Background

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).

Methods

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.

Findings

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.

Interpretation

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.

Funding

Pfizer.

中文翻译：

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托法替尼治疗幼年特发性关节炎：一项双盲、安慰剂对照、停药 3 期随机试验

背景

Tofacitinib 是一种口服 Janus 激酶抑制剂。该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。

方法

这项双盲、停药的 3 期试验招募了 2 岁至 18 岁以下的多关节病程 JIA（扩展性少关节炎、类风湿因子阳性或类风湿因子阴性多发性关节炎，或没有活动性全身特征的全身性 JIA）患者，并完成在 14 个国家的儿科风湿病学国际试验组织和儿科风湿病学协作研究组网络的 64 个中心。患有银屑病关节炎或附着点炎相关关节炎的患者被纳入探索性终点。在研究的第 1 部分，患者接受了 18 周的口服开放标签托法替尼（基于体重的剂量；5 mg 每天两次或更低）。至少达到 JIA/美国风湿病学会 30 反应的患者被随机分配（1：1) 在研究的第 2 部分中使用交互式响应技术系统继续托法替尼或改用安慰剂，为期 26 周。主要终点是多关节病程 JIA 患者第 2 部分第 44 周时的 JIA 复发率；应用了意向治疗原则。在研究的第 1 部分和第 2 部分中，对所有接受一剂或多剂研究药物的患者的安全性进行了评估。该试验已在 ClinicalTrials.gov 注册，NCT02592434。

发现

在 2016 年 6 月 10 日至 2019 年 5 月 16 日期间，入组的 225 名患者中，184 名（82%）患者患有多关节病程 JIA，20 名（9%）患有银屑病关节炎，21 名（9%）患有附着点炎相关关节炎。225 名患者中有 147 名（65%）同时接受了甲氨蝶呤。在第 2 部分中，142 名多关节病程 JIA 患者被分配到托法替尼（n=72）或安慰剂（n=70）组。到第 44 周时，托法替尼的复发率（72 名患者中的 21 名 [29%]）显着低于安慰剂组（70 名患者中的 37 名 [53%]；风险比 0·46，95% CI 0·27–0·79； p=0·0031)。在研究的第 2 部分中，88 名接受托法替尼的患者中有 68 名（77%）发生了不良事件，安慰剂组 85 名患者中有 63 名（74%）发生了不良事件。严重不良事件分别发生在 1 例（1%）和 2 例（2%）中。在整个托法替尼暴露期间，225 名患者中有 107 名（48%）有感染或侵染。

解释

这项关键试验的结果表明，托法替尼是治疗多关节病程 JIA 患者的有效方法。新的口服疗法对儿童和青少年尤其重要，他们可能更愿意避免注射。

资金

辉瑞。