Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial
Open accessAbstract
Background Roughly a third of patients with rheumatoid arthritis treated with biological treatments receive them as monotherapy. Tocilizumab--an inhibitor of interleukin 6 receptor signalling--has been studied as monotherapy in several clinical trials. We assessed the efficacy and safety of tocilizumab monotherapy compared with adalimumab monotherapy for patients with rheumatoid arthritis.Methods We did this randomised, double-blind, parallel-group, phase 4 superiority study in 76 centres in 15 countries in North and South America, Australasia, and Europe. We enrolled patients who were aged at least 18 years, had severe rheumatoid arthritis for 6 months or more, and were intolerant to methotrexate or were inappropriate for continued methotrexate treatment. Patients were randomly assigned (1:1; block size of four) to receive tocilizumab 8 mg per kg bodyweight intravenously every 4 weeks plus placebo subcutaneously every 2 weeks or adalimumab 40 mg subcutaneously every 2 weeks plus placebo intravenously every 4 weeks for 24 weeks. Investigators, patients, and sponsor personnel were masked to assignment. The primary endpoint was change in disease activity score using 28 joints (DAS28) from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01119859.Findings We screened 452 patients and enrolled 326 patients. The intention-to-treat population contained 325 patients (163 assigned to tocilizumab, 162 assigned to adalimumab). Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group (-3·3) than in the adalimumab group (-1·8) patients (difference -1·5, 95% CI -1·8 to -1·1; p<0·0001). 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the tocilizumab group had serious adverse events. More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts.Interpretation Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate was deemed inappropriate. The adverse event profiles of tocilizumab and adalimumab were consistent with previous findings.Funding F Hoffmann-La Roche.
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Intravenous and subcutaneous tocilizumab have been approved for the treatment of adults with moderate to severe active rheumatoid arthritis.
“Intravenous and s.c.TCZ have been approved for the treatment of adults with moderate to severe active RA.111,112”
From Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy (2020) · cites this paper as [111]
Cites
(1992) · PubMed · Cited by 33,716 · see citing works
The MOS 36-ltem Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection
Ware, J. E., & Sherbourne, C. D. (1992) · Medical Care · doi:10.1097/00005650-199206000-00002 · Cited by 30,033 · see citing works
Grundy, S. M., Bilheimer, D. W., Chait, A., Clark, L. T., Denke, M. A., Havel, R. J., Hazzard, W. R., Hulley, S. B., Hunninghake, D. B., Kreisberg, R. A., et al. (1993) · JAMA · doi:10.1001/jama.269.23.3015 · Cited by 27,944 · see citing works
Expert Panel on Detection, E. (2001) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.285.19.2486 · Cited by 26,011 · see citing works
Prevoo, M. L. L., Hof, M. A. V., Kuper, H. H., Leeuwen, M. A. V., van de Putte, L. B. A., & van Riel, P. L. C. M. (1995) · Arthritis & Rheumatism · doi:10.1002/art.1780380107 · Cited by 6,250 · see citing works
Measurement of patient outcome in arthritis
Fries, J. F., Spitz, P. W., Kraines, R. G., & Holman, H. R. (1980) · Arthritis & Rheumatism · doi:10.1002/art.1780230202 · Cited by 4,373 · see citing works
American college of rheumatology preliminary definition of improvement in rheumatoid arthritis
Felson, D. T., Anderson, J. J., Boers, M., Bombardier, C., Fürst, D. E., Goldsmith, C. H., Katz, L. M. G., Lightfoot, R. W., Paulus, H. E., Strand, V., et al. (1995) · Arthritis & Rheumatism · doi:10.1002/art.1780380602 · Cited by 2,825 · see citing works
Smolen, J. S., Beaulieu, A. D., Rubbert‐Roth, A., Ramos-Remus, C., Rovensky, J., Alecock, E., WOODWORTH, T. G., & Alten, R. (2008) · The Lancet · doi:10.1016/s0140-6736(08)60453-5 · Cited by 1,399 · see citing works
Self-citationThe dimensions of health outcomes: the health assessment questionnaire, disability and pain scales.
Fries, J. F., Spitz, P. W., & Young, D. Y. (1982) · PubMed · Cited by 1,312 · see citing works
Emery, P., Keystone, E., Tony, H. P., Cantagrel, A., van Vollenhoven, R., Sanchez, A., Alecock, E., Lee, J., & Kremer, J. (2008) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.092932 · Cited by 1,104 · see citing works
Self-citationGenovese, M. C., McKay, J. D., Nasonov, E. L., Mysler, E. F., da Silva, N. A., Alecock, E., Woodworth, T., & Gomez‐Reino, J. J. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23940 · Cited by 855 · see citing works
Jones, G., Sebba, A., Gu, J., Lowenstein, M. B., Calvo, A., Gomez-Reino, J. J., Siri, D. A., Tomšič, M., Alecock, E., Woodworth, T., et al. (2010) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.105197 · Cited by 797 · see citing works
Felson, D. T., Smolen, J. S., Wells, G. A., Zhang, B., van Tuyl, L. H. D., Funovits, J., Aletaha, D., Allaart, C. F., Bathon, J. M., Bombardieri, S., et al. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2011.149765 · Cited by 771 · see citing works
Self-citationNishimoto, N., Hashimoto, J., Miyasaka, N., Yamamoto, K., Kawai, S., Takeuchi, T., Murata, N., van der Heijde, D. M. F. M., & Kishimoto, T. (2007) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2006.068064 · Cited by 727 · see citing works
Salliot, C., & van der Heijde, D. (2008) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.093690 · Cited by 675 · see citing works
van de Putte, L. B. A., Atkins, C., Malaise, M., Sany, J., Russell, A. S., van Riel, P. L. C. M., Settas, L., Bijlsma, J. W. J., TODESCO, S., Dougados, M., et al. (2004) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2003.013052 · Cited by 619 · see citing works
Self-citationTak, P. P., Smeets, T. J. M., Daha, M. R., Kluin, P. M., Meijers, K. A. E., Brand, R., Meinders, A. E., & Breedveld, F. C. (1997) · Arthritis & Rheumatism · doi:10.1002/art.1780400206 · Cited by 549 · see citing works
Cella, D. F., Yount, S., Sorensen, M., Chartash, E., Sengupta, N., & Grober, J. (2005) · PubMed · Cited by 501 · see citing works
Kremer, J. M., Blanco, R., Brzosko, M., Burgos‐Vargas, R., Halland, A.-M., Vernon, E., Ambs, P., & Fleischmann, R. (2010) · Arthritis & Rheumatism · doi:10.1002/art.30158 · Cited by 405 · see citing works
Fleischmann, R., Cutolo, M., Genovese, M. C., et al. (2011) · Arthritis & Rheumatism · doi:10.1002/art.33383 · Cited by 376 · see citing works
Nishimoto, N., Miyasaka, N., Yamamoto, K., Kawai, S., Takeuchi, T., Azuma, J., & Kishimoto, T. (2008) · Modern Rheumatology · doi:10.1007/s10165-008-0125-1 · Cited by 364 · see citing works
Askling, J., Fored, C. M., Brandt, L., et al. (2007) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2006.062760 · Cited by 334 · see citing works
Mihara, M., Kasutani, K., Okazaki, M., Nakamura, A., Kawai, S., Sugimoto, M., Matsumoto, Y., & Ohsugi, Y. (2005) · International Immunopharmacology · doi:10.1016/j.intimp.2005.05.010 · Cited by 330 · see citing works
Dougados, M., Kissel, K., Sheeran, T. P., Tak, P. P., Conaghan, P. G., Mola, E. M., Schett, G. A., Amital, H., Navarro-Sarabia, F., Hou, A., et al. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-201282 · Cited by 288 · see citing works
Nishimoto, N., Miyasaka, N., Yamamoto, K., et al. (2009) · Modern Rheumatology · doi:10.3109/s10165-008-0125-1 · Cited by 273 · see citing works
Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor
Dayer, J., & Choy, E. (2009) · Rheumatology · doi:10.1093/rheumatology/kep329 · Cited by 270 · see citing works
Heiberg, M. S., Koldingsnes, W., Mikkelsen, K., Rødevand, E., Kaufmann, C., Mowinckel, P., & Kvien, T. K. (2008) · Arthritis Care & Research · doi:10.1002/art.23333 · Cited by 256 · see citing works
Soliman, M. M., Ashcroft, D. M., Watson, K. D., et al. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.139774 · Cited by 217 · see citing works
Humanized Antihuman IL-6 Receptor Antibody, Tocilizumab
Nishimoto, N., & Kishimoto, T. (2007) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-73259-4_7 · Cited by 185 · see citing works
Listing, J., Strangfeld, A., Rau, R., Kekow, J., Gromnica‐Ihle, E., Klopsch, T., Demary, W., Burmester, G. R., & Zink, A. (2006) · Arthritis Research & Therapy · doi:10.1186/ar1933 · Cited by 181 · see citing works
Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries
Xavier Mariette, A., Gottenberg, J., Ravaud, P., et al. (2010) · Lara D. Veeken · doi:10.1093/rheumatology/keq368 · Cited by 173 · see citing works
van Riel, P. L. C. M., van Gestel, A. M., & van de Putte, L. B. A. (1996) · Lara D. Veeken · doi:10.1093/rheumatology/35.suppl_2.4 · Cited by 120 · see citing works
Yazıcı, Y., Shi, N., & John, A. K. (2008) · PubMed · Cited by 96 · see citing works
Cannon, G. W., Mikuls, T. R., Hayden, C. L., Ying, J., Curtis, J. R., Reimold, A. M., Caplan, L., Kerr, G. S., Richards, J. S., Johnson, D. S., et al. (2011) · Arthritis Care & Research · doi:10.1002/acr.20629 · Cited by 93 · see citing works
Gottenberg, J., Dayer, J., Lukas, C., Ducot, B., Chiocchia, G., Cantagrel, A. G., Saraux, A., Roux‐Lombard, P., & Xavier Mariette, A. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-200975 · Cited by 91 · see citing works
de Thurah, A. L., Nørgaard, M., Harder, I., & Stengaard‐Pedersen, K. (2009) · Rheumatology International · doi:10.1007/s00296-009-1160-8 · Cited by 83 · see citing works
Lee, S. H., Chang, H., Yazıcı, Y., et al. (2009) · The Journal of Rheumatology · doi:10.3899/jrheum.080889 · Cited by 63 · see citing works
Grijalva, C. G., Kaltenbach, L. A., Arbogast, P. G., et al. (2010) · Arthritis Care & Research · doi:10.1002/acr.20087 · Cited by 32 · see citing works
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Schmidt-Arras, D., & Rose-John, S. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.02.004 · Cited by 881 · see citing works
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Kang, S., Tanaka, T., Narazaki, M., & Kishimoto, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.026 · Cited by 870 · see citing works
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Rose-John, S., Winthrop, K., & Calabrese, L. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.83 · Cited by 424 · see citing works
Tocilizumab: A review in rheumatoid arthritis
Scott, L. J. (2017) · Drugs · doi:10.1007/s40265-017-0829-7 · Cited by 419 · see citing works
Haanen, J., Ernstoff, M. S., Wang, Y., Menzies, A. M., Puzanov, I., Grivas, P., Larkin, J., Peters, S., Thompson, J. A., & Obeid, M. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.03.285 · Cited by 222 · see citing works
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Burmester, G. R., Rigby, W. F., van Vollenhoven, R. F., Kay, J., Rubbert-Roth, A., Kelman, A., Dimonaco, S., & Mitchell, N. (2016) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2015-207628 · Cited by 194 · see citing works
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Kishimoto, T., & Kang, S. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101220-023458 · Cited by 140 · see citing works
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Monteleone, G., Moscardelli, A., Colella, A., Marafini, I., & Salvatori, S. (2023) · Autoimmunity Reviews · doi:10.1016/j.autrev.2023.103410 · Cited by 105 · see citing works
Mallio, C. A., Napolitano, A., Castiello, G., Giordano, F. M., D'Alessio, P., Iozzino, M., Sun, Y., Angeletti, S., Russano, M., Santini, D., et al. (2021) · Cancers · doi:10.3390/cancers13040652 · Cited by 30 · see citing works
- Authors
- Gabay, C., Emery, P., van Vollenhoven, R., Dikranian, A., Alten, R., Pavelka, K., Klearman, M., Musselman, D., Agarwal, S., Green, J., & Kavanaugh, A.
- Affiliations
- University Hospital of Geneva (CH)
- University of Leeds (GB)
- Genentech (US)
- Roche (United Kingdom) (GB)
- University of California San Diego (US)
- Corresponding author
- Kavanaugh, Arthur
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 381
- Issue
- 9877
- Pages
- 1541-1550
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2102207725
- Cited by
- 672
- References
- 38
- Citations by year
- 2026: 16 · 2025: 30 · 2024: 36 · 2023: 33 · 2022: 37 · 2021: 58 · 2020: 64 · 2019: 52 · 2018: 66 · 2017: 63 · 2016: 58 · 2015: 63 · 2014: 66 · 2013: 28 · 2012: 1
- FWCI
- 57.95
- Type
- journal article
- Language
- en
- Open access
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Roche
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Keywords
- rheumatoid arthritis, tocilizumab, adalimumab, monotherapy, IL-6 receptor inhibitor, TNF inhibitor, DAS28, disease activity, methotrexate intolerance, adverse events, LDL cholesterol, alanine aminotransferase, drug safety, biologic therapy comparison
- MeSH terms
- Adalimumab, Adult, Aged, Arthritis, Rheumatoid, Double-Blind Method, Female, Humans, Male, Middle Aged, Antirheumatic Agents, Antibodies, Monoclonal, Humanized
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