对难治性严重肢体缺血门诊患者双侧给予自体CD133+细胞：来自一项试点随机、双盲、安慰剂对照试验的经验教训。
Bilateral administration of autologous CD133+ cells in ambulatory patients with refractory critical limb ischemia: lessons learned from a pilot randomized, double-blind, placebo-controlled trial.
作者信息
Raval Amish N, Schmuck Eric G, Tefera Girma, Leitzke Cathlyn, Ark Cassondra Vander, Hei Derek, Centanni John M, de Silva Ranil, Koch Jill, Chappell Richard G, Hematti Peiman
机构信息
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
出版信息
Cytotherapy. 2014 Dec;16(12):1720-32. doi: 10.1016/j.jcyt.2014.07.011. Epub 2014 Sep 18.
BACKGROUND AIMS
CD133+ cells confer angiogenic potential and may be beneficial for the treatment of critical limb ischemia (CLI). However, patient selection, blinding methods and end points for clinical trials are challenging. We hypothesized that bilateral intramuscular administration of cytokine-mobilized CD133+ cells in ambulatory patients with refractory CLI would be feasible and safe.
METHODS
In this double-blind, randomized sham-controlled trial, subjects received subcutaneous injections of granulocyte colony-stimulating factor (10 μg/kg per day) for 5 days, followed by leukapheresis, and intramuscular administration of 50-400 million sorted CD133+ cells delivered into both legs. Control subjects received normal saline injections, sham leukapheresis and intramuscular injection of placebo buffered solution. Subjects were followed for 1 year. An aliquot of CD133+ cells was collected from each subject to test for genes associated with cell senescence.
RESULTS
Seventy subjects were screened, of whom 10 were eligible. Subject enrollment was suspended because of a high rate of mobilization failure in subjects randomly assigned to treatment. Of 10 subjects enrolled (7 randomly assigned to treatment, 3 randomly assigned to control), there were no differences in serious adverse events at 12 months, and blinding was preserved. There were non-significant trends toward improved amputation-free survival, 6-minute walk distance, walking impairment questionnaire and quality of life in subjects randomly assigned to treatment. Successful CD133+ mobilizers expressed fewer senescence-associated genes compared with poor mobilizers.
CONCLUSIONS
Bilateral administration of autologous CD133+ cells in ambulatory CLI subjects was safe, and blinding was preserved. However, poor mobilization efficiency combined with high CD133+ senescence suggests futility in this approach.
背景与目的
CD133+细胞具有血管生成潜能，可能对治疗严重肢体缺血（CLI）有益。然而，患者选择、盲法和临床试验终点颇具挑战。我们推测，对难治性CLI门诊患者双侧肌内注射细胞因子动员的CD133+细胞是可行且安全的。
方法
在这项双盲、随机、假手术对照试验中，受试者皮下注射粒细胞集落刺激因子（每天10μg/kg），持续5天，随后进行白细胞分离术，并将5000万至4亿分选的CD133+细胞双侧肌内注射。对照受试者接受生理盐水注射、假白细胞分离术和肌内注射安慰剂缓冲溶液。对受试者随访1年。从每个受试者收集一份CD133+细胞样本，检测与细胞衰老相关的基因。
结果
共筛选70名受试者，其中10名符合条件。由于随机分配至治疗组的受试者动员失败率高，受试者入组暂停。在入组的10名受试者中（7名随机分配至治疗组，3名随机分配至对照组），12个月时严重不良事件无差异，且保持了盲法。随机分配至治疗组的受试者在无截肢生存率、6分钟步行距离、步行障碍问卷和生活质量方面有改善的非显著趋势。与动员效果差的受试者相比，成功的CD133+动员者衰老相关基因表达较少。
结论
对CLI门诊患者双侧注射自体CD133+细胞是安全的，且保持了盲法。然而，动员效率低和CD133+衰老程度高表明这种方法无效。
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