Towards the Lowest Efficacious Dose: Results From a Multicenter Noninferiority Randomized Open‐Label Controlled Trial Assessing Tocilizumab or Abatacept Injection Spacing in Rheumatoid Arthritis in Remission

Objective We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission. Methods This multicenter open‐label noninferiority (NI) randomize...

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Published in:	Arthritis & rheumatology (Hoboken, N.J.) Vol. 76; no. 4; pp. 541 - 552
Main Authors:	Dieudé, Philippe, Giboin, Caroline, Schaeverbeke, Thierry, Constantin, Arnaud, Dernis, Emmanuelle, Salmon, Jean‐Hugues, Gottenberg, Jacques‐Eric, Pertuiset, Edouard, Berenbaum, Francis, Alcaix, Didier, Monnier, Agnès, Piroth, Christine, Lioté, Frédéric, Gaujoux‐Viala, Cécile, Tubach, Florence, Fautrel, Bruno, Desmoulins, F., Mamoune, A., Brousseau, S., Saraux, A., Cornec, D., Tanguy, M.L., Varache, S., Marhadour, T., Kergoulay, C., Clarysse, A., Frayssac, T., Mathieu, S., Maillefert, J.F., Chollet, C., Bessonnet, L., Varin, S., Andre, V., Puecha, X., Rouanet, E., Piot, J.M., Trijau, S., Gouilloux, S., Barrat, S., Guillardeau, A., Ravet, E., Segard, V., Cantagrel, A., Mazieres, B., Jammard, B., Thuillez, D., Peyr, O., Ora, J., Ea, H.K., Frazier, A., Jelin, G., Zylberman‐Yona, H., Palazzo, E., Batard, K., Thomas, T., Locrelle, H., Griffoul, I., Mammou, S., Lepilliez, M.L., Flaisler, F., Erny, F., Gareau, B., Loiseau‐Peres, S., Bloino‐Ayoul, C., Mot, C., Rio, S., Damade, R., Aprelon, S., Lambrecht, J., Durand, E., Cerloth, L., Gaudron, C.L., Sulpice, M., Charbonnier, F., Saadia‐Tounsi, H., Maouel, S., Aboulola, Y., Le Tiec, C., Bensasson, G., Cogulet, V., Poullaouec, C., Stephan, F., Fagnoni, P., Lehmann, A., Bolle, D., Caturla, L., Houet, S., Putrus, R., Flet, L., Mordini, J., Darricau, B., Page, T., Girault, F., Blandin, M., Maillard, C., Tollec, S., Hermelin, I., Roge, P., Gerard, M., Ligier, C.
Format:	Journal Article
Language:	English
Published:	Boston, USA Wiley Periodicals, Inc 01-04-2024 Wiley Subscription Services, Inc
Subjects:	Arm Arthritis Autoimmune diseases Damage Injection Joint diseases Labels Maintenance Patients Remission Remission (Medicine) Rheumatoid arthritis Tapering
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Summary:	Objective We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission. Methods This multicenter open‐label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M‐arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S‐arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2‐year follow‐up analyzed per protocol with a linear mixed‐effects model, evaluated by an NI test based on the one‐sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression. Results Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S‐arm and 112 in M‐arm). At the end of follow‐up, 16.2% of the patients in the S‐arm could discontinue their biologic disease‐modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10–0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0–55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI −6.7 to 34.4). Conclusion The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy.
Bibliography:	The study was sponsored by the Delegation for Clinical Research and Innovation of the AP‐HP. Supported by the French Ministry of Health Programme Hospitalier de Recherche Clinique (grant 2011 – AOM11061), which had no role in study design, data collection, data analysis, data interpretation, writing of the report, or any right in the decision of publication. http://onlinelibrary.wiley.com/doi/10.1002/art.42752 https://onlinelibrary.wiley.com/doi/10.1002/art.42752 ClinicalTrials.gov identifier: NCT01557374. Additional supplementary information cited in this article can be found online in the Supporting Information section Author disclosures are available at . ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	2326-5191 2326-5205
DOI:	10.1002/art.42752