Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial).
Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial).
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DOI：
10.1002/jcsm.12126
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
for and on behalf of the ACT‐ONE study group
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文献类型：
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作者：
Stewart Coats AJ;Ho GF;Prabhash K;von Haehling S;Tilson J;Brown R;Beadle J;Anker SD;for and on behalf of the ACT‐ONE study group
癌症恶病质是发病和死亡的主要原因，目前尚无广泛批准的治疗方法。 ACT-ONE 试验是一项随机、双盲、平行组、安慰剂对照、II 期多中心试验，受试者为 III 期或 IV 期结直肠癌或非小细胞肺癌相关恶病质患者（25-80 岁），测试了两种剂量的 espindolol（一种新型非选择性 β 受体阻滞剂，具有中枢 5-HT1a 和部分 β2 受体激动剂作用）。主要终点是高剂量espindolol和安慰剂之间16周内体重变化率的差异（重复测量的线性混合效应模型）。 87 名患者以 3:2:1 的比例集中分组[42 名高剂量，10mg 每日两次（bd）：31 名安慰剂：14 名低剂量，2.5mg bd]。与安慰剂组体重减轻（−0.21kg/4周，95%CI ‐0.37–0.05）相比，高剂量艾斯平洛尔产生了统计学上和临床上显着的体重增加（+0.54kg/4周，95%CI 0.38–0.70）； P < 0.0001。高剂量艾斯平洛尔使去脂体重显着增加，而脂肪量变化呈中性。握力显着（高剂量-1.15±0.7kg，安慰剂每4周变化-3.51±0.8kg；P=0.0134）、爬楼梯能力和6分钟步行测试均不显着地有利于高剂量espindolol。尽管与安慰剂 (3.2%) 相比，高剂量艾斯平洛尔 (19.1%) 出现呼吸困难的情况较多，但治疗组之间的安全性信号或生存率没有临床显着差异。这项积极的试验表明，espindolol 10 mg bd 可以显着逆转晚期结直肠癌和非小细胞肺癌相关恶病质患者的体重减轻、改善去脂质量并维持脂肪量。这与握力的显着改善相关，支持进一步研究 10mg bd espindolol 用于治疗癌症恶病质。尽管没有动力观察剂量反应，但低剂量的大多数治疗效果介于高剂量和安慰剂之间，这表明艾斯平洛尔的作用可能存在剂量反应。
Cancer cachexia is a major cause of morbidity and mortality with no widely approved treatment. The ACT‐ONE trial is a randomized, double‐blind, parallel group, placebo‐controlled, phase II multicentre trial in patients (25‐80 years) with stages III or IV colorectal cancer or non‐small cell lung cancer‐related cachexia that tested two doses of espindolol (a novel non‐selective β blocker with central 5‐HT1a and partial β2 receptor agonist effects). The primary endpoint was the difference in the rate of weight change over 16 weeks (linear mixed‐effect model for repeated measures) between high‐dose espindolol and placebo. Eighty‐seven patients were randomized centrally in blocks in a ratio 3:2:1 [42 high dose, 10 mg twice daily (bd):31 placebo:14 low dose, 2.5 mg bd]. High‐dose espindolol produced a statistically and clinically significant weight gain (+0.54 kg/4 weeks, 95% CI 0.38–0.70) compared with a weight loss on placebo (−0.21 kg/4 weeks, 95% CI ‐0.37–0.05); P < 0.0001. High‐dose espindolol produced a statistically significant increase in lean body mass, whilst changes in fat mass were neutral. Hand grip strength significantly (high dose −1.15 ± 0.7 kg, placebo −3.51 ± 0.8 kg change per 4 weeks; P = 0.0134), stair climbing power, and 6‐min walk test non‐significantly were all directionally in favour of high‐dose espindolol. There were no clinically significant differences in safety signals or survival between treatment groups, although a numerical excess of dyspnoea was seen with high‐dose espindolol (19.1%) compared with placebo (3.2%). This positive trial showed that espindolol 10 mg bd significantly reversed weight loss, improved fat free mass, and maintained fat mass in advanced colorectal cancer and non‐small cell lung cancer‐related cachexia. This was associated with a significant improvement in handgrip strength, supporting the further investigation of 10 mg bd espindolol for the treatment of cancer cachexia. Although not powered to look at dose response, most treatment effects for low dose lay between high dose and placebo, suggesting that there may be a dose response in the effects of espindolol.