS的减少来衡量 改善血红蛋白和HRQOL。成功将为更大规模的最终审判铺平道路，并建立 为未来研究HHT的其他抗血管生成药物提供了蓝图。 申请者Hanny Al-Samkari博士非常有资格执行这项研究，并致力于成为 独立的止血临床研究员，专注于HHT的药物再利用和生物标记物研究。 他将得到大卫·库特博士的指导，尼尔·扎凯博士、卡拉·鲍尔曼博士和丹·杜达博士将共同担任 导师。每一位导师都为他过渡到独立的HHT NIH提供了独特的专业知识 内科科学家。为了实现他的目标，他提出了一个全面的五年职业发展计划 与研究计划目标相协调的严谨课程作业。MGH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得到国际认可，因此 为完成这些科学和职业发展目标提供理想的环境。