表皮生长因子与生长激素释放六肽联合治疗急性缺血性卒中：一项I/II期非盲、随机临床试验。
Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial.
作者信息
Hernández-Bernal Francisco, Estenoz-García Donner, Gutiérrez-Ronquillo Juan H, Martín-Bauta Yenima, Catasús-Álvarez Karen, Gutiérrez-Castillo Mario, Guevara-Rodríguez Marbelys, Castro-Jeréz Aliuska, Fuentes-González Yoandra, Pinto-Cruz Yulemis, Valenzuela-Silva Carmen, Muzio-González Verena L, Pérez-Saad Héctor, Subirós-Martínez Nelvys, Guillén-Nieto Gerardo E, Garcia-Del-Barco-Herrera Diana
机构信息
Clinical Trial Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
Department of Comprehensive General Medicine, Latin American School of Medicine (ELAM), Havana, Cuba.
出版信息
Front Neurol. 2024 Apr 4;15:1303402. doi: 10.3389/fneur.2024.1303402. eCollection 2024.
OBJECTIVE
This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.
METHODS
A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18-80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.
RESULTS
The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8-11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06-1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03-1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.
CONCLUSION
EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.
CLINICAL TRIAL REGISTRATION
RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.
目的
本研究检验了基于表皮生长因子（EGF）和生长激素释放六肽（GHRP6）的神经保护联合疗法对急性缺血性中风患者是否安全的假设，该疗法允许高达30%的严重不良事件（SAE）具有已证实的因果关系。
方法
进行了一项多中心、随机、开放标签、对照的I-II期平行组临床试验（2017年7月至2018年1月）。年龄在18 - 80岁、计算机断层扫描确诊为缺血性中风且症状发作后不到12小时的患者被随机分配到研究组I（75μg重组人表皮生长因子 + 3.5mg GHRP6静脉注射，n = 10）、II（75μg重组人表皮生长因子 + 5mg GHRP6静脉注射，n = 10）或III（标准护理对照组，n = 16）。联合疗法每日两次给药，共7天。主要终点是6个月内的安全性。次要终点包括神经学（美国国立卫生研究院卒中量表，NIHSS）和功能[巴氏指数和改良Rankin量表（mRS）]结果。
结果
研究人群的平均年龄为66±11岁，男性21名（58.3%），基线NIHSS中位数评分为9（95%置信区间：8 - 11），平均治疗时间为7.3±2.8小时。分析基于意向性治疗原则进行。对照组16名患者中有9名（56.2%）报告了严重不良事件，I组10名患者中有3名（30%）（优势比（OR）：0.33；95%置信区间：0.06 - 1.78），II组10名患者中有2名（20%）（OR：0.19；95%置信区间：0.03 - 1.22）；I组仅1名患者的两起事件归因于干预治疗。每组对研究假设的依从性均大于0.90。通过NIHSS、巴氏指数和mRS的推断分析及其中度至强效效应量证明，接受EGF + GHRP6治疗的患者在90天和180天时神经学和功能均有良好进展。在6个月时，比例分析表明联合治疗的患者生存率更高。包括合并治疗组和效用加权mRS的辅助分析也显示了这种联合疗法的益处。
结论
EGF + GHRP6疗法是安全的。本研究中治疗的功能益处支持进行III期研究。
临床试验注册
古巴临床试验公共注册处的RPCEC00000214，唯一标识符：IG/CIGB - 845I/IC/1601
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