乌司奴单抗治疗银屑病、银屑病关节炎和克罗恩病的安全性：Ⅱ/Ⅲ期临床开发项目的综合分析。
Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs.
机构信息
Institute of Translational Medicine and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Office 04, Ground Floor, ITM, North Block, Heritage Building, Mindelson Way, Edgbaston, Birmingham, B15 2TH, UK.
Axial Spondyloarthritis Clinic, University of California San Francisco, 400 Parnassus Ave., Floor B1, San Francisco, CA, 94143, USA.
出版信息
Drug Saf. 2019 Jun;42(6):751-768. doi: 10.1007/s40264-019-00797-3.
INTRODUCTION
Theoretical risks of biologic agents remain under study.
OBJECTIVE
The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials.
METHODS
Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]).
RESULTS
Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications.
CONCLUSIONS
Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications.
TRIAL REGISTRATIONS
ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.
简介
生物制剂的理论风险仍在研究中。
目的
本研究旨在整合来自 12 项乌司奴单抗注册试验的 1 年安全性数据。
方法
患者患有中重度斑块型银屑病、活动性银屑病关节炎（PsA）（±甲氨蝶呤）或中重度克罗恩病（CD；免疫调节剂/皮质类固醇治疗失败/不耐受）。银屑病患者接受皮下注射乌司奴单抗 45/90mg 或安慰剂，通常在第 0 周、第 4 周，然后此后每 12 周一次，而 CD 患者接受单次静脉注射乌司奴单抗（130mg 或基于体重范围的约 6mg/kg 剂量）或安慰剂诱导剂量在第 0 周，随后在第 8 周皮下注射乌司奴单抗 90mg，此后每 8/12 周一次。预先定义的安全性事件的发生率在事后进行整合（根据随访时间调整，每 100 患者-年[PYs]报告）。
结果
在 6280 名入组患者中，5884 名乌司奴单抗治疗患者（银屑病：3117；PsA：1018；CD：1749）在 1 年内贡献了 4521PYs，而安慰剂治疗患者的 PYs 为 674PYs（8 至 16 周对照期为 829PYs 和 385PYs）。在接受乌司奴单抗和安慰剂治疗的患者中，疾病合并的感染发生率/100PYs（95%置信区间）分别为 125.4（122.2-128.7）和 129.4（120.9-138.3）在第 1 年，并且在接受或不接受甲氨蝶呤治疗的患者中没有明显增加（92.5[84.2-101.5]与 115.3[109.9-121.0]），或在基线时接受或不接受皮质类固醇治疗的患者中显著增加（116.3[107.3-125.9]与 107.3[102.0-112.8]）。主要不良心血管事件（0.5[0.3-0.7]与 0.3[0.0-1.1]）、恶性肿瘤（0.4[0.2-0.6]与 0.2[0.0-0.8]）和死亡（0.1[0.0-0.3]与 0.0[0.0-0.4]）在各适应症中均较为罕见。
结论
乌司奴单抗在批准的适应症中注册试验中表现出一致且良好的安全性。
试验注册
ClinicalTrials.gov 标识符：NCT00320216、NCT00267969、NCT00307437、NCT00454584、NCT00267956、NCT01009086、NCT01077362、NCT00265122、NCT00771667、NCT01369329、NCT01369342 和 NCT01369355。
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