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.
Original language | English |
---|---|
Pages (from-to) | 457-468 |
Number of pages | 12 |
Journal | The Lancet |
Volume | 390 |
Issue number | 10093 |
DOIs | |
State | Published - 29 Jul 2017 |
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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. / Fleischmann, Roy; Mysler, Eduardo; Hall, Stephen; Kivitz, Alan J.; Moots, Robert J.; Luo, Zhen; DeMasi, Ryan; Soma, Koshika; Zhang, Richard; Takiya, Liza; Tatulych, Svitlana; Mojcik, Christopher; Krishnaswami, Sriram; Menon, Sujatha; Smolen, Josef S.; Adams, Luthando; Ally, Mahmood M.; du Plooy, Maria C.; Louw, Ingrid C.; Nayiager, Savithree; Nel, Christoffel B.; Nel, Debra; Reuter, Helmuth; Soloman, Ahmed S.; Spargo, Catherine E.; Hall, Stephen; Rischmueller, Maureen; Sharma, Shunil D.; Will, Robert K.; Youssef, Peter P.; Arroyo, Caroline; Baes, Rosario P.; Dulos, Roger B.; Hao, Llewellyn T.; Lanzon, Allan E.; Lichauco, Juan Javier T.; Mangubat, Jill H.; Ramiterre, Edgar B.; Reyes, Bernadette Heizel M.; Tan, Perry P.; Choe, Jung Yoon; Kang, Young Mo; Kwon, Seong Ryul; Lee, Sang Heon; Lee, Shin Seok; Yoo, Dae Hyun; Lin, Hsiao Yi; Luo, Shue Fen; Tsai, Shih Tzu; Tsai, Wen Chan; Tseng, Jui Cheng; Wei, Cheng Chung C.; Asavatanabodee, Paijit; Nantiruj, Kanokrat; Nilganuwong, Surasak; Uea-Areewongsa, Parichat; Majstorovic, Ljubinka Bozic; Bacic, Suada Mulic; Batalov, Anastas Z.; Georgieva-Slavcheva, Gabriela; Mihailova, Mariyana; Nikolov, Nikolay G.; Penev, Dimitar P.; Spasov, Yuliy A.; Stanimirova, Krasimira; Todorov, Stoyan; Toncheva, Antoaneta R.; Yordanova, Nadezhda; Mosterova, Zdenka; Novosad, Libor; Prochazkova, Leona; Stehlikova, Helena; Stejfova, Zuzana; Kiseleva, Natalia; Pank, Lea; Savi, Triin; Alexandra, Balbir Gurman; Amital, Howard; Mevorach, Dror; Rosner, Itzhak A.; Mihailova, Anna; Stumbra-Stumberga, Evija; Basijokiene, Vida; Lietuvininkiene, Virginija; Unikiene, Dalia; Brzezicki, Jan; Dudek, Anna M.; Glowacka-Kulesz, Maria B.; Grabowicz-Wasko, Barbara; Hajduk-Kubacka, Sabina; Hilt, Joanna; Hrycaj, Pawel; Jeka, Slawomir; Kolasa, Renata; Krogulec, Marek; Mastalerz, Hanna; Olak-Popko, Anna; Owczarek, Elzbieta; Ruzga, Zofia; Walczak, Alina; Ancuta, Codrina I.; Ancuta, Ioan; Balanescu, Andra R.; Berghea, Florian; Bojin, Silvia; Arvunescu, Mihaela A.Ianuli; Ionescu, Ruxandra M.; Mociran, Eugenia; Pavel, Mariana; Rednic, Simona; Voie, Adriana; Zainea, Carmen M.; Bugrova, Olga V.; Demin, Alexander; Ershova, Olga B.; Gavrisheva, Inna A.; Krechikova, Diana G.; Kuropatkin, Gennady V.; Marusenko, Irina M.; Menshikova, Irina V.; Noskov, Sergey M.; Rebrov, Andrey P.; Smakotina, Svetlana A.; Yakushin, Sergey S.; Zhilyaev, Evgeny; Ramos, Juan Jose Amarelo; Garcia, Francisco Javier Blanco; Nebro, Antonio Fernandez; Esteban, Silvia Perez; Burson, Juan Miguel Sanchez; Sala, Raimon Sanmarti; Ataman, Sebnem; Hizmetli, Sami; Kuru, Omer; Douglas, Karen M.; Emery, Paul; Moots, Robert J.; Ong, Voon H.; Sheeran, Thomas P.; Faraawi, Rafat Y.; Lessard, Clode; Mendoza, Carlos Abud; Avila-Armengol, Hilario Ernesto; Zapata, Francisco I.Avila; Irazoque-Palazuelos, Fedra Consuelo; Cecena, Marco Antonio Maradiaga; Pacheco-Tena, Cesar F.; Rizo-Rodriguez, Juan C.; Rodriguez-Torres, Isaura M.; Aelion, Jacob A.; Caciolo, Barbara A.; Calmes, James M.; Chatpar, Prem; Dayal, Nimesh; De Jesus, Alex; Dikranian, Ara H.; Diri, Erdal; Fairfax, Michael J.; Fenton, Ira F.; Fleischmann, Roy M.; Gaylis, Norman B.; George, Ronald L.; Halter, Dale G.; Hernandez, Paul; Hole, Susan A.; Hou, Antony C.; Huff, John P.; Kafaja, Suzanne; Kennedy, Alastair C.; Kenney, Howard; Kimmel, Steven C.; Kirby, Brian S.; Kivitz, Alan J.; Legerton, Clarence W.; Lindsey, Stephen M.; Mallepalli, Jyothi R.; Mathews, Steven D.; Metyas, Samy K.; Mizutani, Wesley T.; Najam, Sabeen; Nascimento, Joao M.; Pang, Shirley W.; Patel, Rakesh C.; Poiley, Jeffrey E.; Ramirez, Carlos E.; Reddy, Riteesha; Rehman, Qaiser; Schnitz, William M.; Scoville, Craig D.; Shergy, William J.; Silverfield, Joel C.; Singhal, Atul K.; Smallwood-Sherrer, Yvonne R.; Songcharoen, Suthin N.; Stack, Michael T.; Stohl, William; Su, Tien I.K.; Udell, James; Waraich, Saleem; Weidmann, Charles E.; Wei, Nathan; Wiesenhutter, Craig W.; Winkler, Anne E.; Zagar, Karen E.; Berman, Alberto; Mysler, Eduardo F.; Hidalgo, Rodolfo A.Pardo; Venarotti, Horacio O.; Sariego, Irmgadt Annelise Goecke; Calabresse, Renato E.Jimenez; Ruiz-Tagle, Juan Ignacio Vargas; Vargas, Luis Fernando M.Bellatin; Berrocal, Alfredo E.; Portocarrero, Manuel Gustavo Leon; Jesus, Felix; Pena, Romero.
In: The Lancet, Vol. 390, No. 10093, 29.07.2017, p. 457-468.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy)
T2 - a phase 3b/4, double-blind, head-to-head, randomised controlled trial
AU - Fleischmann, Roy
AU - Mysler, Eduardo
AU - Hall, Stephen
AU - Kivitz, Alan J.
AU - Moots, Robert J.
AU - Luo, Zhen
AU - DeMasi, Ryan
AU - Soma, Koshika
AU - Zhang, Richard
AU - Takiya, Liza
AU - Tatulych, Svitlana
AU - Mojcik, Christopher
AU - Krishnaswami, Sriram
AU - Menon, Sujatha
AU - Smolen, Josef S.
AU - Adams, Luthando
AU - Ally, Mahmood M.
AU - du Plooy, Maria C.
AU - Louw, Ingrid C.
AU - Nayiager, Savithree
AU - Nel, Christoffel B.
AU - Nel, Debra
AU - Reuter, Helmuth
AU - Soloman, Ahmed S.
AU - Spargo, Catherine E.
AU - Hall, Stephen
AU - Rischmueller, Maureen
AU - Sharma, Shunil D.
AU - Will, Robert K.
AU - Youssef, Peter P.
AU - Arroyo, Caroline
AU - Baes, Rosario P.
AU - Dulos, Roger B.
AU - Hao, Llewellyn T.
AU - Lanzon, Allan E.
AU - Lichauco, Juan Javier T.
AU - Mangubat, Jill H.
AU - Ramiterre, Edgar B.
AU - Reyes, Bernadette Heizel M.
AU - Tan, Perry P.
AU - Choe, Jung Yoon
AU - Kang, Young Mo
AU - Kwon, Seong Ryul
AU - Lee, Sang Heon
AU - Lee, Shin Seok
AU - Yoo, Dae Hyun
AU - Lin, Hsiao Yi
AU - Luo, Shue Fen
AU - Tsai, Shih Tzu
AU - Tsai, Wen Chan
AU - Tseng, Jui Cheng
AU - Wei, Cheng Chung C.
AU - Asavatanabodee, Paijit
AU - Nantiruj, Kanokrat
AU - Nilganuwong, Surasak
AU - Uea-Areewongsa, Parichat
AU - Majstorovic, Ljubinka Bozic
AU - Bacic, Suada Mulic
AU - Batalov, Anastas Z.
