Introduction

The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC).

Methods

PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention.

Results

Overall, 310 participants were randomized to twice-daily eliapixant 25 mg (n = 75), 75 mg (n = 78), 150 mg (n = 80), or placebo (n = 77). A statistically significant dose–response signal with eliapixant was detected for the primary endpoint (all dose–response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43–51 (57–65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% (n = 1) of the placebo group and 1–16% (n = 1–13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant.

Conclusion

Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG.

Trial Registration

ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020.

中文翻译：

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Eliapixant 治疗难治性慢性咳嗽的疗效和安全性：随机、安慰剂对照 2b 期 PAGANINI 研究

介绍

PAGANINI 研究评估了选择性 P2X3 拮抗剂 Eliapixant 对难治性慢性咳嗽 (RCC) 患者的疗效和安全性。

方法

PAGANINI 是一项随机、双盲、平行组、安慰剂对照、多中心、剂量探索、2b 期研究。筛选时肾细胞癌持续时间≥ 12 个月且咳嗽严重程度≥ 40 毫米（视觉模拟量表）的成人入组。参与者按 1:1:1:1 随机分配至每日两次 25 mg、75 mg 或 150 mg 口服 eliapixant 或安慰剂，为期 12 周。主要终点是干预 12 周后 24 小时咳嗽计数相对于基线的变化。

结果

总体而言，310 名参与者被随机分配至每日两次 elapixant 25 mg（n  = 75）、75 mg（n  = 78）、150 mg（n  = 80）或安慰剂（n  = 77）。主要终点检测到 eliapixant 具有统计学显着性的剂量反应信号（所有剂量反应模型，调整后p  < 0.1；单侧）。服用安慰剂的 39 名 (51%) 参与者和接受 eliapixant 的 43-51 名 (57-65%) 参与者报告了不良事件 (AE)。最常见的 AE 是味觉障碍， 安慰剂组的发生率为 1% ( n = 1)，安慰剂组的发生率为 1-16% ( n = 1) = 1–13) 以剂量相关的方式确定 eliapixant 组。一名接受 150 mg 每日两次 eliapixant 治疗的参与者发生了 1 例中度药物性肝损伤。

结论

Eliapixant 在 RCC 中表现出功效和良好的味道耐受性。然而，药物引起的肝损伤导致在 eliapixant 临床试验中加强了肝脏监测，并终止了拜耳公司所有适应症的整个开发计划。

试用注册

ClinicalTrials.gov 标识符 NCT04562155；2020 年 9 月 18 日注册。