IRCCS Istituto Giannina Gaslini, UOSID Centro Trial, PRINTO, Genova, Italy.
College of Medicine, University of Cincinnati, and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Lancet. 2021 Nov 27;398(10315):1984-1996. doi: 10.1016/S0140-6736(21)01255-1. Epub 2021 Nov 9.
Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Pfizer.
托法替尼是一种口服 Janus 激酶抑制剂。这项试验评估了托法替尼与安慰剂在多关节病程幼年特发性关节炎（JIA）患者中的疗效和安全性。
这项双盲、撤药阶段 3 期试验纳入了年龄在 2 岁至 18 岁以下、患有多关节病程 JIA（扩展寡关节炎、类风湿因子阳性或类风湿因子阴性多关节炎或无全身表现的全身 JIA）的患者，试验在 14 个国家的儿科风湿病国际试验组织和儿科风湿病合作研究组网络的 64 个中心进行。患有银屑病关节炎或附着点相关关节炎的患者也被纳入探索性终点。在研究的第 1 部分中，患者接受了为期 18 周的口服开放标签托法替尼（基于体重的剂量；5mg，每日两次或更低）治疗。在第 1 部分中达到至少 JIA/美国风湿病学会 30 缓解的患者使用交互式响应技术系统（1:1）随机分配继续接受托法替尼或在第 2 部分研究中转换为安慰剂，为期 26 周。第 2 部分的主要终点是在研究的第 44 周时多关节病程 JIA 患者的 JIA 发作率；采用意向治疗原则。所有接受了至少一剂研究药物的患者在第 1 部分和第 2 部分研究中均进行了安全性评估。这项试验在 ClinicalTrials.gov 注册，NCT02592434。
在 2016 年 6 月 10 日至 2019 年 5 月 16 日期间，225 名入组患者中，184 名（82%）患者患有多关节病程 JIA，20 名（9%）患者患有银屑病关节炎，21 名（9%）患者患有附着点相关关节炎。225 名患者中有 147 名（65%）接受了甲氨蝶呤联合治疗。在第 2 部分中，142 名多关节病程 JIA 患者被分配接受托法替尼（n=72）或安慰剂（n=70）治疗。第 44 周时，托法替尼的发作率明显低于安慰剂（72 名患者中有 21 名[29%]，70 名患者中有 37 名[53%]；风险比 0.46，95%CI 0.27-0.79；p=0.0031）。在第 2 部分研究中，接受托法替尼治疗的 88 名患者中有 68 名（77%）和安慰剂组的 85 名患者中有 63 名（74%）发生了不良事件。分别有 1 名（1%）和 2 名（2%）患者发生严重不良事件。在整个托法替尼暴露期间，225 名患者中有 107 名（48%）发生了感染或寄生虫感染。在这项研究中没有死亡。
这项关键试验的结果表明，托法替尼是多关节病程 JIA 患者的有效治疗方法。新的口服疗法对儿童和青少年尤其重要，因为他们可能更愿意避免注射。
辉瑞。
