Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-Naive Patients With Moderately-to-Severely Active Rheumatoid Arthritis (SELECT-EARLY): A Multicenter, Multi-Country, Randomized, Double-Blind, Active Comparator-Controlled Trial

Abstract

Objective: The SELECT-EARLY trial was undertaken to study the effect of upadacitinib, an oral, reversible Janus kinase 1-selective inhibitor, as monotherapy in patients with predominantly early rheumatoid arthritis who were naive for or had limited exposure to methotrexate (MTX).

Methods: Patients (n = 947) were randomized 1:1:1 to receive once-daily doses of upadacitinib 15 mg or 30 mg or weekly MTX (7.5-20 mg/week) for 24 weeks. The primary end points were the proportion of patients who met the American College of Rheumatology 50% (ACR50) improvement criteria at week 12, and the proportion in whom a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <2.6 was achieved at week 24. Data are presented through week 24.

Results: At baseline, the median disease duration was 0.5 years (range 0-44 years). A total of 840 patients (89%) completed 24 weeks of treatment. The study met both primary end points for upadacitinib 15 mg and 30 mg versus MTX (ACR50 was achieved at week 12 in 52% and 56% of patients, respectively, versus 28% [P < 0.001], and DAS28-CRP <2.6 was achieved at week 24 in 48% and 50% of patients, respectively, versus 19% [P < 0.001]). Statistically significant and clinically meaningful improvements in multiple patient-reported outcomes (PROs) were recorded for both upadacitinib doses versus MTX. Overall, 88% of patients receiving upadacitinib 15 mg and 89% of patients receiving 30 mg, respectively, had no radiographic progression (modified total Sharp score ≤0) compared to 78% of those receiving MTX (P < 0.01). Through week 24, the frequency of treatment-emergent adverse events was similar between the MTX arm (65%) and upadacitinib 15 mg arm (64%), but was slightly higher in the upadacitinib 30 mg arm (71%). Six deaths were reported (2 in the upadacitinib 15 mg arm, 3 in the upadacitinib 30 mg arm, and 1 in the MTX arm).

Conclusion: Our findings indicate that patients receiving either dose of upadacitinib monotherapy experienced significant improvements in clinical, radiographic, and PROs compared to patients receiving MTX.

Trial registration: ClinicalTrials.gov NCT02706873.

Figure 1

Profile of the SELECT‐EARLY trial of upadacitinib (UPA) 15 mg once daily (QD) and upadacitinib 30 mg once daily compared to methotrexate (MTX) in patients with rheumatoid arthritis. Only primary reasons for discontinuation are listed. One patient (ongoing) in the upadacitinib 30 mg arm completed week 24 after the cutoff date and was not included in these analyses. *The most frequent reason for screening failure was not meeting the inclusion criterion for high‐sensitivity C‐reactive protein.

Figure 2

Proportions of patients receiving methotrexate (MTX), upadacitinib (UPA) 15 mg once daily (QD), and upadacitinib 30 mg once daily who met the end points of American College of Rheumatology criteria for 20% improvement (ACR20) (A), 50% improvement (ACR50) (B), and 70% improvement (ACR70) (C), and a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <2.6 (D) over 24 weeks. The primary end points for this study were the ACR50 response rate at week 12 and DAS28‐CRP <2.6 at week 24. Missing data were imputed using the nonresponder imputation method. Patients who met the rescue criteria at week 16 or week 20 were treated as nonresponders at all visits after the first visit at which rescue medication was received. ** = P < 0.01; *** = P < 0.001, versus MTX.

Figure 3

Proportions of patients receiving methotrexate (MTX), upadacitinib (UPA) 15 mg once daily (QD), and upadacitinib 30 mg once daily in whom low disease activity and remission according to the Clinical Disease Activity Index (CDAI) and the Simplified Disease Activity Index (SDAI), and American College of Rheumatology/European League Against Rheumatism Boolean remission, was achieved over 24 weeks. For calculation of the CDAI, SDAI, and Boolean remission rates at each visit, all missing data were imputed using the nonresponder imputation method. Patients who met the rescue criteria at week 16 or week 20 were treated as nonresponders at all visits after the first visit at which rescue medication was received. Boolean remission is defined as a tender joint count of ≤1, swollen joint count of ≤1, C‐reactive protein level of ≤1 mg/dl, and patient global assessment of disease activity of ≤1 (on a 0–10 scale) at any time point. * = P < 0.05; ** = P < 0.01; *** = P < 0.001, versus MTX.

Figure 4

Physical function and radiographic structural damage in patients receiving methotrexate (MTX), upadacitinib (UPA) 15 mg once daily (QD), and upadacitinib 30 mg once daily. A and B, Least squares (LS) mean change in the Health Assessment Questionnaire (HAQ) disability index (DI) (A) and the proportion of patients in whom a minimum clinically important difference (MCID) in HAQ DI was achieved (B) over 24 weeks. C and D, LS mean change from baseline in modified total Sharp score (mTSS), erosion score, and joint space narrowing (JSN) (C) and the probability of change from baseline in modified total Sharp score (D) at week 24. The LS mean changes from baseline are based on the analysis of covariance model with geographic region as fixed factors and baseline value as covariate. The last observation carried forward method was used for mean change from baseline in HAQ DI for patients who received rescue medication; nonresponder imputation was used for MCID in HAQ DI. Linear extrapolation was used for change from baseline in modified total Sharp score, erosion score, and JSN. Analyses of the MCID in HAQ DI included only patients with a baseline HAQ DI of ≥0.22. * = P < 0.05; ** = P < 0.01; *** = P < 0.001, versus MTX.