Background ABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile. Methods We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America. We enrolled patients who were 18 years or older with rheumatoid arthritis and inadequate response or intolerance to biological disease-modifying antirheumatic drugs. Eligible patients were randomly assigned (3:2:2:2:2:1) via interactive response technology to receive daily, orally administered ABBV-599 (ie, upadacitinib 15 mg plus elsubrutinib 60 mg), elsubrutinib 60 mg, elsubrutinib 20 mg, elsubrutinib 5 mg, upadacitinib 15 mg, or placebo. Randomisation was stratified by the number of previous biological disease-modifying antirheumatic drugs. The investigator, study site personnel, and patients were masked throughout the study. The primary endpoint was change from baseline in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 for all patients who received a study drug. Pharmacokinetics and safety were also assessed. This study is registered with ClinicalTrials.gov, number NCT03682705. Findings Between Oct 8, 2018, and March 26, 2020, 242 patients were randomly assigned to receive ABBV-599 (n=62), elsubrutinib 60 mg (n=41), elsubrutinib 20 mg (n=39), elsubrutinib 5 mg (n=41), upadacitinib 15 mg (n=40), or placebo (n=19). Of the 242 patients, 204 (84%) were female, 38 (16%) were male, and 220 (91%) were White; the mean age at baseline was 58·0 years (SD 11·3). Compared with placebo, the least squares mean changes from baseline in DAS28-CRP were –1·44 (90% CI –2·03 to –0·85; p