Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response

Abstract

Background: In SELECT-COMPARE, a randomised double-blind study, upadacitinib 15 mg once daily was superior to placebo or adalimumab on background methotrexate (MTX) for treating rheumatoid arthritis signs and symptoms and inhibited radiographical progression versus placebo at 26 weeks. Here we report 48-week safety and efficacy in patients who continued their original medication or were rescued to the alternative medication for insufficient response.

Methods: Patients on MTX received upadacitinib 15 mg, placebo or adalimumab for 48 weeks. Rescue without washout, from placebo or adalimumab to upadacitinib or upadacitinib to adalimumab occurred if patients had <20% improvement in tender joint count (TJC) or swollen joint count (SJC) (weeks 14/18/22) or Clinical Disease Activity Index (CDAI) >10 (week 26); remaining placebo patients were switched to upadacitinib at week 26. Efficacy was analysed by randomised group (non-responder imputation), as well as separately for rescued patients (as observed). Treatment-emergent adverse events per 100 patient-years were summarised.

Results: Consistent with responses through week 26, from weeks 26 to 48, responses by randomised group including low disease activity, clinical remission and improvements in pain and function remained superior for upadacitinib versus adalimumab; radiographical progression remained lower for upadacitinib versus placebo (linear extrapolation). Although both switch groups responded, a higher proportion of patients rescued to upadacitinib from adalimumab achieved CDAI ≤10 at 6 months postswitch versus patients rescued from upadacitinib to adalimumab. Safety at week 48 was comparable to week 26.

Conclusion: Upadacitinib+MTX demonstrated superior clinical and functional responses versus adalimumab+MTX and maintained inhibition of structural damage versus placebo+MTX through week 48. Patients with an insufficient response to adalimumab or upadacitinib safely achieved clinically meaningful responses after switching to the alternative medication without washout.

Trial registration: ClinicalTrials.gov NCT02629159.

Keywords: dmards (biologic); dmards (synthetic); methotrexate; rheumatoid arthritis.

Conflict of interest statement

Competing interests: RF has received research grants and consulting fees from AbbVie, Eli Lilly, and Pfizer. MG has served as a consultant for, and has received grants from, AbbVie, Eli Lilly, Pfizer, Galapagos, and Gilead. EM has received research grants and consulting fees from AbbVie, Eli Lilly, Pfizer, Roche, BMS, and Sandoz. LB has served as a speaker on behalf of, and received consulting fees and research grants from, Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly and Novartis. CP is an employee and shareholder of Spire Sciences, has served as a speaker on behalf of Amgen, Bristol-Myers Squibb and has served as a consultant for Centrexion, Crescendo Bioscience, Daiichi Sankyo, EMD Serono, Five Prime, Flexion Therapeutics, Genentech, Gilead, GlaxoSmithKline, Pfizer, Plexikkon, Regeneron, Roche and SetPoint. PD has received speaker fees from BMS, Sanofi, Eli Lilly, and Celltrion. AO has served as a speaker on behalf of, and has received consulting fees and/or research grants from BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly and Novartis. JVE, YL, and I-HS are employees of AbbVie and may own stock or stock options.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Disposition of patients through week 48. At weeks 14, 18 and 22, patients who had 10 were rescued. Regardless of CDAI low disease activity achievement at week 26, all remaining PBO patients were switched to UPA. ADA, adalimumab; AE, adverse events; CDAI, Clinical Disease Activity Index; PBO, placebo; MTX, methotrexate; UPA, upadacitinib.

Figure 2

Proportions of patients achieving disease activity states over 48 weeks (NRI). Vertical line at week 26 indicates the end of the PBO-controlled period. Treatment groups are by initial randomisation. *p≤0.05; **p≤0.01; ***p≤0.001 for comparison of UPA versus PBO; #p≤0.05; ##p≤0.01; ###, p≤0.001 for comparison of UPA versus ADA. Error bars reflect 95% CI.¶Indicates multiplicity-controlled comparisons of UPA versus PBO. Observations after rescue were handled using NRI (patients rescued at weeks 14–22) and LOCF (patients rescued at week 26) for binary endpoints. ADA, adalimumab; CDAI, Clinical Disease Activity Index; DAS28(CRP), 28-joint Disease Activity Score based on C-reactive protein; LOCF; last observation carried forward; MTX, methotrexate; NRI, non-responder imputation; PBO, placebo; SDAI, Simplified Disease Activity Index; UPA, upadacitinib.

Figure 3

Radiographic progression through week 48 (linear extrapolation). Treatment groups are by initial randomisation. Results based on reading session 2. *p≤0.05; **p≤0.01; ***p≤0.001 for comparison of UPA versus PBO. Error bars reflect 95% CI. For the PBO group, all data at week 48 were imputed by linear extrapolation. X-ray data collected at treatment switching or at discontinuation of PBO (for patients who discontinued PBO) were used for extrapolation. Specifically, for PBO patients who switched to UPA at week 26, the week 26 X-ray was used for extrapolation to impute the data at week 48. For patients randomised to UPA or ADA who were rescued, data at week 48 were also imputed by linear extrapolation using X-ray data collected at treatment switching. Statistical analysis comparing UPA to ADA was not prespecified; nominal p values were not significant. ADA, adalimumab; BL, baseline; JSN, joint space narrowing; PBO, placebo; mTSS, modification of the total Sharp Score; MTX, methotrexate; UPA, upadacitinib.

Figure 4

Proportions of patients who were switched from ADA to UPA 15 mg once daily or vice versa achieving disease activity states over 48 weeks (as observed). Vertical line at week 26 indicates the end of the PBO-controlled period. Numbers of patients at selected visits are indicated below the graphs. Groups are by sequence of treatments. ADA, adalimumab; CDAI, Clinical Disease Activity Index; DAS28(CRP), 28-joint Disease Activity Score based on C-reactive protein; PBO, placebo; UPA, upadacitinib.