BACKGROUND Patients with refractory angina (RA) have poor quality of life and new therapies are needed. XC001 is a novel adenoviral vector expressing multiple isoforms of vascular endothelial growth factor (VEGF) promoting an enhanced local angiogenic effect. METHODS The Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment (EXACT) trial is a 6-month (with 6-month extension) phase 1/2, first-in-human, multicenter, open-label, single-arm, dose-escalation study to evaluate the safety, tolerability, and preliminary efficacy of XC001 in patients with RA. The trial will enroll 33 patients in an initial (n = 12) ascending dose-escalation phase (1 × 109, 1 × 1010, 4 × 1010, and 1 × 1011 viral particles), followed by phase 2 (n = 21) assessing the highest tolerated dose. Patients must have stable Canadian Cardiovascular Society (CCS) class II-IV angina on maximally tolerated medical therapy without options for conventional revascularization, demonstrable ischemia on stress testing, and angina limiting exercise tolerance. XC001 will be delivered directly to ischemic myocardium via surgical transthoracic epicardial access. The primary outcome is safety via adverse event monitoring through 6 months. Efficacy assessments include difference from baseline to month 6 in time to 1 mm of ST segment depression, time to angina, and total exercise duration; myocardial blood flow at rest, and stress and coronary flow reserve by positron emission tomography; quality of life; CCS functional class; and angina frequency. CONCLUSIONS The EXACT trial will determine whether direct intramyocardial administration of XC001 in patients with RA is safe and evaluate its effect on exercise tolerance, myocardial perfusion, angina and physical activity, informing future clinical investigation. CLINICAL TRIAL REGISTRATION NCT04125732.

中文翻译：

---

XC001 基因治疗难治性心绞痛冠状动脉治疗的心外膜递送（精确试验）：基本原理、设计和临床考虑。

背景难治性心绞痛 (RA) 患者的生活质量较差，需要新的治疗方法。XC001 是一种新型腺病毒载体，表达血管内皮生长因子 (VEGF) 的多种同种型，促进增强的局部血管生成作用。方法 XC001 基因治疗难治性心绞痛冠状动脉治疗 (EXACT) 的心外膜递送试验是一项为期 6 个月（延长 6 个月）的 1/2 期、首次人体、多中心、开放标签、单臂、剂量递增研究，以评估 XC001 在 RA 患者中的安全性、耐受性和初步疗效。该试验将在初始 (n = 12) 递增剂量递增阶段（1 × 109、1 × 1010、4 × 1010 和 1 × 1011 病毒颗粒）招募 33 名患者，然后是第 2 阶段（n = 21）评估最高耐受剂量。患者必须有稳定的加拿大心血管学会 (CCS) II-IV 级心绞痛，接受最大耐受药物治疗，没有常规血运重建的选择，压力测试显示缺血，以及心绞痛限制运动耐量。XC001 将通过外科经胸心外膜通路直接输送到缺血心肌。通过 6 个月的不良事件监测，主要结果是安全性。疗效评估包括从基线到第 6 个月在 ST 段压低 1 mm、心绞痛时间和总运动持续时间方面的差异；静息时心肌血流量，正电子发射断层扫描压力和冠状动脉血流储备；生活质量; CCS功能类；和心绞痛频率。结论 EXACT 试验将确定在 RA 患者中直接心肌内给药 XC001 是否安全，并评估其对运动耐量、心肌灌注、心绞痛和体力活动的影响，为未来的临床研究提供信息。临床试验注册 NCT04125732。