Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials
Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials
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DOI：
10.1016/j.cgh.2018.11.035
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发表时间：
2019-07-01
影响因子：
12.6
通讯作者：
Chan, Gary
中科院分区：
文献类型：
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作者：
Sandborn, William J.;Panes, Julian;Chan, Gary
背景与目的：托法替尼是一种口服小分子抗结肠炎药，在多个国家被批准用于治疗溃疡性结肠炎（UC）。我们报告了托法替尼治疗的中重度UC患者的综合安全性分析。（5或10 mg，每日两次）作为3个队列进行分析：感应（II期和III期诱导研究，n = 1220），维持（III期维持研究，n = 592）和总体（在II期、III期或开放标签、长期扩展研究中接受托法替布5或10 mg每日两次的患者，n = 1157; 1613患者-年暴露）。发病率（IR;每100患者年暴露事件的患者）评估选定不良事件。结果：在维持队列中，治疗组之间选定不良事件的IR相似，除了接受托法替尼5 mg每日两次的患者中带状疱疹感染的IR在数字上更高（2.1;接受托法替布10 mg每日2次治疗的患者的IR（IR，6.6; 95% CI，3.2-12.2）显著高于安慰剂组（IR，1.0，95% CI，0.0-5.4）。对于整个队列（84%接受托法替布10 mg每日两次的平均剂量），IR为：死亡，0.2（95% CI，0.1-0.6）;严重感染，2.0（95% CI，1.4-2.8）;机会性感染，1.3（95% CI，0.8-2.0）;带状疱疹感染，4.1（95% CI，3.1-5.2）;恶性（不包括非黑色素瘤皮肤癌），0.7（95% CI，0.3-1.2）;非黑色素瘤皮肤癌，0.7（95% CI，0.3-1.2）;主要心血管不良事件，0.2（95% CI，0.1-0.6）;胃肠道穿孔，0.2（95% CI，0.0-0.5）。在接受托法替尼治疗的中重度UC患者的安全性分析中，我们观察到与带状疱疹感染的剂量关系。尽管随访时间相对较短，但托法替尼治疗UC患者的安全性特征似乎与类风湿性关节炎患者和接受生物制剂治疗的UC患者报告的安全性特征相似，带状疱疹感染的IR较高除外。
BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule inhibitor of JAR approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC.METHODS: Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years' exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events.RESULTS: In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4-6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2-12.2) vs placebo (IR, 1.0, 95% CI, 0.0-5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1-0.6); serious infections, 2.0 (95% CI, 1.4-2.8); opportunistic infections, 1.3 (95% CI, 0.8-2.0); herpes zoster infection, 4.1 (95% CI, 3.1-5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3-1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3-1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1-0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0-0.5).CONCLUSIONS: In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection.