本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2312100

摘要内容如下：

背景

原发性胆汁性胆管炎患者的有效治疗方法有限。Seladelpar是一种过氧化物酶体增殖物激活受体δ激动剂，具有潜在的益处。

方法

在这项3期、12个月、双盲、安慰剂对照试验中，我们将对熊去氧胆酸反应不佳或有不可接受的副作用病史的患者随机（以2:1的比例）分配接受每日10 mg剂量的口服Seladelpar或安慰剂。主要终点是生化反应，其定义为碱性磷酸酶水平低于正常范围上限的1.67倍，从基线下降15%或更多，并且在第12个月时总胆红素水平正常。关键的次要终点是第12个月时碱性磷酸酶水平的正常化和瘙痒数字评定量表（范围，从基线到第6个月，在基线评分至少为4（表明中度至重度瘙痒）的患者中，0[无瘙痒]至10[可想象的最严重瘙痒]。

结果

在193例接受随机分组和治疗的患者中，93.8%的患者接受了熊去氧胆酸作为标准背景治疗。与安慰剂组相比，Seladelpar组中出现生化反应的患者比例更高（61.7%对20.0%；差41.7个百分点；95%可信区间[CI]，27.7至53.4，p<0.001）。与接受安慰剂的患者相比，接受Seladelpar的患者碱性磷酸酶水平正常化的比例也更高（25.0%vs.0%；差25.0个百分点；95%可信区间为18.3~33.2，P<0.001）。与安慰剂相比，Seladelpar导致瘙痒数字评定量表评分的降低幅度更大（与基线相比的最小二乘平均变化为-3.2 vs.-1.7；最小二乘均值差，-1.5；95%可信区间，-2.5~-0.5，P=0.005）。Seladelpar组和安慰剂组分别有86.7%和84.6%的患者报告了不良事件，严重不良事件分别为7.0%和6.2%。

结论

在这项涉及原发性胆汁性胆管炎患者的试验中，SELADELPAR组出现生化反应和碱性磷酸酶正常化的患者百分比显著高于安慰剂组。Seladelpar还显著减少了基线时有中度至重度瘙痒的患者的瘙痒。两组不良事件的发生率和严重程度相似。（由Cymabay Therapeutics资助；响应ClinicalTrials.gov编号，NCT04620733；Eudract编号:2020-004348-27。）

英文原文如下：

Abstracts

BACKGROUND  Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits.

METHODS  In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).

RESULTS  Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.

CONCLUSIONS  In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).

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