Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease
Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease
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DOI：
10.1177/1358863x14557151
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发表时间：
2014-12-01
影响因子：
3.5
通讯作者：
Hiatt, William R.
中科院分区：
文献类型：
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作者：
Olson, Eric;Demopoulos, Laura;Hiatt, William R.
缺氧诱导因子（HIF）-脯氨酰羟化酶（PHD）抑制剂稳定缺氧诱导因子（HIF）可能会改善缺血性疾病，如外周动脉疾病（PAD）。这项多中心、随机、安慰剂对照研究评价了GSK 1278863（一种口服PHD抑制剂）在PAD受试者中的安全性和疗效。该研究评估了两种活性治疗模式：单次给药和亚慢性每日给药（分别为300 mg单次给药和15 mg每日给药，持续14天）。与安慰剂相比，两种方案都不能改善运动表现（6分钟步行试验（6 MWT;英尺）中较基线的变化，（GSK 1278863，安慰剂）：单次给药（-46，-44），p=0.96;重复给药（9，8），p=0.99;收缩次数变化至跛行发作（测角法）：单次给药（4，-1），p=0.053;重复给药（-2，1），p=0.08）。小牛肌肉活检子研究显示HIF靶基因的mRNA或蛋白水平没有增加。与安慰剂相比，接受GSK 1278863的受试者中发生不良事件的受试者更多，特别是在300 mg单次给药后。因此，在这种情况下评估GSK 1278863的安全性需要更大的人群暴露于该药物更长的时间。这些数据不支持使用试验方案时GSK 1278863在PAD中的获益。ClinicalTrials.gov标识符：NCT 01673555
Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). This multicenter, randomized, placebo-controlled study evaluated the safety and efficacy of GSK1278863 (an oral PHD inhibitor) in subjects with PAD. The study assessed two active treatment paradigms: single dosing and subchronic daily dosing (300 mg single dose and 15 mg daily for 14 days, respectively). Neither regimen improved exercise performance compared with placebo (change from baseline in the 6-minute walk test (6MWT; feet), (GSK1278863, placebo): single dose (-46, -44), p=0.96; repeat dose (9, 8), p=0.99; change in number of contractions to onset of claudication (goniometry): single dose (4, -1), p=0.053; repeat dose (-2, 1), p=0.08). A calf-muscle biopsy substudy showed no increases in mRNA or protein levels of HIF target genes. More subjects receiving GSK1278863 than placebo experienced adverse events, particularly following the 300 mg single dose. Thus, assessing the safety of GSK1278863 in this setting would require a larger population exposed to the agent for a longer duration. These data do not support a benefit of GSK1278863 in PAD using the regimens tested. ClinicalTrials.gov Identifier: NCT01673555