This is a Phase 3b/4 multicenter study that includes 2 periods. Period 1 is a 12-week randomized, double-blind, double-dummy, active comparator-controlled period designed to compare the efficacy and safety of upadacitinib (15 mg QD) + MTX versus dalimumab (40 mg eow) + MTX in adult subjects with moderately to severely active RA following an inadequate response or intolerance to a single TNFi. Period 2 is a 36-week blinded extension period to evaluate the safety, tolerability, and efficacy of upadacitinib 15 mg QD+ MTX, or adalimumab 40 mg eow+ MTX, in subjects with RA who have completed Period 1.

 Diagnosis of RA for ≥ 3 months prior to screening based on the 2010 ACR/EULAR classification criteria for RA.  Subjects have been treated for ≥ 3 consecutive months prior to screening with 1 TNFi (originator or biosimilar) for RA (except adalimumab [originator or biosimilar]), but continue to exhibit active RA, or had to discontinue due to intolerability, irrespective of treatment duration. Up to 15% of subjects who were intolerant to 1 TNFi will be allowed to enroll. Subjects must have been on oral or parenteral MTX therapy ≥ 3 months and on a stable prescription of 15 to 25 mg/week (or ≥ 10 mg/week in subjects intolerant of MTX at doses ≥ 15 mg/week) for ≥ 4 weeks prior to the first dose of study drug. In addition, all subjects should take a dietary supplement of folic acid or folinic acid throughout the study participation.  Additional local requirements for MTX may apply.  Subject meets both of the following disease activity criteria:  ≥ 6 swollen joint (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at screening and baseline;  hsCRP ≥ 3 mg/L (central lab, ULN 2.87 mg/L) at screening.