Charité-Universitätsmedizin, Berlin, Germany.
Albany Medical College, Albany, NY, USA.
Lancet. 2018 Jun 23;391(10139):2503-2512. doi: 10.1016/S0140-6736(18)31115-2. Epub 2018 Jun 18.
Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).
This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426.
Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58-70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60-73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29-42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42-55) patients receiving upadacitinib 15 mg and 105 (48%; 41-55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12-22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial.
Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms.
AbbVie Inc.
Upadacitinib 是一种选择性的 Janus 激酶 1 抑制剂，在中度至重度类风湿关节炎的 2 期研究中显示出疗效。我们旨在评估 Upadacitinib 在对常规合成疾病修饰抗风湿药物（csDMARDs）反应不足的患者中的疗效。
这是一项在 35 个国家的 150 个地点进行的双盲、安慰剂对照试验。我们招募了年龄在 18 岁或以上、患有活动性类风湿关节炎 3 个月或以上的患者，这些患者接受 csDMARDs 治疗至少 3 个月，且在研究入组前至少 4 周稳定剂量，且对至少一种以下 csDMARDs 反应不足：甲氨蝶呤、柳氮磺胺吡啶或来氟米特。我们使用交互反应技术，将接受稳定背景 csDMARDs 的患者（2:2:1:1）随机分配，接受每日一次的延长释放制剂 Upadacitinib 15 mg 或 30 mg，或安慰剂，治疗 12 周。患者、研究者和资助者对分配情况均不知情。在 12 周后，服用安慰剂的患者根据预先指定的随机分组接受每日一次的 Upadacitinib 15 mg 或 30 mg。主要终点是在第 12 周时达到美国风湿病学会标准（ACR20）改善 20%的患者比例，以及使用 C 反应蛋白（DAS28[CRP]）评估的 28 个关节疾病活动评分达到 3.2 或更低的患者比例。我们在所有接受至少一剂研究药物的随机分配患者的全分析集（full analysis set）中进行了疗效分析，并使用无应答者推断（non-responder imputation）评估主要结局。本研究在 ClinicalTrials.gov 注册，编号为 NCT02675426。
在 2015 年 12 月 17 日至 2016 年 12 月 22 日期间，对 1083 名患者进行了资格评估，其中 661 名被招募并随机分配接受 Upadacitinib 15 mg（n=221）、Upadacitinib 30 mg（n=219）或安慰剂（n=221）治疗。所有患者均接受了至少一剂研究药物治疗，618 名（93%）完成了 12 周的治疗。在第 12 周时，接受 Upadacitinib 15 mg 治疗的 221 名患者中有 141 名（64%；95%CI 58-70）和接受 Upadacitinib 30 mg 治疗的 219 名患者中有 145 名（66%；60-73）达到 ACR20，而接受安慰剂治疗的 221 名患者中有 79 名（36%；29-42）（p<0.0001 各剂量组与安慰剂组相比）。接受 Upadacitinib 15 mg 治疗的 221 名患者中有 107 名（48%；95%CI 42-55）和接受 Upadacitinib 30 mg 治疗的 219 名患者中有 105 名（48%；41-55）达到 DAS28（CRP）<3.2，而接受安慰剂治疗的 221 名患者中有 38 名（17%；12-22）（p<0.0001 各剂量组与安慰剂组相比）。接受 Upadacitinib 15 mg 治疗的 221 名患者中有 125 名（57%）、接受 Upadacitinib 30 mg 治疗的 219 名患者中有 118 名（54%）和接受安慰剂治疗的 221 名患者中有 108 名（49%）报告了不良反应。在任何一组中发生率≥5%的最常见不良反应（adverse events）为恶心（接受 Upadacitinib 15 mg 治疗的 221 名患者中有 16 名[7%]；接受 Upadacitinib 30 mg 治疗的 219 名患者中有 3 名[1%]；接受安慰剂治疗的 221 名患者中有 7 名[3%]）、鼻咽炎（接受 Upadacitinib 15 mg 治疗的 221 名患者中有 12 名[5%]；接受 Upadacitinib 30 mg 治疗的 219 名患者中有 13 名[6%]；接受安慰剂治疗的 221 名患者中有 9 名[4%]）、上呼吸道感染（接受 Upadacitinib 15 mg 治疗的 221 名患者中有 12 名[5%]；接受 Upadacitinib 30 mg 治疗的 219 名患者中有 12 名[5%]；接受安慰剂治疗的 221 名患者中有 9 名[4%]）和头痛（接受 Upadacitinib 15 mg 治疗的 221 名患者中有 9 名[4%]；接受 Upadacitinib 30 mg 治疗的 221 名患者中有 7 名[3%]；接受安慰剂治疗的 221 名患者中有 12 名[5%]）。与安慰剂相比，接受 Upadacitinib（15 mg 或 30 mg）联合 csDMARDs 治疗的患者（221 名接受 15 mg 的患者中有 64%[29%]；219 名接受 30 mg 的患者中有 69%[32%]）报告的感染更多（29%）。报告了 3 例带状疱疹感染（安慰剂组 1 例[<1%]；Upadacitinib 15 mg 组 1 例[<1%]；Upadacitinib 30 mg 组 1 例[<1%]）和 1 例原发性水痘带状疱疹病毒感染（Upadacitinib 30 mg 组 1 例[<1%]），2 例恶性肿瘤（均在 Upadacitinib 30 mg 组），1 例经裁决的主要不良心血管事件（Upadacitinib 30 mg 组），5 例严重感染（安慰剂组 1 例[<1%]；Upadacitinib 15 mg 组 1 例[<1%]；Upadacitinib 30 mg 组 3 例[1%]）。试验期间无死亡报告。
接受 Upadacitinib（15 mg 或 30 mg）联合 csDMARDs 治疗的中度至重度类风湿关节炎患者的临床症状和体征有显著改善。
AbbVie Inc.
