Genovese MC, et al. - In this phase 3 trial authors evaluated the safety and efficacy of upadacitinib in patients with an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs). Given that upadacitinib was safe and efficacious in the treatment of patients with active rheumatoid arthritis in phase 2 studies. Rapid and significant improvements were led by both doses of upadacitinib vs placebo over 12 weeks in patients with refractory rheumatoid arthritis.

Methods

• Experts conducted this double-blind, randomised controlled phase 3 trial at 153 sites in 26 countries.
• They included the patients 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).
• They 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 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 were the two separate primary endpoints.
• In the modified intention-to-treat population of all patients who received at least one dose of study drug, efficacy and safety analyses were done.
• Up to week 24 of this ongoing study, data are presented.

Results

• As per data, 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upadacitinib 30 mg; n=85 placebo then upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient was withdrawn from the 15 mg upadacitinib group before the start of study treatment.
• Results demonstrated the mean disease duration to be 13·2 years (SD 9·5); Out of 498 patients, 235 (47%) 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.
• Findings suggested that at week 12, 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 achieved ACR20 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 vs 24 (14%; 9-20) of 169 patients receiving placebo (p < 0·0001 for each dose vs placebo).
• Data suggested that the overall numbers of patients with adverse events up to week 12 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).
• Authors noted that at week 12, upper respiratory tract infection were the most common adverse events occurring in at least 5% of patients in any treatment group (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%]).
• They found higher number of patients with serious adverse events was 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.
• Compared to the upadacitinib 15 mg and placebo groups, more patients in the upadacitinib 30 mg group had serious infections, herpes zoster, and adverse events leading to discontinuation.
• During the placebo-controlled phase of the study, patients receiving upadacitinib reported one case of pulmonary embolism, three malignancies, one major adverse cardiovascular event, and one death were reported; none were reported in patients receiving placebo.