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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钴：奥贝胆酸治疗原发性胆汁性胆管炎的验证性试验（安慰剂和外部对照）。


简介 奥贝胆酸 (OCA) 治疗原发性胆汁性胆管炎 (PBC) 在 3 期 POISE 试验中获得有条件批准。 COBALT 验证性试验评估了 OCA 治疗是否能改善 PBC 患者的临床结局。方法 将随机接受 OCA (5-10 mg) 治疗的患者与安慰剂（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、腹水不受控制或因肝代偿失调住院。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 RCT 中，主要终点发生在 28.6% 的 OCA 患者 (n = 168) 和 28.9% 的安慰剂患者 (n = 166) 中；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，特别是在安慰剂组中。使用审查加权的逆概率和处理分析来纠正这些，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 患者和 21.5% 的非 OCA 患者中（HR = 0.39；95% 置信区间 = 0.22-0.69；P = 0.001）。随机对照试验中没有发现新的安全信号。讨论 功能性揭盲和治疗交叉，尤其是安慰剂组，混淆了随机对照试验中与 OCA 相关结果的意向治疗估计。与现实世界的 EC 比较表明，OCA 治疗显着降低了负面临床结果的风险。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 患者的临床结果。