Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial.,The Lancet

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Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial.
The Lancet ( IF 98.4 ) Pub Date : 2020-03-13 , DOI: 10.1016/s0140-6736(20)30263-4
Philip J Mease ₁ , Proton Rahman ₂ , Alice B Gottlieb ₃ , Alexa P Kollmeier ₄ , Elizabeth C Hsia ₅ , Xie L Xu ₄ , Shihong Sheng ₆ , Prasheen Agarwal ₆ , Bei Zhou ₆ , Yanli Zhuang ₇ , Désirée van der Heijde ₈ , Iain B McInnes ₉ ,

Affiliation

Background

The interleukin-23 (IL-23)/T-helper 17 cell pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, an IL-23 inhibitor that specifically binds the IL-23 p19 subunit, significantly and safely improved psoriatic arthritis in a phase 2 study. DISCOVER-2 was a phase 3 trial to assess guselkumab in biologic-naive patients with psoriatic arthritis.

Methods

This phase 3, double-blind, placebo-controlled study was done at 118 sites in 13 countries across Asia, Europe, and North America. We enrolled biologic-naive patients with active psoriatic arthritis (at least five swollen joints, at least five tender joints, and C-reactive protein ≥0·6 mg/dL) despite standard therapies. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive protein concentration) to subcutaneous injections of guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) response at week 24 in all patients per assigned treatment group. Safety was assessed in all patients per treatment received. This trial is registered at , (active, not recruiting).

Findings

From July 13, 2017, to Aug 3, 2018, 1153 patients were screened, of whom 741 were randomly assigned to receive guselkumab every 4 weeks (n=246), every 8 weeks (n=248), or placebo (n=247). One patient in the every 4 weeks group and one in the placebo group did not start treatment, and the remaining 739 patients started treatment; 716 patients continued treatment up to week 24. Significantly greater proportions of patients in the guselkumab every 4 weeks group (156 [64%] of 245 [95% CI 57–70]) and every 8 weeks group (159 [64%] of 248 [58–70]) than in the placebo group (81 [33%] of 246 [27–39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22–39] for the every 4 weeks group and 31% [23–40] for the every 8 weeks group; both p<0·0001). Up to week 24, serious adverse events occurred in eight (3%) of 245 patients receiving guselkumab every 4 weeks (three serious infections), three (1%) of 248 receiving guselkumab every 8 weeks (one serious infection), and seven (3%) of 246 receiving placebo (one serious infection). No deaths occurred.

Interpretation

Guselkumab, a human monoclonal antibody that specifically inhibits IL-23 by binding the cytokine's p19 subunit, was efficacious and demonstrated an acceptable benefit–risk profile in patients with active psoriatic arthritis who were naive to treatment with biologics. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis.

Funding

Janssen Research and Development.

中文翻译：

Guselkumab用于初生性活动性银屑病关节炎（DISCOVER-2）的患者：一项双盲，随机，安慰剂对照的3期临床试验。

背景

白细胞介素23（IL-23）/ T-helper 17细胞途径与银屑病关节炎的发病机制有关。在2期研究中，Guselkumab是一种与IL-23 p19亚基特异性结合的IL-23抑制剂，可显着安全地改善银屑病关节炎。DISCOVER-2是一项3期试验，用于评估初生银屑病关节炎患者中的guselkumab。

方法

该第三阶段，双盲，安慰剂对照研究是在亚洲，欧洲和北美的13个国家/地区的118个地点进行的。尽管采用标准疗法，但我们招募了具有生物学性质的活动性银屑病关节炎患者（至少五个关节肿胀，至少五个嫩关节和C反应蛋白≥0·6 mg / dL）。将患者随机分配（1：1：1，由计算机生成的置换区块；按基线改变疾病的抗风湿药使用和C反应蛋白浓度分层），每4周皮下注射100 mg的guselkumab。guselkumab 100 mg在第0、4周，然后每8周一次；或安慰剂。主要终点是每个指定治疗组所有患者在第24周时美国风湿病学会（ACR20）反应改善20％。评估接受治疗的所有患者的安全性。

发现

从2017年7月13日到2018年8月3日，对1153例患者进行了筛查，其中741名患者被随机分配为每4周（n = 246），每8周（n = 248）或安慰剂（n = 247）接受guselkumab的治疗）。每4周一次的一组患者和安慰剂组的一名患者未开始治疗，其余739名患者开始治疗。716位患者继续治疗直至第24周。每4周组（156 [64％]的245 [95％CI 57-70]）和每8周组（159 [64％]的患者）中的guselkumab患者比例显着增加248 [58–70]）比安慰剂组（246 [27–39]中的81 [33％]）在第24周达到了ACR20响应（百分比差异与每4周一次的安慰剂组为31％[95％CI 22-39]，每8周一次的组为31％[23-40]。均p <0·0001）。直到第24周，每4周接受guselkumab的245例患者中有8（3％）发生严重不良事件（三例严重感染），每8周接受guselkumab的248例患者中有3（1％）发生（1次严重感染），而7例接受安慰剂的246名患者中占3％（一种严重感染）。没有死亡发生。