Guselkumab用于患有活动性银屑病关节炎的患者，如果是初生或曾接受过TNFα抑制剂治疗（DISCOVER-1），则为双盲，随机，安慰剂对照的3期临床试验。,The Lancet

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Guselkumab用于患有活动性银屑病关节炎的患者，如果是初生或曾接受过TNFα抑制剂治疗（DISCOVER-1），则为双盲，随机，安慰剂对照的3期临床试验。
The Lancet ( IF 98.4 ) Pub Date : 2020-03-13 , DOI: 10.1016/s0140-6736(20)30265-8
Atul Deodhar ₁ , Philip S Helliwell ₂ , Wolf-Henning Boehncke ₃ , Alexa P Kollmeier ₄ , Elizabeth C Hsia ₅ , Ramanand A Subramanian ₆ , Xie L Xu ₄ , Shihong Sheng ₇ , Prasheen Agarwal ₇ , Bei Zhou ₇ , Yanli Zhuang ₈ , Christopher T Ritchlin ₉ ,

Affiliation

背景

许多银屑病关节炎患者对肿瘤坏死因子（TNF）抑制剂的反应不足。Guselkumab是通过IL-23 p19亚基结合的白介素23（IL-23）的特异性抑制剂，在2期试验中以可接受的安全性显着改善了银屑病关节炎的体征和症状。

方法

这项多中心，双盲，随机，安慰剂对照的3期临床试验在亚洲，澳大拉西亚，欧洲和北美的13个国家/地区的86个地点进行，并招募了患有活动性银屑病关节炎的成人（至少三个肿胀和三个压痛关节）尽管采用标准疗法，但C反应蛋白仍≥0·3 mg / dL）。资格标准包括对标准治疗的反应不足或不耐受，包括至少4个月的前体药物，至少3个月的非生物疾病改良抗风湿药（DMARD）或至少4周的非甾体类抗炎药对于银屑病关节炎。大约30％的研究参与者以前可能曾接受过一种或两种TNF抑制剂。患者被随机分配（1：1：1，计算机生成的排列区块；通过基线DMARD和先前使用的TNF抑制剂进行分层），每4周皮下注射Guselkumab 100 mg; guselkumab 100 mg在第0、4周，然后每8周一次；或匹配的安慰剂。主要终点是在每个分配的治疗组中，使用无反应者插补的所有患者在第24周时美国风湿病学会改善20％（ACR20）。评估接受治疗的所有患者的安全性。该试用版的注册网址为，（处于活动状态，而非正在招募中）。

发现

从2017年8月28日至2018年8月17日，我们筛选了624名患者，其中381名患者被随机分配并每4周（n = 128），每8周（n = 127）进行guselkumab或安慰剂（n = 126）。362名患者继续接受研究治疗，直至第24周。达到了主要终点：每4周组中的guselkumab患者比例显着提高（在第48周中有76 [59％]，在128 [95％CI 50-68]中达到了ACR20） ]）和每8周组（127 [43–61]中的66 [52％]）比安慰剂组（126 [15-30]中的28 [22％]），与安慰剂的百分比差异为37％（每4周组95％CI 26-48），每8周组30％（19-41）（均p <0·0001）。直到第24周，没有发生每4周接受guselkumab的患者的严重不良事件，每8周接受过guselkumab的患者有四（3％）位，五（4％）名接受安慰剂的患者。直到第24周，安慰剂组的一名患者死于心力衰竭，两名严重感染；没有接受古塞珠单抗治疗的患者死亡或受到严重感染。

解释

Guselkumab表现出良好的获益-风险特征，对于活动性银屑病关节炎患者可能是一种有效的治疗选择。

资金

Janssen研究与开发。

"点击查看英文标题和摘要"

Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial.

Background

Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial.

Methods

This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at , (active, not recruiting).

Findings

From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50–68]) and every 8 weeks group (66 [52%] of 127 [43–61]) than in the placebo group (28 [22%] of 126 [15–30]), with percentage differences versus placebo of 37% (95% CI 26–48) for the every 4 weeks group and 30% (19–41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections.