Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY)
- Maxime Dougados1,
- Karsten Kissel2,
- Tom Sheeran3,
- Paul P Tak4,
- Philip G Conaghan5,
- Emilio Martín Mola6,
- Georg Schett7,
- Howard Amital8,
- Federico Navarro-Sarabia9,
- Antony Hou10,
- Corrado Bernasconi2,
- TWJ Huizinga11
- 1Department of Rheumatology, Cochin Hospital, Paris, France
- 2F Hoffmann-La Roche Ltd, Basel, Switzerland
- 3Cannock Rheumatology Centre, Cannock, UK
- 4Department of Clinical Immunology and Rheumatology, AMC University of Amsterdam, Amsterdam, The Netherlands (GlaxoSmithKline since Jan 2011)
- 5Section of Musculoskeletal Disease, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK
- 6Department of Rheumatology, Universidad Autónoma de Madrid, Madrid, Spain
- 7Department of Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany
- 8Department of Medicine, Sheba Medical Center, Tel-Hashomer, Israel
- 9Rheumatology Department, Hospital Universitario Virgen Macarena, Sevilla, Spain
- 10Inland Rheumatology Clinical Trials, Upland, California, USA
- 11Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
- Correspondence to Maxime Dougados, Department of Rheumatology, APHP, Cochin Hospital, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France;
Contributors MD, KK, PPT, PGC, EMM, GS, CB and TWJH designed the study and analysed and interpreted the data. MD, TS, PPT, PGC, EMM, GS, HA, FNS, AH and TWJH along with other investigators were involved in generating the data at their clinical research sites. All authors were involved in writing the manuscript and approved it.
- Accepted 7 March 2012
- Published Online First 5 May 2012
Objective In patients with active rheumatoid arthritis (RA) despite methotrexate, to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy.
Methods Double-blind, 2-year study in which adults with active RA (DAS28 >4.4) despite methotrexate were randomly assigned either to continue methotrexate with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO). The primary endpoint was the DAS28–erythrocyte sedimentation rate (ESR) remission rate at week 24. Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage.
Results Of 556 randomly assigned patients, 512 (92%) completed 24 weeks. DAS28–ESR remission rates were 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8% (TCZ+MTX) and 70.3%/40.2%/25.4%/5.1% (TCZ+PBO; differences not significant). A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%). Radiographic progression was small and not different between groups (Genant–Sharp score progression ≤ smallest detectable change in 91% (TCZ+MTX) and 87% (TCZ+PBO)). Rates per 100 patient-years of serious adverse events and serious infections were 21 and six, respectively, for TCZ+MTX and 18 and six, respectively, for TCZ+PBO. Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO patients, respectively.
Conclusion No clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed. The combination was more commonly associated with transaminase increases. Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients.
Funding The ACT-RAY study was funded by F Hoffmann-La Roche Ltd, Basel, Switzerland (Roche). Roche was involved in developing the study design, in the analysis and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication, through Roche employees, contractors and funding of third party support such as contract research organisations. All these activities happened in close collaboration with the external members of the scientific steering committee.
Competing interests MD has participated in symposia and advisory boards organised by Roche and received consulting fees and his department has received research grants from Roche for conducting clinical trials and/or clinical epidemiological studies. KK is an employee of F Hoffmann-La Roche. TS received consulting fees and research grants from Roche. PPT's department has received Roche funds as grants and consulting fees or honorarium. PPT is an employee of and has stock/stock options for GlaxoSmithKline. PGC has received research grants from Centocor Inc and Roche and has been a speaker for Astra Zeneca, Bioberica, Bristol-Myers Squibb, Centocor Inc, Merck Pharmaceuticals, Novartis Pharmaceutical Corporation, Pfizer and Roche. EMM has received consulting fees and been an educational lecturer for Abbott Immunology, Roche MSD, Pfizer and UCB. GS received consulting fees from Roche. FNS has consulted for Pfizer, UCB, Abbott and Roche and has been a speaker for Roche, Pfizer, Abbott and MSD, and his department has received research grants from Roche, Pfizer and Abbott. AH has no competing interests to report. CB is a contractor of F Hoffmann-La Roche. TWJH has received consulting fees and has been a speaker for Abbott Immunology, Axis Shield Diagnostics, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Roche, Novartis Pharmaceuticals, Schering-Plough, UCB and Wyeth-Pfizer.
Ethics approval The study was approved by the appropriate institutional review boards/ethics committees.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published Online First. The link to the supplementary data has been corrected.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode