DISEASE ACTIVITY-GUIDED TAPERING OF BIOLOGICS IN PATIENTS WITH INFLAMMATORY ARTHRITIS: A RANDOMISED, OPEN-LABEL, EQUIVALENCE TRIAL

Background Traditionally, biologics are maintained lifelong at standard dose in patients with inflammatory arthritis (IA) when sustained low disease activity (LDA) is reached. However, evidence of possible tapering is emerging but data on the optimal approach is lacking. Objectives The primary outcomes at 18 months follow-up are: Superiority: The proportion of patients reduced to ≤50% of their baseline biologic dose. Equivalence: Disease activity (rheumatoid arthritis [RA] and psoriatic arthritis [PsA]: Disease Activity Score28-C-Reactive Protein [DAS28-CRP] and axial spondyloarthritis [axSpA]: Ankylosing Spondylitis Disease Activity Score [ASDAS]). Methods The BIODOPT trial was a randomised, open-label, equivalence trial (EudraCT 2017-001970-41). Eligible patients were adults with RA, PsA, or axSpA in LDA on stable biologic doses during ≥12 months. The randomisation ratio was 2:1 (tapering:continuation) stratified by diagnosis, centre, and repeated biologic failures. In the tapering group, the biologic dosing interval was prolonged by 25% every four months until flare or discontinuation. The continuation group was kept on their baseline biologic dosing interval; however, a small increase was allowed (as usual practise) if requested by the patient. The sample size calculation was based on a pre-defined equivalence margin of ±0.5 disease activity points (1.2] or ASDAS [>1.1]) yielding a power of 87% for 180 enrolled patients. All analyses were based on the intention-to-treat population. Continuous outcomes were analysed with repeated-measures linear mixed-effects models with group, diagnosis, centre, repeated biologic failures, time point, and the interaction between group and time as fixed factors and the baseline value of the relevant variable as a covariate. Categorical outcomes were analysed using logistic regression with missing data imputed as trial failures. Results Between May, 2018, and March, 2020, 142 patients were enrolled of which 95 were randomised to tapering and 47 to continuation; inclusion was closed in April 2020 due to national implications of the coronavirus pandemic. At 18 months, significantly more patients in the tapering group (35 patients [(37%]) achieved a significant reduction in their biologic dose (≥50%) compared to the continuation group (one patient [2%]), absolute risk difference (RD) 35%, 95%CI: 24% to 45%, p<0.0001, Table 1. Furthermore, disease activity at 18 months was within the equivalence margins of ±0.5, mean difference between groups 0.08, 95%CI: -0.12 to 0.29; Table 1 and Figure 1. Flares were more frequent in the tapering group (39 [41%] vs 10 [21%], RD 0.20, 95%CI: 0.04 to 0.35, p=0.011) but managed with rescue therapy (e.g. biologic dose escalation or glucocorticoids) as only one patient (1%) in the tapering group and three patients (6%) in the continuation group lost therapeutic response and were switched to another biological agent. Table 1. Comparison at 18 months in the ITT population Outcome Tapering group N = 95 Continuation group N = 47 Group difference (95%CI ) p-value Primary outcome: Biologics reduced to ≤50%, n (%) 35 (37%) 1 (2%) 0.35 (0.24 to 0.45) <0.001 Disease activity, LSMeans (SE) 1.84 (0.15) 1.75 (0.16) 0.08 (-0.12 to 0.29) 0.428 Key secondary outcomes: Remission 1 , n (%) 63 (66%) 33 (70%) -0.04 (-0.20 to 0.12) 0.637 Low disease activity 2 , n (%) 79 (83%) 41 (87%) -0.04 (-0.16 to 0.08) 0.511 Flares 3 , n (%) 39 (41%) 10 (21%) 0.20 (0.04 to 0.35) 0.011 N: number, CI: confidence interval, LSMeans: Least squares means, SE: Standard error. 1 : RA or PsA: DAS28-CRP <2.6. AxSpA: ASDAS <1.3. 2 : RA or PsA: DAS28-CRP <3.2. AxSpA: ASDAS <2.1. 3 : RA or PsA: ΔDAS28-CRP >1.2 or ΔDAS28-CRP >0.6 AND current DAS28-CRP ≥3.2. AxSpA: inflammatory back pain AND ΔASDAS ≥0.9 and/or ≥1 swollen joint. Conclusion Across IA conditions, a significant reduction of biologic dose is possible with disease activity-guided tapering while maintaining a similar disease activity state compared to continuation of biologic as usual care. Acknowledgements The authors thank patients, research personnel, and the patient research partners for their contribution to the BIODOPT trial, data manager JHW for technical support and for uploading the concealed allocation sequence, and CCH for data management. The Parker Institute, Bispebjerg and Frederiksberg Hospital is supported by a core grant from the Oak Foundation (OCAY-18-774-OFIL). Disclosure of Interests Line Uhrenholt Speakers bureau: Abbvie, Eli Lilly, Janssen, and Novartis, Robin Christensen: None declared, Lene Dreyer Speakers bureau: Eli Lilly, Galderma and Janssen, Grant/research support from: BMS (outside the present work), Ellen-Margrethe Hauge Speakers bureau: AbbVie, Sanofi, Sobi, and SynACT Pharma, Grant/research support from: Roche, Novartis, and Novo Nordic Foundation (outside the present work), Annette Schlemmer Speakers bureau: Eli Lilly, Anne Gitte Loft Speakers bureau: AbbVie, MSD, Novartis and UCB, Consultant of: Eli-Lilly, Janssen-Cilag, MSD, Novartis, and UCB, Mads Nyhuus Bendix Rasch Speakers bureau: Sobi, Hans Christian Horn: None declared, Katrine Gade: None declared, Peter C. Taylor Consultant of: AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Inc, Roche, and Sanofi, Grant/research support from: Celgene, and Galapagos (outside the present work), Salome Kristensen: None declared.