INTRODUCTION Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in patients with PBC improve with OCA therapy. METHODS Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database. RESULTS In the RCT, the primary endpoint occurred in 28.6% of OCA (n = 168) and 28.9% of placebo patients (n = 166; intent-to-treat analysis hazard ratio [HR] = 1.01, 95% confidence interval = 0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting and as-treated analyses shifted the HR to favor OCA. In the EC (n = 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR = 0.39; 95% confidence interval = 0.22-0.69; P = 0.001). No new safety signals were identified in the RCT. DISCUSSION Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the intent-to-treat estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

中文翻译：

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COBALT：奥贝胆酸与安慰剂和外部对照治疗原发性胆汁性胆管炎的验证性试验。


引言 奥贝胆酸 （OCA） 治疗原发性胆汁性胆管炎 （PBC） 在 3 期 POISE 试验中被有条件批准。COBALT 确证性试验评估了 OCA 治疗是否改善了 PBC 患者的临床结果。方法 将随机分配至 OCA （5-10 mg） 的患者与安慰剂 （随机对照试验 [RCT] 或外部对照 （EC） 进行比较。主要复合终点是死亡时间、肝移植、终末期肝病模型评分 ≥15、不受控制的腹水或因肝功能失代偿住院。预先指定的倾向评分加权 EC 组源自美国医疗保健索赔数据库。结果 在随机对照试验中，主要终点发生在 28.6% 的 OCA （n = 168） 和 28.9% 的安慰剂患者 （n = 166;意向治疗分析风险比 [HR] = 1.01,95% 置信区间 = 0.68-1.51），但发生了功能性揭盲和与商业治疗的交叉，尤其是在安慰剂组中。使用删失权重的逆概率和处理时分析来纠正这些，使 HR 转向有利于 OCA。在 EC （n = 1,051） 中，加权主要终点发生在 10.1% 的 OCA 和 21.5% 的非 OCA 患者中 （HR = 0.39;95% 置信区间 = 0.22-0.69;P = 0.001）。在 RCT 中没有发现新的安全性信号。讨论 功能性揭盲和治疗交叉，特别是在安慰剂组中，混淆了 RCT 中与 OCA 相关结局的意向治疗估计。与真实世界 EC 的比较表明，OCA 治疗显著降低了负面临床结局的风险。这些分析证明了 EC 数据在验证性试验中的价值，并表明 OCA 治疗可改善 PBC 患者的临床结局。