托法替布长达 9.5 年的长期安全性：类风湿关节炎临床开发项目的综合综合分析。
Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme.
机构信息
Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, Texas, USA.
University of Occupational and Environmental Health, Kitakyushu, Japan.
出版信息
RMD Open. 2020 Oct;6(3). doi: 10.1136/rmdopen-2020-001395.
OBJECTIVE
Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA.
METHODS
Data were pooled for patients with RA who received ≥1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years [PY]; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest.
RESULTS
7061 patients received tofacitinib (total exposure: 22 875 PY; median [range] exposure: 3.1 [0 to 9.6] years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis [TB]) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months.
CONCLUSION
This represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time.
TRIAL REGISTRATION NUMBERS
NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661.For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1.
目的
托法替尼是一种用于治疗类风湿关节炎（RA）的口服 Janus 激酶（JAK）抑制剂。我们报告了截至 2017 年 3 月，托法替尼最大的综合安全性分析，该分析使用了来自 I 期、II 期、III 期、IIIb/IV 期和长期扩展研究中成年 RA 患者的数据。
方法
汇总了接受过≥1 剂托法替尼治疗的 RA 患者的数据。对于关注的不良事件（AE），获得首次发生的不良事件发生率（IR；每 100 患者年[PY]的患者数；95%CI）。
结果
7061 例患者接受了托法替尼治疗（总暴露量：22875 PY；中位数[范围]暴露量：3.1[0 至 9.6]年）。严重 AE、严重感染、带状疱疹（所有）、机会性感染（不包括结核病[TB]）和 TB 的发生率分别为 9.0（8.6 至 9.4）、2.5（2.3 至 2.7）、3.6（3.4 至 3.9）、0.4（0.3 至 0.5）和 0.2（0.1 至 0.2）。恶性肿瘤（不包括非黑色素瘤皮肤癌[NMSC]）、NMSC 和淋巴瘤的发生率分别为 0.8（0.7 至 0.9）、0.6（0.5 至 0.7）和 0.1（0.0 至 0.1）。胃肠穿孔、深静脉血栓形成、肺栓塞、静脉血栓栓塞、动脉血栓栓塞和主要不良心血管事件的发生率分别为 0.1（0.1 至 0.2）、0.2（0.1 至 0.2）、0.1（0.1 至 0.2）、0.3（0.2 至 0.3）、0.4（0.3 至 0.5）和 0.4（0.3 至 0.5）。死亡率的发生率为 0.3（0.2 至 0.3）。IR 在 6 个月至>78 个月的时间内基本保持一致。
结论
这是迄今为止 RA 中 JAK 抑制剂的最大临床数据集。IR 与托法替尼 RA 临床开发项目的先前报告基本一致，并且随着时间的推移保持稳定。
试验注册号码
NCT01262118；NCT01484561；NCT00147498；NCT00413660；NCT00550446；NCT00603512；NCT00687193；NCT01164579；NCT00976599；NCT01059864；NCT01359150；NCT02147587；NCT00960440；NCT00847613；NCT00814307；NCT00856544；NCT00853385；NCT01039688；NCT02187055；NCT00413699；NCT00661661。有关综合安全性分析中包含的 I 期、II 期、III 期、IIIb/IV 期和长期扩展研究的摘要，请参见在线补充表 1。
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