艾拉菲诺与安慰剂在原发性胆汁性胆管炎中的安全性概况：随机对照试验的系统评价、荟萃分析及试验序贯分析。
完整摘要 · 中文译文
背景：尽管elafibranor的安全性已在针对二线原发性胆汁性胆管炎（PBC）药物的3结局网络荟萃分析以及以严重不良事件（AE）为唯一安全性终点的混合设计综述中得到探讨，但尚无任何综述对专门针对安慰剂对照的、涵盖10个结局的elafibranor证据库应用试验序贯分析（TSA）或推荐意见分级评估、制定与评价（GRADE）确定性评估。PBC是一种影响小胆管的慢性自身免疫性肝病，约有30%至40%的患者对一线熊去氧胆酸（UDCA）治疗应答不足。Elafibranor是一种双重过氧化物酶体增殖物激活受体α/δ激动剂，于2024年获得美国食品药品监督管理局和欧洲药品管理局批准作为二线选择，但其安全性特征尚未有汇总的随机证据。 方法：我们对比较elafibranor与安慰剂在UDCA应答不足PBC患者中的随机对照试验进行了系统评价和荟萃分析，检索了PubMed、Scopus和Embase，时间截至2026年6月。共纳入3项随机对照试验（Schattenberg 2021、Kowdley 2024/ELATIVE、Levy 2026/ELMWOOD），共274例患者（elafibranor组n = 183；安慰剂组n = 91），所有试验均具有低偏倚风险。采用随机效应模型对10个安全性结局进行汇总，并应用GRADE和TSA。 结果：Elafibranor在所有预设安全性结局上与安慰剂相比均无显著差异。主要结局为任何不良事件，其相对危险度为1.06（95%置信区间：0.97–1.16；I² = 0%）。趋势有利于elafibranor。 fibranor 对瘙痒（RR 0.77）和疲劳（RR 0.71）有效，而对恶心和治疗相关不良事件的增加幅度不大且无统计学显著性。各结局的 GRADE 确定性均为中等，仅因不精确性而降级。TSA 确认任何不良事件均为无效，但发现其余 9 个结局的把握度严重不足，仅积累了所需信息量的 2.2% 至 9.7%。 结论：Elafibranor 总体安全性良好，且在改善瘙痒和疲劳方面呈现令人鼓舞的趋势。然而，现有证据仍不足以对罕见或长期安全性信号得出明确结论，凸显了开展更大规模、具有充分把握度试验的必要性。将 GRADE 和 TSA 联合应用于这一专门的、安慰剂对照的 elafibranor 证据基础，有助于区分哪些安全性信号确实为阴性，哪些为把握度不足，而更广泛的二线 PBC 比较研究尚未能解决这一区分问题。
完整摘要 · 英文原文
BACKGROUND: While elafibranor's safety has been addressed within a 3 outcome network meta-analysis of second-line primary biliary cholangitis (PBC) agents and within a mixed design review using serious adverse events (AEs) as its sole safety endpoint, no review has yet applied trial sequential analysis (TSA) or Grading of Recommendations Assessment, Development and Evaluation (GRADE) certainty assessment to a dedicated, 10-outcome, placebo-controlled elafibranor evidence base. PBC is a chronic autoimmune liver disease affecting the small bile ducts, with approximately 30% to 40% of patients failing to respond adequately to first-line ursodeoxycholic acid (UDCA) therapy. Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, received Food and Drug Administration and European Medicines Agency approval in 2024 as a second-line option, yet no pooled randomized evidence for its safety profile had been synthesized. METHODS: We conducted a systematic review and meta-analysis of RCTs comparing elafibranor with placebo in UDCA-inadequate-responder PBC patients, searching PubMed, Scopus, and Embase through June 2026. Three RCTs (Schattenberg 2021, Kowdley 2024/ELATIVE, Levy 2026/ELMWOOD) enrolling 274 patients (elafibranor n = 183; placebo n = 91) were included, all with low risk of bias. Ten safety outcomes were pooled via a random-effects model, with GRADE and TSA. RESULTS: Elafibranor showed no significant difference from placebo across any prespecified safety outcome. The primary outcome, any AE, showed RR 1.06 (95% CI: 0.97-1.16; I2 = 0%). Trends favored elafibranor for pruritus (RR 0.77) and fatigue (RR 0.71), with modest nonsignificant increases for nausea and treatment-related AEs. GRADE certainty was moderate across outcomes, downgraded solely for imprecision. TSA confirmed futility for any AE but found the remaining 9 outcomes substantially underpowered, with only 2.2% to 9.7% of required information accrued. CONCLUSION: Elafibranor shows a broadly reassuring safety profile, with encouraging trends toward improved pruritus and fatigue. However, evidence remains insufficient for definitive conclusions on rare or long-term safety signals, underscoring the need for larger, adequately powered trials. Jointly applying GRADE and TSA to this dedicated, placebo-controlled elafibranor evidence base clarifies which safety signals are genuinely null versus underpowered, a distinction broader second-line PBC comparisons have not resolved.