BACKGROUND: Phase 2 studies with upadacitinib, a selective Janus kinase 1 (JAK1) 
inhibitor, have shown safety and efficacy in the treatment of patients with 
active rheumatoid arthritis. We did this study to further assess the safety and 
efficacy of upadacitinib in patients with an inadequate response to biologic 
disease-modifying anti-rheumatic drugs (bDMARDs).
METHODS: We did this double-blind, randomised controlled phase 3 trial at 153 
sites in 26 countries. Patients were aged 18 years or older, had active 
rheumatoid arthritis and previous inadequate response or intolerance to bDMARDs, 
and were receiving concomitant background conventional synthetic DMARDS 
(csDMARDs). We randomly assigned patients (2:2:1:1) by interactive response 
technology to receive once-daily oral extended-release upadacitinib 15 mg or 30 
mg or placebo for 12 weeks, followed by upadacitinib 15 mg or 30 mg from week 12 
onwards. The two separate primary endpoints were the proportions of patients 
achieving a 20% improvement in American College of Rheumatology criteria (ACR20) 
at week 12 and the proportion of patients achieving a 28-joint disease activity 
score using C-reactive protein (DAS28[CRP]) of 3·2 or less at week 12. Efficacy 
and safety analyses were done in the modified intention-to-treat population of 
all patients who received at least one dose of study drug. Data are presented up 
to week 24 of this ongoing study. The trial is registered with 
ClinicalTrials.gov (NCT02706847).
FINDINGS: Between March 15, 2016, and Jan 10, 2017, 499 patients were randomly 
assigned (n=165 upadacitinib 15 mg; n=165 upadacitinib 30 mg; n=85 placebo then 
upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient 
was withdrawn from the 15 mg upadacitinib group before the start of study 
treatment. Mean disease duration was 13·2 years (SD 9·5); 235 (47%) of 498 
patients had received one previous bDMARD, 137 (28%) had received two, and 125 
(25%) had received at least three; 451 (91%) patients completed treatment up to 
week 12 and 419 (84%) patients completed treatment up to week 24. At week 12, 
ACR20 was achieved by 106 (65%; 95% CI 57-72) of 164 patients receiving 
upadacitinib 15 mg and 93 (56%; 49-64) of 165 patients receiving upadacitinib 30 
mg compared with 48 (28%; 22-35) of 169 patients receiving placebo (p<0·0001 for 
each dose vs placebo). DAS28(CRP) of 3·2 or less was achieved by 71 (43%; 95% CI 
36-51) of 164 patients receiving upadacitinib 15 mg and 70 (42%; 35-50) of 165 
patients receiving upadacitinib 30 mg versus 24 (14%; 9-20) of 169 patients 
receiving placebo (p<0·0001 for each dose vs placebo). Up to week 12, overall 
numbers of patients with adverse events were similar for the placebo group (95 
[56%] of 169) and the upadacitinib 15 mg group (91 [55%] of 164), but higher in 
the upadacitinib 30 mg group (111 [67%] of 165). At week 12, the most common 
adverse events occurring in at least 5% of patients in any treatment group were 
upper respiratory tract infection (13 [8%] of 169 in the placebo group; 13 [8%] 
of 164 in the upadacitinib 15 mg group; ten [6%] of 165 in the upadacitinib 30 
mg group), nasopharyngitis (11 [7%]; seven [4%]; nine [5%]), urinary tract 
infection (ten [6%]; 15 [9%]; nine [5%]), and worsening of rheumatoid arthritis 
(ten [6%]; four [2%]; six [4%]). The number of patients with serious adverse 
events was higher in the upadacitinib 30 mg group (12 [7%]) than in the 
upadacitinib 15 mg group (eight [5%]); no serious adverse events were reported 
in patients receiving placebo. More patients in the upadacitinib 30 mg group had 
serious infections, herpes zoster, and adverse events leading to discontinuation 
than in the upadacitinib 15 mg and placebo groups. During the placebo-controlled 
phase of the study, one case of pulmonary embolism, three malignancies, one 
major adverse cardiovascular event, and one death were reported in patients 
receiving upadacitinib; none were reported in patients receiving placebo.
INTERPRETATION: Both doses of upadacitinib led to rapid and significant 
improvements compared with placebo over 12 weeks in patients with refractory 
rheumatoid arthritis.
FUNDING: AbbVie Inc.