Cilofexor in non-cirrhotic primary sclerosing cholangitis (PRIMIS): a randomised, double-blind, multicentre, placebo-controlled, phase 3 trial.

The PRIMIS trial evaluated the efficacy and harms of the farnesoid X-activated receptor agonist cilofexor in participants with non-cirrhotic PSC.

PRIMIS试验评估了法尼索X激活受体激动剂西洛非索在非肝硬化PSC患者中的疗效和危害。

Methods

In this phase 3, double-blind, placebo-controlled, multicentre trial (205 sites across 16 countries), adults aged 18-75 years with non-cirrhotic (F0-F3 [Ludwig classification]) large-duct PSC were randomly assigned (2:1) via an interactive web response system to receive cilofexor 100 mg or placebo (identical in appearance) orally once daily for 96 weeks.

在这项3期、双盲、安慰剂对照的多中心试验中（涉及16个国家的205个试验地点），年龄在18-75岁之间的非肝硬化（Ludwig分类F0-F3）大管型原发性硬化性胆管炎患者通过交互式网络响应系统随机分配（2:1），每天一次口服接受100 mg的cilofexor或外观相同的安慰剂，为期96周。

Randomisation was stratified by ursodeoxycholic acid use (yes or no) and the presence of bridging fibrosis (F3 vs F0-F2), with a block size of six within each stratum.

随机分组按熊去氧胆酸使用情况（是或否）和桥接纤维化（F3 vs F0-F2）进行分层，每个分层内采用六人一组的分组大小。

Participants, personnel directly involved in the conduct of the study, and outcome assessors were masked to treatment assignment.

参与者、直接参与研究执行的人员以及结果评估者对治疗分配情况进行了盲法处理。

The primary endpoint was the proportion of participants with histological progression of liver fibrosis (a stage increase of one or more [Ludwig classification]) at week 96.

主要终点是第96周时，肝脏纤维化组织学进展（Ludwig分类中一个或多个阶段增加）的参与者比例。

After study termination, the primary endpoint analysis set was amended to include all participants in the harms analysis set (all who received at least one dose of the study drug) who had biopsy data at baseline and week 96.

研究终止后，主要终点分析集被修订，包括所有在基线和第96周有活检数据的参与者，这些参与者至少接受了研究药物的一次剂量（所有伤害分析集中的人员）。

This trial is complete (ClincalTrials.gov, NCT03890120).

该试验已完成（ClincalTrials.gov, NCT03890120）。

Results

Between June 13, 2019, and July 22, 2021, 419 participants were randomly assigned, and 416 were included in the full and harms analysis sets (cilofexor: n=277; placebo: n=139); 257 (62%) men and 159 (38%) women.

在2019年6月13日至2021年7月22日期间，共有419名参与者被随机分配，其中416名被纳入完整和不良事件分析集（cilofexor组：n=277；安慰剂组：n=139）；257名（62%）为男性，159名（38%）为女性。

The study was terminated early on Sept 26, 2022, after a planned interim futility analysis after 160 patients had reached 96 weeks of follow-up indicated a 6·8% probability of detecting a significant difference between cilofexor over placebo (futility boundary ≤10%).

在2022年9月26日，研究因计划中的中期无效性分析而提前终止，当时已有160名患者完成了96周的随访，分析显示cilofexor与安慰剂之间存在显著差异的概率为6.8%（无效性边界≤10%）。

In the final analysis of the primary endpoint, for which 133 patients in the cilofexor group and 64 in the placebo group had liver biopsy results available, fibrosis progression occurred in 41 (31%) participants in the cilofexor group and 21 (33%) in the placebo group at week 96 (treatment difference -1·4% [95% CI -15·2 to 12·3]; p=0·42).

在主要终点的最终分析中，对于有肝活检结果的患者，133名在西洛非群组和64名在安慰剂组，96周时，西洛非群组有41名（31%）参与者和安慰剂组有21名（33%）发生了纤维化进展（治疗差异-1.4% [95% 置信区间-15.2至12.3]；p=0.42）。

The most common adverse events were pruritus (cilofexor: 136 [49%] of 277 patients; placebo: 50 [36%] of 139 patients; grade 3 or higher in 11 [4%] patients in the cilofexor group and one [1%] patient in the placebo group), COVID-19 (cilofexor: 65 [23%]; placebo: 26 [19%]), and upper abdominal pain (cilofexor: 40 [14%]; placebo 20 [14%]).

最常见的不良事件是瘙痒（西洛非群：277名患者中的136名（49%）；安慰剂：139名患者中的50名（36%）；西洛非群组中有11名（4%）患者和安慰剂组中有1名（1%）患者为3级或更高级别），COVID-19（西洛非群：65名（23%）；安慰剂：26名（19%）），以及上腹痛（西洛非群：40名（14%）；安慰剂20名（14%））。

The proportion of serious adverse events was similar between groups (cilofexor: 53 [19%]; placebo: 26 [19%]).

两组间严重不良事件的比例相似（cilofexor组：53例[19%]；安慰剂组：26例[19%]）。

There were no treatment-related deaths.

没有与治疗相关的死亡事件。

interpretation

Cilofexor did not significantly reduce the rate of fibrosis progression (vs placebo) in participants with non-cirrhotic PSC.

Cilofexor在非肝硬化原发性硬化性胆管炎患者中，并没有显著降低纤维化进展的速率（与安慰剂相比）。

A greater percentage of cilofexor-treated participants had pruritus than placebo-treated participants; this study provides valuable harms data for cilofexor and other drugs in its class.

接受Cilofexor治疗的参与者中，瘙痒的发生率高于接受安慰剂治疗的参与者；这项研究为Cilofexor及其同类药物提供了宝贵的安全性数据。

funding

Gilead Sciences.

吉利德科学公司。