Linerixibat in patients with primary biliary cholangitis and cholestatic pruritus (GLISTEN): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

We aimed to evaluate the safety and efficacy of linerixibat, an ileal bile acid transporter inhibitor, as a specific antipruritic therapy in patients with PBC.

我们的目标是评估作为PBC患者特异性抗瘙痒治疗的线性利巴韦林（一种回肠胆酸转运蛋白抑制剂）的安全性和有效性。

Methods

We conducted a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Patients with PBC and moderate-to-severe pruritus (Worst Itch Numerical Rating Scale [WI-NRS] ≥4) were recruited at 115 centres in 19 countries.

我们进行了一项随机、多中心、双盲、安慰剂对照的III期临床试验。招募了来自19个国家115个中心的原发性胆汁性胆管炎（PBC）患者，这些患者伴有中度至重度瘙痒（最痒数字评分量表[WI-NRS]≥4）。

Patients were randomly assigned to receive either oral linerixibat 40 mg twice a day or a matching placebo through an interactive online response system, with pruritus severity (moderate or severe) and concomitant pruritus treatment (bile acid binding resins, other treatments, or none) as stratification factors.

患者通过互动式在线响应系统随机分配，接受口服linerixibat 40 mg每日两次或匹配的安慰剂治疗，瘙痒程度（中度或重度）和伴随瘙痒治疗（胆汁酸结合树脂、其他治疗或无治疗）作为分层因素。

The primary endpoint was change in pruritus over 24 weeks assessed using the WI-NRS, ranging from 0 (no itching) to 10 (worst imaginable itching).

主要终点是24周内瘙痒程度的变化，使用WI-NRS评分评估，范围从0（无瘙痒）到10（最严重的瘙痒）。

Efficacy analyses included all randomly allocated patients; safety analyses included all randomly allocated patients who received one dose of study treatment or more.

疗效分析包括所有随机分配的患者；安全性分析包括所有随机分配且至少接受一次研究治疗的患者。

This study is registered with ClinicalTrials.gov, number NCT04950127.

本研究已在ClinicalTrials.gov注册，注册号为NCT04950127。

Results

From Dec 1, 2021, to May 13, 2024, a total of 238 patients were randomly assigned to receive either linerixibat (n=119) or placebo (n=119).

从2021年12月1日至2024年5月13日，共有238名患者被随机分配接受linerixibat（n=119）或安慰剂（n=119）。

One (<1%) of 119 patients randomly allocated to receive placebo withdrew before receiving treatment.

在随机分配接受安慰剂的119名患者中，有一名患者（<1%）在治疗前退出。

Patients receiving linerixibat experienced significant improvement in pruritus over 24 weeks compared with placebo (least-squares mean change from baseline -2·86 [95% CI -3·23 to -2·50] for linerixibat vs -2·15 [-2·51 to -1·78] for placebo; adjusted mean difference -0·72 [95% CI -1·15 to -0·28]; p=0·0013).

接受linerixibat治疗的患者在24周内与安慰剂相比，瘙痒症状显著改善（linerixibat组基线变化的最小二乘平均值为-2.86 [95%置信区间-3.23至-2.50]，安慰剂组为-2.15 [-2.51至-1.78]；调整后的平均差异为-0.72 [95%置信区间-1.15至-0.28]；p=0.0013）。

Gastrointestinal adverse events were more frequent in patients treated with linerixibat than with placebo (72 [61%] of 119 vs 21 [18%] of 118 had diarrhoea; 22 [18%] vs four [3%] had abdominal pain).

与安慰剂组相比，接受linerixibat治疗的患者胃肠道不良事件更为频繁（119名患者中有72名[61%]出现腹泻；118名患者中有21名[18%]出现腹泻；119名患者中有22名[18%]出现腹痛，而安慰剂组分别为4名[3%]）。

Treatment discontinuations due to gastrointestinal adverse events occurred in eight (7%) of 119 patients in the linerixibat group (of which five were due to diarrhoea) and one (<1%) of 118 in the placebo group.

因胃肠道不良事件导致治疗中断的情况在linerixibat组的119名患者中有8名（7%）（其中5例因腹泻），而安慰剂组的118名患者中只有1例（<1%）发生。

Serious adverse events were reported in 14 (12%) of 119 patients receiving linerixibat and four (3%) of 118 receiving placebo.

在接受linerixibat治疗的119名患者中，有14名（12%）报告了严重不良事件，而在接受安慰剂治疗的118名患者中，有4名（3%）报告了严重不良事件。

No deaths were reported during the study.

研究期间没有报告死亡病例。

interpretation

Linerixibat significantly improved pruritus versus placebo, supporting its potential to address a major symptom of PBC.

Linerixibat 相比安慰剂显著改善了瘙痒症状，支持了其解决原发性胆汁性胆管炎（PBC）主要症状的潜力。

An expected increase in diarrhoea in linerixibat-treated patients was observed.

在使用 linerixibat 治疗的患者中，观察到了预期的腹泻增加。

funding

GSK.

GSK。