Results of an International Postmarketing Surveillance Study of pl-VEGF165 Safety and Efficacy in 210 Patients with Peripheral Arterial Disease.
Results of an International Postmarketing Surveillance Study of pl-VEGF165 Safety and Efficacy in 210 Patients with Peripheral Arterial Disease.
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DOI：
10.1007/s40256-016-0210-3
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Isaev A
中科院分区：
文献类型：
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作者：
Deev R;Plaksa I;Bozo I;Isaev A
慢性下肢缺血的有效治疗是血管外科医生面临的最具挑战性的问题之一。目前的药物治疗仅起辅助作用，不能阻止疾病进展，需要新的治疗方法。 pl-VEGF165是一种基因治疗药物，经过临床研究后，于2011年在俄罗斯被批准用于治疗动脉粥样硬化性外周动脉疾病（PAD）。该研究药物是一种原始基因构建体，其中pl-VEGF165 1.2 mg为活性物质。这项上市后监测研究的目的是评估基因治疗在常规临床实践中对患者的安全性（识别不常见的副作用）和疗效。俄罗斯和乌克兰 33 个医疗机构总共招募了 210 名 II-III 期慢性肢体缺血患者（根据 AV Pokrovsky 修改的 Fontaine 分类）。对照组（n = 60）接受不含前列腺素和前列环素的保守治疗，治疗组（n = 150）接受pl-VEGF165治疗，分两次肌肉注射，总剂量为2.4 mg。对无痛步行距离 (PWD)（Fontaine II-III 期的主要疗效标准）、血流线速度 (BFLV) 和踝臂指数 (ABI) 进行为期 6 个月的监测。研究开始 6 个月后，初步评估了试验方案中 pl-VEGF165 基因转移的安全性；在例行就诊和计划外医疗请求期间记录了不良事件（AE）和严重不良事件（SAE）。总体而言，治疗组的 PWD 增加了 177%，从 100.3 ± 6.9 增加到 277.1 ± 16.2 m (p = 0.0001)，而对照组的平均值没有变化 (p = 0.218)。治疗组中的 BFLV 和 ABI 值均增加了 24% (p = 0.0001)，但对照组中则有所下降。 III 期疾病的治疗效果最大：PWD 增加 683% (p = 0.0001)。没有记录到与血管生成治疗相关的 AE 或副作用，治疗组和对照组的目标保肢率分别为 96% 和 97%。本研究获得的结果与2011年完成的IIb/III期注册临床研究中观察到的结果没有显着差异。pl-VEGF165肌内基因转移是常规临床实践中治疗慢性下肢缺血所致中重度跛行的有效治疗方法。 ClinicalTrials.gov 标识符：NCT02369809。
The effective treatment of chronic lower limb ischemia is one of the most challenging issues confronting vascular surgeons. Current pharmacological therapies play an auxiliary role and cannot prevent disease progression, and new treatment methods are needed. pl-VEGF165, a gene therapy drug, was approved in Russia for the treatment of atherosclerotic peripheral arterial disease (PAD) after clinical studies in 2011. The study drug is an original gene construction in which pl-VEGF165 1.2 mg is the active substance. This postmarketing surveillance study was undertaken to evaluate the safety (identification of uncommon side effects) and efficacy of gene therapy in patients in routine clinical practice. In total, 210 patients with stage II–III chronic limb ischemia (according to the Fontaine classification modified by AV Pokrovsky) in 33 healthcare facilities in Russia and the Ukraine were enrolled in the study. The control group (n = 60) received conservative therapy without prostaglandins and prostacyclins, and the treatment group (n = 150) received treatment with pl-VEGF165 as two intramuscular injections for a total dose of 2.4 mg. Pain-free walking distance (PWD) (the primary efficacy criterion for Fontaine stages II–III), blood flow linear velocity (BFLV), and ankle-brachial index (ABI) were monitored for 6 months. The safety of pl-VEGF165 gene transfer in terms of the trial protocol was initially evaluated 6 months after the start of the study; adverse events (AEs) and serious adverse events (SAEs) were recorded during both routine visits and unscheduled requests for medical care. Overall, PWD increased by 177%, from 100.3 ± 6.9 to 277.1 ± 16.2 m (p = 0.0001), in the treatment group, whereas the mean value was unchanged in the control group (p = 0.218). Both BFLV and ABI values increased by 24% (p = 0.0001) in the treatment group but decreased in the control group. The greatest therapeutic effect was observed for stage III disease: PWD increased by 683% (p = 0.0001). No angiogenic therapy-related AEs or side effects were recorded, and target limb salvage was 96 and 97% in the treatment and control groups, respectively. The results obtained in this study are not significantly different from those observed in the phase IIb/III registration clinical study completed in 2011. pl-VEGF165 intramuscular gene transfer is an effective treatment for moderate to severe claudication due to chronic lower limb ischemia in routine clinical practice. ClinicalTrials.gov identifier: NCT02369809.