BACKGROUND: 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).
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: AbbVie Inc.