背景:原发性胆汁性胆管炎患者的有效治疗方法有限。Seladelpar,过氧化物酶体增殖物激活受体δ激动剂,有潜在的好处。
方法:在此12个月的第3阶段,双盲,安慰剂对照试验,我们随机分配(以2∶1的比例)对熊去氧胆酸反应不充分或有不可接受的副作用史的患者,接受每日10mg口服seladelpar或安慰剂.主要终点是生化反应,这被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,12个月时总胆红素水平正常。关键次要终点是12个月时碱性磷酸酶水平的正常化和瘙痒数字评定量表评分的变化(范围,0[无痒]至10[可以想象的最坏痒])在基线评分至少为4(表明中度至重度瘙痒)的患者中,从基线到第6个月。
结果:在193名接受随机分组和治疗的患者中,93.8%接受熊去氧胆酸作为标准的护理背景疗法。与安慰剂组相比,seladelpar组的患者中有更多的生化反应(61.7%vs.20.0%;差异,41.7个百分点;95%置信区间[CI],27.7至53.4,P<0.001)。与接受安慰剂的患者相比,接受seladelpar的患者中碱性磷酸酶水平的正常化也发生了更大的百分比(25.0%vs.0%;差异,25.0个百分点;95%CI,18.3至33.2,P<0.001)。与安慰剂相比,Seladelpar在瘙痒数字评分量表上的评分降低幅度更大(与基线相比的最小二乘均值变化,-3.2vs.-1.7;最小二乘均差,-1.5;95%CI,-2.5至-0.5,P=0.005)。在seladelpar组中86.7%的患者和安慰剂组中84.6%的患者报告了不良事件,严重不良事件占7.0%和6.2%,分别。
结论:在这项涉及原发性胆汁性胆管炎患者的试验中,与安慰剂组相比,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更高.Seladelpar还显着减少了基线时中度至重度瘙痒患者的瘙痒。两组不良事件的发生率和严重程度相似。(由CymaBay治疗学资助;RESPONSEClinicalTrials.gov编号,NCT04620733;EudraCT编号,2020-004348-27。).
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.).