Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: the VEDERA trial

Paul Emery, Sarah Horton, Raluca Bianca Dumitru, Kamran Naraghi, Désirée van der Heijde, Richard J Wakefield, Elizabeth M A Hensor, Maya H Buch, Paul Emery, Sarah Horton, Raluca Bianca Dumitru, Kamran Naraghi, Désirée van der Heijde, Richard J Wakefield, Elizabeth M A Hensor, Maya H Buch

Abstract

Objectives: We sought to confirm in very early rheumatoid arthritis (ERA) a much greater superiority (30%) of first-line etanercept+methotrexate (ETN+MTX) over treat-to-target MTX (MTX-TT) than previously reported in ERA (14%); and explore whether ETN following initial MTX secures a comparable response to first-line ETN+MTX.

Methods: Pragmatic, open-label, randomised controlled trial of treatment-naïve ERA (≤12 months symptom), Disease Activity Score 28 joint (DAS28)-erythrocyte sedimentation rate (ESR) ≥3.2, rheumatoid factor (RF)+/-anticitrullinated peptide antibody (ACPA) positive or ultrasound power Doppler (PD) if RF and ACPA negative. Subjects were randomised 1:1 to ETN+MTX; or MTX-TT, escalated to ETN if week 24 DAS28-ESR ≥2.6 and intramuscular corticosteroid at protocolised time points. Primary endpoint of week 48 DAS28ESR remission with clinical and imaging secondary endpoints.

Results: We randomised 120 patients, 60 to each arm (71% female, 73% RF/84% ACPA positive, median (IQR) symptom duration 20.3 (13.1, 30.8) weeks; mean (SD) DAS28 5.1 (1.1)). Remission rates with ETN+MTX and MTX-TT, respectively, were 38% vs 33% at week 24; 52% vs 38% at week 48 (ORs 1.6, 95% CI 0.8 to 3.5, p=0.211). Greater, sustained DAS28-ESR remission observed with ETN+MTX versus MTX-TT (42% and 27%, respectively; p=0.035). PD was fully suppressed by week 48 in over 90% in each arm. Planned exploratory analysis revealed OR 2.84, 95% CI 0.8 to 9.6) of achieving remission after 24 weeks of ETN administered first line compared with administered post-MTX.

Conclusions: Compared with remission rates typically reported with first-line tumour necrosis factor inhabitor+MTX versus MTX-TT, we did not demonstrate a larger effect in very ERA. Neither strategy conferred remission in the majority of patients although ultrasound confirmed local inflammation suppression. Poorer ETN response following failure of MTX-TT is also suggested. Trial registration number NCT02433184.

Keywords: anti-TNF; early rheumatoid arthritis; etanercept; remission; ultrasound.

Conflict of interest statement

Competing interests: PE has undertaken clinical trials and provided expert advice to Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz and Lilly. PE has received consultant fees from BMS, AbbVie, Pfizer, MSD, Novartis, Roche and UCB. PE has received research grants paid to his employer from AbbVie, BMS, Pfizer, MSD and Roche. MHB has provided expert advice and received consultant fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Pfizer, Roche, Sandoz, Sanofi and UCB and has received research grants paid to her employer from Pfizer Bristol-Myers Squibb Ltd, Roche, UCB. DvdH has provided expert advice and received consultant fees from Abbvie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingleheim, Celgene, Cyxone, Daichii, Eisai, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
CONSORT flow diagram participant flow diagram up to week 96. CONSORT, Consolidated Standards of Reporting Trials.
Figure 2
Figure 2
(A) DAS28-ESR remission rates in ETN+MTX (n=60) and MTX-TT (n=60). Percentage patient estimated via multiple imputation. (B) Individual DAS28-ESR scores over time in ETN+MTX (n=60) and MTX-TT (n=60). DAS28, Disease Activity Score 28 joint; ESR, erythrocyte sedimentation rate; ETN, etanercept; MTX, methotrexate; TT, treat-to-target.
Figure 3
Figure 3
Proportion of patients achieving DAS28-ESR remission following 24 weeks ETN exposure, either received first-line (ETN+MTX) or following failure to achieve remission on MTX-TT (MTX-TTb). Percentage patient estimated via multiple imputation. DAS, Disease Activity Score 28 joint; ESR, erythrocyte sedimentation rate; ETN, etanercept; MTX, methotrexate; TT, treat-to-target.
Figure 4
Figure 4
Patient-reported outcomes over time. ESR, erythrocyte sedimentation rate; ETN, etanercept; HAQ-DI, Health Assessment Questionnaire Disability Index; MTX, methotrexate; RAQoL, Rheumatoid Arthritis Quality of Life; TT, treat-to-target; VAS, Visual Analogue Scale.

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