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Lancet. 2017 Jul 29;390(10093):457-468. doi: 10.1016/S0140-6736(17)31618-5. Epub 2017 Jun 16.

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.

Collaborators (201)

Adams L, Ally MM, du Plooy MC, Louw IC, Nayiager S, Nel CB, Nel D, Reuter H, Soloman AS, Spargo CE, Hall S, Rischmueller M, Sharma SD, Will RK, Youssef PP, Arroyo C, Baes RP, Dulos RB, Hao LT, Lanzon AE, Lichauco JJT, Mangubat JH, Ramiterre EB, Reyes BHM, Tan PP, Choe JY, Kang YM, Kwon SR, Lee SH, Lee SS, Yoo DH, Lin HY, Luo SF, Tsai ST, Tsai WC, Tseng JC, Wei CC, Asavatanabodee P, Nantiruj K, Nilganuwong S, Uea-Areewongsa P, Majstorovic LB, Bacic SM, Batalov AZ, Georgieva-Slavcheva G, Mihailova M, Nikolov NG, Penev DP, Spasov YA, Stanimirova K, Todorov S, Toncheva AR, Yordanova N, Mosterova Z, Novosad L, Prochazkova L, Stehlikova H, Stejfova Z, Kiseleva N, Pank L, Savi T, Alexandra BG, Amital H, Mevorach D, Rosner IA, Mihailova A, Stumbra-Stumberga E, Basijokiene V, Lietuvininkiene V, Unikiene D, Brzezicki J, Dudek AM, Glowacka-Kulesz MB, Grabowicz-Wasko B, Hajduk-Kubacka S, Hilt J, Hrycaj P, Jeka S, Kolasa R, Krogulec M, Mastalerz H, Olak-Popko A, Owczarek E, Ruzga Z, Walczak A, Ancuta CI, Ancuta I, Balanescu AR, Berghea F, Bojin S, Arvunescu MAI, Ionescu RM, Mociran E, Pavel M, Rednic S, Voie A, Zainea CM, Bugrova OV, Demin A, Ershova OB, Gavrisheva IA, Krechikova DG, Kuropatkin GV, Marusenko IM, Menshikova IV, Noskov SM, Rebrov AP, Smakotina SA, Yakushin SS, Zhilyaev E, Ramos JJA, Garcia FJB, Nebro AF, Esteban SP, Burson JMS, Sala RS, Ataman S, Hizmetli S, Kuru O, Douglas KM, Emery P, Moots RJ, Ong VH, Sheeran TP, Faraawi RY, Lessard C, Mendoza CA, Avila-Armengol HE, Zapata FIA, Irazoque-Palazuelos FC, Cecena MAM, Pacheco-Tena CF, Rizo-Rodriguez JC, Rodriguez-Torres IM, Aelion JA, Caciolo BA, Calmes JM, Chatpar P, Dayal N, De Jesus A, Dikranian AH, Diri E, Fairfax MJ, Fenton IF, Fleischmann RM, Gaylis NB, George RL, Halter DG, Hernandez P, Hole SA, Hou AC, Huff JP, Kafaja S, Kennedy AC, Kenney H, Kimmel SC, Kirby BS, Kivitz AJ, Legerton CW, Lindsey SM, Mallepalli JR, Mathews SD, Metyas SK, Mizutani WT, Najam S, Nascimento JM, Pang SW, Patel RC, Poiley JE, Ramirez CE, Reddy R, Rehman Q, Schnitz WM, Scoville CD, Shergy WJ, Silverfield JC, Singhal AK, Smallwood-Sherrer YR, Songcharoen SN, Stack MT, Stohl W, Su TK, Udell J, Waraich S, Weidmann CE, Wei N, Wiesenhutter CW, Winkler AE, Zagar KE, Berman A, Mysler EF, Hidalgo RAP, Venarotti HO, Sariego IAG, Calabresse REJ, Ruiz-Tagle JIV, Vargas LFMB, Berrocal AE, Portocarrero MGL, Jesus F, Pena R.

Author information

1
University of Texas Southwestern Medical Center and Metroplex Clinical Research Center, Dallas, TX, USA. Electronic address: rfleischmann@arthdocs.com.
2
Organización Médica de Investigación, Buenos Aires, Argentina.
3
Department of Medicine, Monash University, Cabrini Health, Malvern, VIC, Australia.
4
Altoona Center for Clinical Research, Duncansville, PA, USA.
5
Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
6
Pfizer Inc, Shanghai, China.
7
Pfizer Inc, Collegeville, PA, USA.
8
Pfizer Inc, Groton, CT, USA.
9
Pfizer Inc, New York, NY, USA.
10
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.

Abstract

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.

PMID:
28629665
DOI:
10.1016/S0140-6736(17)31618-5
[Indexed for MEDLINE]

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