Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.
School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA.
Lancet. 2014 May 10;383(9929):1637-1647. doi: 10.1016/S0140-6736(13)62337-5. Epub 2014 Feb 5.
BACKGROUND: Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. METHODS: In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22-28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987. FINDINGS: 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores -2.29 [SD 1.75] vs -1.60 [1.66]; difference of adjusted least square means -0.69 [SE 0.25]; 95% CI -1.19 to -0.20; p=0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo. INTERPRETATION: EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients. FUNDING: Spinifex Pharmaceuticals.
背景：现有治疗带状疱疹后神经痛和一般神经病理性疼痛的方法疗效有限，且存在不良反应。血管紧张素 II 型受体（AT2R）是神经病理性疼痛的一个新靶点。EMA401 是一种高选择性 AT2R 拮抗剂，正在开发成为一种新型神经病理性疼痛治疗药物。我们评估了 EMA401 治疗带状疱疹后神经痛患者的疗效。
方法：在这项多中心、安慰剂对照、双盲、随机、2 期临床试验中，我们招募了来自六个国家 29 个中心的至少有 6 个月病史的带状疱疹后神经痛患者（年龄 22-89 岁）。我们将 183 名参与者随机分为接受 EMA401（每日两次，每次 100mg）或安慰剂治疗 28 天。随机化根据中央随机分组方案进行，按研究地点进行分层，该方案由一位独立的、未设盲的统计学家生成。每个地点的患者和工作人员对治疗分配均设盲。我们评估了 EMA401 的疗效、安全性和药代动力学。主要疗效终点是从基线到最后一周（第 22-28 天）的平均疼痛强度变化，使用 11 点数字评分量表进行评估。主要疗效分析采用意向治疗。本试验在澳大利亚和新西兰临床试验注册中心注册，编号为 ACTRN12611000822987。
结果：92 名患者被分配到 EMA401 组，91 名患者被分配到安慰剂组。与安慰剂组相比，接受 EMA401 治疗的患者在治疗的最后一周报告的疼痛明显减轻（疼痛评分的平均下降值 -2.29 [1.75] 与 -1.60 [1.66]；调整后的最小二乘均值差值 -0.69 [0.25]；95%CI-1.19 至-0.20；p=0.0066）。未发生与 EMA401 相关的严重不良事件。总体而言，在 EMA401 组中，有 32 名患者报告了 56 次治疗中出现的不良事件，而接受安慰剂的 29 名患者中，有 45 名患者报告了此类事件。
结论：在 28 天的治疗结束时，与安慰剂相比，EMA401（每日两次，每次 100mg）可显著缓解带状疱疹后神经痛。EMA401 患者耐受性良好。
资助：Spinifex Pharmaceuticals。
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