Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized Phase II trial.
Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized Phase II trial.
复制标题
在慢性缺血性心力衰竭患者中单一施用基质细胞衍生的因子1非病毒基因治疗后，一年中心室重塑和临床状况的变化：Stop-HF随机II期试验。
DOI：
10.1093/eurheartj/ehv254
复制
发表时间：
2015-09-01
影响因子：
39.3
通讯作者：
Penn MS
中科院分区：
文献类型：
--
作者：
Chung ES;Miller L;Patel AN;Anderson RD;Mendelsohn FO;Traverse J;Silver KH;Shin J;Ewald G;Farr MJ;Anwaruddin S;Plat F;Fisher SJ;AuWerter AT;Pastore JM;Aras R;Penn MS
基质细胞衍生因子-1（SDF-1）通过细胞存活、内源性干细胞募集和血管发生机制促进组织修复。基质细胞衍生因子-1质粒治疗心力衰竭患者（STOP-HF）是一项II期、双盲、随机、安慰剂对照试验，旨在评价通过肌内膜注射向缺血性心力衰竭（IHF）患者提供质粒基质细胞衍生因子-1（pSDF-1）单次治疗的安全性和有效性。93例IHF受试者接受稳定的基于指南的药物治疗，左心室射血分数（LVEF）≤ 40%，完成明尼苏达心力衰竭生活问卷（MLWHFQ）和6分钟步行距离（6 MWD），以1：1：1的比例随机接受15或30 mg剂量的pSDF-1或安慰剂单次治疗（通过肌内注射）。在注射后4个月和12个月评估安全性和有效性参数。左心室功能和结构指标通过超声造影进行评估，并由设盲的独立核心实验室进行量化。基质细胞衍生因子-1质粒治疗心力衰竭患者的效力基于4个月时6 MWD和MLWHFQ的变化。基线时受试者特征为（平均值± SD）：年龄65 ± 9岁，LVEF 28 ± 7%，左心室收缩末期容积（LVESV）167 ± 66 mL，N末端脑利钠肽前体（BNP）（NTproBNP）1120 ± 1084 pg/mL，MLWHFQ 50 ± 20分，6 MWD 289 ± 99 m。患者为最近一次心肌梗死后11 ± 9年。所有受试者均接受了研究注射，未发生严重不良事件。62例患者接受药物治疗，未发生非预期的严重产品相关不良事件。主要终点是6 MWD和MLWHFQ从基线至4个月随访的变化的复合终点。未达到主要终点（P = 0.89）。对于接受pSDF-1治疗的患者，12个月时LVEF有改善的趋势（安慰剂vs. 15 mg vs. 30 mg ΔLVEF：−2 vs. −0.5 vs. 1.5%，P = 0.20）。基于入组时LVEF的三分位数对pSDF-1的作用进行的预先规定的分析显示，从最低LVEF到最高LVEF，EF和LVESV有所改善。在12个月时，接受30 mg pSDF-1治疗的EF第一个三分位数（<26%）的患者显示EF增加7%，而安慰剂组减少4%（ΔLVEF = 11%，P = 0.01）。LVESV也有改善的趋势，12个月时，治疗患者的LVESV降低18.5 mL，而安慰剂组增加15 mL（ΔLVESV = 33.5 mL，P = 0.12）。舒张末期和收缩末期容积的变化相当于接受30 mg pSDF-1治疗的患者每搏输出量增加14 mL，而安慰剂组减少-11 mL（ΔSV = 25 mL，P = 0.09）。此外，与安慰剂相比，30 mg治疗组在12个月时NTproBNP有改善的趋势（−784 pg/mL，P = 0.23）。盲法安慰剂对照STOP-HF试验证明了单次内分泌给药pSDF-1的安全性，但未能证明其主要终点是治疗后4个月的综合评分改善。通过预先指定的分析，STOP-HF试验证明了在高危缺血性心肌病中减弱LV重构和改善EF的潜力。安全性特征支持pSDF-1重复给药，左心室重塑程度表明在未来更大规模的试验中有可能改善结局。
Stromal cell-derived factor-1 (SDF-1) promotes tissue repair through mechanisms of cell survival, endogenous stem cell recruitment, and vasculogenesis. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure (STOP-HF) is a Phase II, double-blind, randomized, placebo-controlled trial to evaluate safety and efficacy of a single treatment of plasmid stromal cell-derived factor-1 (pSDF-1) delivered via endomyocardial injection to patients with ischaemic heart failure (IHF). Ninety-three subjects with IHF on stable guideline-based medical therapy and left ventricular ejection fraction (LVEF) ≤40%, completed Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and 6-min walk distance (6 MWD), were randomized 1 : 1 : 1 to receive a single treatment of either a 15 or 30 mg dose of pSDF-1 or placebo via endomyocardial injections. Safety and efficacy parameters were assessed at 4 and 12 months after injection. Left ventricular functional and structural measures were assessed by contrast echocardiography and quantified by a blinded independent core laboratory. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was powered based on change in 6 MWD and MLWHFQ at 4 months. Subject profiles at baseline were (mean ± SD): age 65 ± 9 years, LVEF 28 ± 7%, left ventricular end-systolic volume (LVESV) 167 ± 66 mL, N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) 1120 ± 1084 pg/mL, MLWHFQ 50 ± 20 points, and 6 MWD 289 ± 99 m. Patients were 11 ± 9 years post most recent myocardial infarction. Study injections were delivered without serious adverse events in all subjects. Sixty-two patients received drug with no unanticipated serious product-related adverse events. The primary endpoint was a composite of change in 6 MWD and MLWHFQ from baseline to 4 months follow-up. The primary endpoint was not met (P = 0.89). For the patients treated with pSDF-1, there was a trend toward an improvement in LVEF at 12 months (placebo vs. 15 mg vs. 30 mg ΔLVEF: −2 vs. −0.5 vs. 1.5%, P = 0.20). A pre-specified analysis of the effects of pSDF-1 based on tertiles of LVEF at entry revealed improvements in EF and LVESV from lowest-to-highest LVEF. Patients in the first tertile of EF (<26%) that received 30 mg of pSDF-1 demonstrated a 7% increase in EF compared with a 4% decrease in placebo (ΔLVEF = 11%, P = 0.01) at 12 months. There was also a trend towards improvement in LVESV, with treated patients demonstrating an 18.5 mL decrease compared with a 15 mL increase for placebo at 12 months (ΔLVESV = 33.5 mL, P = 0.12). The change in end-diastolic and end-systolic volume equated to a 14 mL increase in stroke volume in the patients treated with 30 mg of pSDF-1 compared with a decrease of −11 mL in the placebo group (ΔSV = 25 mL, P = 0.09). In addition, the 30 mg-treated cohort exhibited a trend towards improvement in NTproBNP compared with placebo at 12 months (−784 pg/mL, P = 0.23). The blinded placebo-controlled STOP-HF trial demonstrated the safety of a single endocardial administration of pSDF-1 but failed to demonstrate its primary endpoint of improved composite score at 4 months after treatment. Through a pre-specified analysis the STOP-HF trial demonstrates the potential for attenuating LV remodelling and improving EF in high-risk ischaemic cardiomyopathy. The safety profile supports repeat dosing with pSDF-1 and the degree of left ventricular remodelling suggests the potential for improved outcomes in larger future trials.