Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial
Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial
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DOI：
10.1016/s0140-6736(16)30137-4
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发表时间：
2016-06-11
期刊：
影响因子：
168.9
通讯作者：
DeMaria, Anthony
中科院分区：
文献类型：
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作者：
Patel, Amit N.;Henry, Timothy D.;DeMaria, Anthony
Ixmyelocel-T是一种扩增的多细胞疗法，通过选择性扩增两种关键类型的骨髓单核细胞（CD 90+间充质干细胞和CD 45 + CD 14+自体荧光+活化巨噬细胞）从患者自身骨髓中产生。早期临床试验表明，心肌内输注ixmyelocel-T可能改善缺血性扩张型心肌病心力衰竭患者的临床、功能、症状和生活质量结局。我们的目的是评估基于导管的经血管内注射ixmyelocel-T细胞治疗心力衰竭和射血分数降低患者的安全性和有效性。（ixCELL-DCM），来自北美31个研究中心的纽约心脏协会III或IV级缺血性扩张型心肌病所致症状性心力衰竭患者，左心室射血分数35%或更低、自动植入式心律转复除颤器和不适合血运重建程序的患者在骨髓抽吸时被随机分配（1：1）接受ixmyelocel-T或安慰剂，并随访12个月。通过交互式（语音/网络）应答系统进行随机化。每个研究中心的药剂师、主治医生和协调员均未设盲，但随访团队完全设盲。主要终点是基于独立临床终点委员会的盲态裁定的全因死亡、心血管住院和治疗急性失代偿性心力衰竭的计划外门诊访视的复合终点。主要疗效终点分析和安全性分析通过修改意向治疗进行。该试验注册于ClinicalTrials.gov，编号NCT 01670981。结果在2013年4月2日至2015年1月28日期间，126名参与者被随机分配接受ixmyelocel-T（n=66）或安慰剂（n=60）。114例（90%）患者构成改良的意向治疗人群，109例（87%）患者纳入符合方案的主要疗效分析（ixmyelocel-T组58例，安慰剂组51例）。在47例患者中观察到主要疗效终点：安慰剂组51例患者中25例（49%）发生50起事件，ixmyelocel-T组58例患者中22例（38%）发生38起事件，与安慰剂组相比，心脏事件减少37%（风险比0.63 [95%CI 0.42-0.97]; p= 0.0344）。安慰剂组51名参与者中有41名（75%）发生严重不良事件，而ixmyelocel-T组58名参与者中有31名（53%）发生严重不良事件（p= 0.0197）。与安慰剂相比，在患有心力衰竭和因缺血性扩张型心肌病导致射血分数降低的患者中经血管内注射ixmyelocel-T导致裁定的临床心脏事件显著减少，从而改善患者结局。
Background Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions.Methods In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1: 1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981.Findings Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0.63 [95% CI 0.42-0.97]; p= 0.0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p= 0.0197).Interpretation To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes.