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Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial

2017; Elsevier BV; Volume: 390; Issue: 10093 Linguagem: Inglês

10.1016/s0140-6736(17)31618-5

1474-547X

Roy Fleischmann, Eduardo Mysler, Stephen Hall, Alan Kivitz, Robert J. Moots, Zhen Luo, Ryan DeMasi, Koshika Soma, Richard Zhang, Liza Takiya, Svitlana Tatulych, Christopher F. Mojcik, Sriram Krishnaswami, Sujatha Menon, Josef S Smolen, Luthando Adams, Mahmood M. T. M. Ally, Maria C du Plooy, Ingrid Louw, Savithree Nayiager, Christoffel B Nel, Debra Nel, Helmuth Reuter, Ahmed S Soloman, Catherine Elizabeth Spargo, Stephen Hall, Maureen Rischmueller, S Sharma, Robert Will, Peter Youssef, Caroline Arroyo, Rosario P Baes, Roger B Dulos, Llewellyn T. Hao, A Lanzon, Juan Javier Lichauco, Jill H Mangubat, Edgar Ramiterre, Bernadette Heizel M. Reyes, Perry Pua Tan, Jung‐Yoon Choe, Young Mo Kang, Seong‐Ryul Kwon, Sang‐Heon Lee, Shin‐Seok Lee, Dae‐Hyun Yoo, Hsiao-Yi Lin, Shue‐Fen Luo, Shih-Tzu Tsai, Wen‐Chan Tsai, Jui-Cheng Tseng, James Cheng‐Chung Wei, Paijit Asavatanabodee, Kanokrat Nantiruj, Surasak Nilganuwong, Parichat Uea‐Areewongsa, Ljubinka Bozic Majstorovic, Suada Mulic Bacic, Anastas Batalov, Gabriela Georgieva-Slavcheva, Mariyana Mihailova, Nikolay G Nikolov, Dimitar P Penev, Yuliy A Spasov, Krasimira Stanimirova, Stoyan Todorov, Antoaneta A. Toncheva, Nadezhda Yordanova, Zdenka Mosterova, Libor Novosád, Leona Procházková, Helena Stehlikova, Zuzana Stejfova, Natalia Kiseleva, Lea Pank, Triin Savi, Balbir-Gurman Alexandra, Howard Amital, Dror Mevorach, Itzhak Rosner, Anna Mihailova, Evija Stumbra-Stumberga, Vida Basijokiene, Virginija Lietuvininkiene, Dalia Unikienė, Jan Brzezicki, Anna Dudek, Maria B Glowacka-Kulesz, Barbara Grabowicz-Wasko, Sabina Hajduk-Kubacka, Joanna Hilt, Paweł Hrycaj, Sławomir Jeka, Renata Kolasa, Marek Krogulec, Hanna Mastalerz, Anna Olak-Popko, E Owczarek, Zofia Ruzga, Alina Walczak, Codrina Ancuţa, I. Ancuta, Andra Bălănescu, F. Berghea, S. Bojin, Mihaela A Ianuli Arvunescu, Ruxandra Ionescu, Eugenia Mociran, Mariana Pavel, Simona Rednic, Adriana Voie, Carmen M Zainea, О. В. Бугрова, Dëmin Aa, О. Б. Ершова, Inna A Gavrisheva, D. G. Krechikova, Gennady V Kuropatkin, И. М. Марусенко, I. V. Menshikova, С М Носков, А. П. Ребров, С. А. Смакотина, S. S. Yakushin, Evgeny Zhilyaev, Juan Jose Amarelo Ramos, Francisco Javier Blanco Garcia, Antonio Fernández‐Nebro, Silvia Pérez, Juan Miguel Sánchez Bursón, Raimón Sanmartí, Şebnem Ataman, Sami Hizmetli, Ömer Kuru, Karen M. Douglas, Paul Emery, Robert J. Moots, Voon H Ong, Thomas Sheeran, R. Faraawi, Clode Lessard, Carlos Abud‐Mendoza, Hilario Ernesto Avila-Armengol, Francisco I Avila Zapata, Fedra Irazoque-Palazuelos, Marco Antonio Maradiaga Cecena, César Pacheco‐Tena, Juan C. Rizo‐Rodríguez, Isaura M Rodriguez-Torres, Jacob Aelion, Barbara A Caciolo, James M Calmes, P. Chatpar, Nimesh Dayal, Alex De Jesus, Ara Dikranian, Erdal Diri, Michael Fairfax, Ira F Fenton, Roy Fleischmann, Norman Gaylis, Ronald L George, D Halter, Paul Hernandez, Susan A Hole, Antony Hou, J P Huff, Suzanne Kafaja, A C Kennedy, H. Mark Kenney, Steven C. Kimmel, Brian S Kirby, Alan Kivitz, Clarence W. Legerton, Stephen M. Lindsey, Jyothi Mallepalli, Steven D Mathews, Samy Metyas, Wesley Mizutani, Sabeen Najam, Joao M Nascimento, Shirley Pang, Rakesh Patel, Jeffrey E. Poiley, Carlos E. Ramírez, Riteesha Reddy, Qaiser Rehman, William Schnitz, Craig D. Scoville, William Shergy, Joel C. Silverfield, Atul Singhal, Yvonne R Smallwood-Sherrer, S Songcharoen, Michael T. Stack, William Stohl, Tien-I K Su, James Udell, Saleem Waraich, Charles E Weidmann, Nathan Wei, Craig W. Wiesenhutter, Anne E. Winkler, Karen E Zagar, Alberto Berman, Eduardo Mysler, Rodolfo A Pardo Hidalgo, Horacio O Venarotti, I. A. G. Sariego, Renato E Jimenez Calabresse, Juan Ignacio Vargas Ruiz-Tagle, Luis Fernando M Bellatin Vargas, Alfredo E Berrocal, Manuel Gustavo León Portocarrero, Felix Jesus, Romero Pena,

Systemic Lupus Erythematosus Research

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. Methods ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. Findings 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Interpretation Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Funding Pfizer Inc.