Burmester GR, et al. - Given phase 2 studies in patients with moderate-to-severe rheumatoid arthritis showed the efficacy of upadacitinib (a selective inhibitor of Janus kinase 1), researchers tested its efficacy in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). They observed that treatment with upadacitinib (15 mg or 30 mg) in combination with csDMARDs resulted in significant improvements in clinical signs and symptoms of patients with moderately to severely active rheumatoid arthritis.

Methods

• This double-blind, placebo-controlled trial was conducted at 150 sites in 35 countries and included 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.
• They 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 by using interactive response technology.
• Patients, investigators, and the funder were masked to allocation.
• In accord with the prespecified randomisation assignment, 15 mg or 30 mg of upadacitinib once daily was administered after 12 weeks to patients taking placebo.
• 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 were included as primary endpoints.
• Efficacy analyses were carried out in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and non-responder imputation was used for evaluation of the primary outcomes.

Results

• Eligibility assessment was performed in 1083 patients between Dec 17, 2015, and Dec 22, 2016.
• Recruitment of 661/ 1083 patients was followed by their randomization to upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221).
• At least one dose of study drug was received by all patients, and 12 weeks of treatment completion was reported in 618 (93%).
• Relative to 79 (36%; 29–42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo), 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 achieved ACR20 at week 12.
• Relative to 38 (17%; 12–22) patients receiving placebo (p<0·0001 for each dose vs placebo), 107 (48%; 95% CI 42–55) patients receiving upadacitinib 15 mg and 105 (48%; 41–55) patients receiving upadacitinib 30 mg met DAS28(CRP) of 3·2 or less.
• A total of 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 experienced adverse events.
• 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%]) were documented as the most frequently reported adverse events (≥5% of patients in any group).
• Compared with placebo (47 [21%] of 221 patients), more infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg).
• Researchers also reported 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).
• During the trial, no deaths were reported.