Kalliomäki Jarkko, Jonzon Bror, Huizar Karin, O'Malley Michael, Andersson Anita, Simpson David M
AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden.
Mount Sinai Medical Center, Department of Neurology, Box 1052, New York, NY 10029, USA.
Scand J Pain. 2013 Apr 1;4(2):77-83. doi: 10.1016/j.sjpain.2012.10.003.
Background and aims Preclinical data suggest that the chemokine receptor 2 (CCR2) is involved in the pathophysiology of neuropathic pain through modulation of neuronal excitability, synaptic transmission and activation of spinal cord microglia. CCR2-antagonists have shown to be effective in preclinical models of neuropathic pain. The aim of this study was to evaluate the analgesic efficacy, safety and tolerability of a novel CCR2-antagonist, AZD2423, in patients with painful diabetic neuropathy (PDN). Methods This was a double-blind, randomized, parallel-group, multi-center study in patients with symmetric distal sensory polyneuropathy due to type 1 or 2 diabetes and duration of neuropathic pain between 3 months and 5 years. Concomitant treatment with neuropathic pain medications (e.g. anticonvulsants, tricyclic antidepressants, serotonin-noradrenaline uptake inhibitors, opioids, topical lidocaine or capsaicin) was not allowed. 134 patients with PDN were equally randomized to 28 days oral administration of 20 mg AZD2423,150 mg AZD2423, or placebo. The primary efficacy variable was the change of average pain score from 5-days baseline to the last 5 days of treatment, measured with numerical rating scale (NRS, 0-10). The secondary efficacy measures included NRS worst pain scores, patient global impression of change, pain interference on sleep and activity, and neuropathic pain symptom inventory (NPSI). Results The change of NRS average pain score was not significantly different between treatment groups (AZD2423 20mg: -1.50; AZD2423 150 mg: -1.35; placebo: -1.61). The NPSI total score and three out of five subscores (evoked pain, pressing/deep pain and paresthesia/dysesthesia) tended to be reduced more by AZD2423 150 mg than by placebo. No other secondary efficacy variables differed between treatment groups. The frequency and type of adverse events for AZD2423 were similar to placebo. The achieved plasma levels of AZD2423 in the two dose groups were in line with predictions from pharmacokinetic data previously obtained in healthy volunteers. Dose-dependent increase of plasma levels of the ligand of CCR2 (CCL2; chemokine ligand 2) and decrease of the mean levels of monocytes (-27% by AZD2423 150 mg) suggested that the administrated doses of AZD2423 interacted with the CCR2 target. Conclusion The CCR2-antagonist AZD2423 showed no analgesic efficacy in PDN based on NRS average pain scores and global and functional pain outcome measures. The NPSI data suggested possible effects on certain sensory components of pain. There were no major safety or tolerability concerns. Implications Treatment with a CCR2-antagonist does not have a clinically important analgesic effect in an overall PDN population.
背景与目的 临床前数据表明，趋化因子受体2（CCR2）通过调节神经元兴奋性、突触传递以及脊髓小胶质细胞的激活，参与神经性疼痛的病理生理过程。CCR2拮抗剂在神经性疼痛的临床前模型中已显示出有效性。本研究的目的是评估新型CCR2拮抗剂AZD2423在疼痛性糖尿病神经病变（PDN）患者中的镇痛疗效、安全性和耐受性。方法 这是一项针对1型或2型糖尿病所致对称性远端感觉性多发性神经病变且神经性疼痛病程在3个月至5年之间的患者的双盲、随机、平行组、多中心研究。不允许同时使用神经性疼痛药物（如抗惊厥药、三环类抗抑郁药、5-羟色胺-去甲肾上腺素再摄取抑制剂、阿片类药物、局部利多卡因或辣椒素）。134例PDN患者被平均随机分为三组，分别口服28天的20mg AZD2423、150mg AZD2423或安慰剂。主要疗效变量是从5天基线期到治疗最后5天平均疼痛评分的变化，采用数字评分量表（NRS，0 - 10）进行测量。次要疗效指标包括NRS最严重疼痛评分、患者总体变化印象、疼痛对睡眠和活动的干扰以及神经性疼痛症状量表（NPSI）。结果 各治疗组间NRS平均疼痛评分的变化无显著差异（AZD2423 20mg组：-1.50；AZD2423 150mg组：-1.35；安慰剂组：-1.61）。AZD2423 150mg组的NPSI总分及五个子评分中的三个（诱发性疼痛、压迫/深部疼痛和感觉异常/感觉迟钝）较安慰剂组有更大程度的降低趋势。各治疗组间其他次要疗效变量无差异。AZD2423不良事件的频率和类型与安慰剂相似。两个剂量组中AZD2423达到的血浆水平与先前在健康志愿者中获得的药代动力学数据预测结果一致。CCR2配体（CCL2；趋化因子配体2）血浆水平的剂量依赖性升高以及单核细胞平均水平的降低（AZD2423 150mg组降低27%）表明，所给予的AZD2423剂量与CCR2靶点相互作用。结论 基于NRS平均疼痛评分以及总体和功能性疼痛结局指标，CCR2拮抗剂AZD2423在PDN中未显示出镇痛疗效。NPSI数据提示对疼痛的某些感觉成分可能有作用。无重大安全性或耐受性问题。意义 在总体PDN人群中，用CCR2拮抗剂治疗无临床重要的镇痛效果。
