Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial.
Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial.
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DOI：
10.1016/s2468-1253(17)30326-6
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发表时间：
2018-01
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影响因子：
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通讯作者：
Forbes SJ
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作者：
Newsome PN;Fox R;King AL;Barton D;Than NN;Moore J;Corbett C;Townsend S;Thomas J;Guo K;Hull D;Beard HA;Thompson J;Atkinson A;Bienek C;McGowan N;Guha N;Campbell J;Hollyman D;Stocken D;Yap C;Forbes SJ
小规模研究的结果表明，干细胞疗法对肝硬变患者是安全有效的，但还没有进行足够有力的随机对照试验。我们评价了粒细胞集落刺激因子(G-CSF)和造血干细胞输注在肝硬变患者中的安全性和有效性。这项多中心、开放标签、随机对照的第二阶段试验在英国三家医院进行，纳入了代偿性肝硬变患者，MELD评分为11.0-15.5。患者被随机分配到(1：1：1)接受标准护理(对照组)，皮下注射G-CSF15μg/kg，连续5天，或接受G-CSF5天，然后进行白细胞分离和静脉输注三种剂量的CD133阳性造血干细胞(每公斤输注0.2 × 10 6细胞)。随机试验是由英国癌症研究临床试验小组的工作人员使用最小化算法进行的，该算法根据试验地点和肝病的原因进行分层。主要结果是3个月时肝脏疾病严重程度的改善(MELD的变化)以及MELD评分随时间的变化趋势。在修改后的意向治疗人群中进行了分析，其中包括所有接受至少一天治疗的患者。安全性是根据接受的治疗进行评估的。这项试验于2009年11月18日在当前对照试验中注册；ISRCTN，编号91288089；以及欧洲临床试验数据库，编号2009-010335-41。在2010年5月18日至2015年2月26日期间，27名患者被随机分配到标准护理组，26名患者被分配到G-CSF组，28名患者被分配到G-CSF加干细胞输注组。从第0天到第90天，标准护理组的MELD中位数变化为−0.5(−1.5~1.1)，G-CSF组为−0·5(−1·7~0.5)，G-CSF加干细胞输注组为−0·5(−1.3~1.0)。我们发现，随着时间的推移，治疗组和对照组之间的MELD变化趋势没有差异(G-CSF组与标准护理组的p=0.55，G-CSF+干细胞输注组与标准护理组的p=0.75)。严重不良事件发生率G-CSF+干细胞输注组(12例[43%])高于G-CSF组(3例[11%])和标准治疗组(3例[12%])。最常见的严重不良事件是腹水(G-CSF组2例，G-CSF+干细胞输注组2例，其中1例因腹水入院2次)，败血症(G-CSF+干细胞输注组4例)，脑病(G-CSF+干细胞输注组3例，其中1例脑病入院2次)。三名患者死亡，包括一名标准护理组(静脉曲张出血)和两名G-CSF和干细胞输注组(一名心肌梗死和一名进展性肝病)。无论是否输注造血干细胞，G-CSF均不能改善肝功能障碍或肝纤维化，与标准治疗相比，可能与不良事件的发生率增加有关。国家健康研究所，朱尔斯·索恩爵士慈善信托基金。
Results of small-scale studies have suggested that stem-cell therapy is safe and effective in patients with liver cirrhosis, but no adequately powered randomised controlled trials have been done. We assessed the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) and haemopoietic stem-cell infusions in patients with liver cirrhosis. This multicentre, open-label, randomised, controlled phase 2 trial was done in three UK hospitals and recruited patients with compensated liver cirrhosis and MELD scores of 11·0–15·5. Patients were randomly assigned (1:1:1) to receive standard care (control), treatment with subcutaneous G-CSF (lenograstim) 15 μg/kg for 5 days, or treatment with G-CSF for 5 days followed by leukapheresis and intravenous infusion of three doses of CD133-positive haemopoietic stem cells (0·2 × 106 cells per kg per infusion). Randomisation was done by Cancer Research UK Clinical Trials Unit staff with a minimisation algorithm that stratified by trial site and cause of liver disease. The coprimary outcomes were improvement in severity of liver disease (change in MELD) at 3 months and the trend of change in MELD score over time. Analyses were done in the modified intention-to-treat population, which included all patients who received at least one day of treatment. Safety was assessed on the basis of the treatment received. This trial was registered at Current Controlled Trials on Nov 18, 2009; ISRCTN, number 91288089; and the European Clinical Trials Database, number 2009-010335-41. Between May 18, 2010, and Feb 26, 2015, 27 patients were randomly assigned to the standard care, 26 to the G-CSF group, and 28 to the G-CSF plus stem-cell infusion group. Median change in MELD from day 0 to 90 was −0·5 (IQR −1·5 to 1·1) in the standard care group, −0·5 (−1·7 to 0·5) in the G-CSF group, and −0·5 (−1·3 to 1·0) in the G-CSF plus stem-cell infusion group. We found no evidence of differences between the treatment groups and control group in the trends of MELD change over time (p=0·55 for the G-CSF group vs standard care and p=0·75 for the G-CSF plus stem-cell infusion group vs standard care). Serious adverse events were more frequent the in G-CSF and stem-cell infusion group (12 [43%] patients) than in the G-CSF (three [11%] patients) and standard care (three [12%] patients) groups. The most common serious adverse events were ascites (two patients in the G-CSF group and two patients in the G-CSF plus stem-cell infusion group, one of whom was admitted to hospital with ascites twice), sepsis (four patients in the G-CSF plus stem-cell infusion group), and encephalopathy (three patients in the G-CSF plus stem-cell infusion group, one of whom was admitted to hospital with encephalopathy twice). Three patients died, including one in the standard care group (variceal bleed) and two in the G-CSF and stem-cell infusion group (one myocardial infarction and one progressive liver disease). G-CSF with or without haemopoietic stem-cell infusion did not improve liver dysfunction or fibrosis and might be associated with increased frequency of adverse events compared with standard care. National Institute of Health Research, The Sir Jules Thorn Charitable Trust.