AU - Georgieva-Slavcheva, Gabriela
AU - Mihailova, Mariyana
AU - Nikolov, Nikolay G.
AU - Penev, Dimitar P.
AU - Spasov, Yuliy A.
AU - Stanimirova, Krasimira
AU - Todorov, Stoyan
AU - Toncheva, Antoaneta R.
AU - Yordanova, Nadezhda
AU - Mosterova, Zdenka
AU - Novosad, Libor
AU - Prochazkova, Leona
AU - Stehlikova, Helena
AU - Stejfova, Zuzana
AU - Kiseleva, Natalia
AU - Pank, Lea
AU - Savi, Triin
AU - Alexandra, Balbir Gurman
AU - Amital, Howard
AU - Mevorach, Dror
AU - Rosner, Itzhak A.
AU - Mihailova, Anna
AU - Stumbra-Stumberga, Evija
AU - Basijokiene, Vida
AU - Lietuvininkiene, Virginija
AU - Unikiene, Dalia
AU - Brzezicki, Jan
AU - Dudek, Anna M.
AU - Glowacka-Kulesz, Maria B.
AU - Grabowicz-Wasko, Barbara
AU - Hajduk-Kubacka, Sabina
AU - Hilt, Joanna
AU - Hrycaj, Pawel
AU - Jeka, Slawomir
AU - Kolasa, Renata
AU - Krogulec, Marek
AU - Mastalerz, Hanna
AU - Olak-Popko, Anna
AU - Owczarek, Elzbieta
AU - Ruzga, Zofia
AU - Walczak, Alina
AU - Ancuta, Codrina I.
AU - Ancuta, Ioan
AU - Balanescu, Andra R.
AU - Berghea, Florian
AU - Bojin, Silvia
AU - Arvunescu, Mihaela A.Ianuli
AU - Ionescu, Ruxandra M.
AU - Mociran, Eugenia
AU - Pavel, Mariana
AU - Rednic, Simona
AU - Voie, Adriana
AU - Zainea, Carmen M.
AU - Bugrova, Olga V.
AU - Demin, Alexander
AU - Ershova, Olga B.
AU - Gavrisheva, Inna A.
AU - Krechikova, Diana G.
AU - Kuropatkin, Gennady V.
AU - Marusenko, Irina M.
AU - Menshikova, Irina V.
AU - Noskov, Sergey M.
AU - Rebrov, Andrey P.
AU - Smakotina, Svetlana A.
AU - Yakushin, Sergey S.
AU - Zhilyaev, Evgeny
AU - Ramos, Juan Jose Amarelo
AU - Garcia, Francisco Javier Blanco
AU - Nebro, Antonio Fernandez
AU - Esteban, Silvia Perez
AU - Burson, Juan Miguel Sanchez
AU - Sala, Raimon Sanmarti
AU - Ataman, Sebnem
AU - Hizmetli, Sami
AU - Kuru, Omer
AU - Douglas, Karen M.
AU - Emery, Paul
AU - Moots, Robert J.
AU - Ong, Voon H.
AU - Sheeran, Thomas P.
AU - Faraawi, Rafat Y.
AU - Lessard, Clode
AU - Mendoza, Carlos Abud
AU - Avila-Armengol, Hilario Ernesto
AU - Zapata, Francisco I.Avila
AU - Irazoque-Palazuelos, Fedra Consuelo
AU - Cecena, Marco Antonio Maradiaga
AU - Pacheco-Tena, Cesar F.
AU - Rizo-Rodriguez, Juan C.
AU - Rodriguez-Torres, Isaura M.
AU - Aelion, Jacob A.
AU - Caciolo, Barbara A.
AU - Calmes, James M.
AU - Chatpar, Prem
AU - Dayal, Nimesh
AU - De Jesus, Alex
AU - Dikranian, Ara H.
AU - Diri, Erdal
AU - Fairfax, Michael J.
AU - Fenton, Ira F.
AU - Fleischmann, Roy M.
AU - Gaylis, Norman B.
AU - George, Ronald L.
AU - Halter, Dale G.
AU - Hernandez, Paul
AU - Hole, Susan A.
AU - Hou, Antony C.
AU - Huff, John P.
AU - Kafaja, Suzanne
AU - Kennedy, Alastair C.
AU - Kenney, Howard
AU - Kimmel, Steven C.
AU - Kirby, Brian S.
AU - Kivitz, Alan J.
AU - Legerton, Clarence W.
AU - Lindsey, Stephen M.
AU - Mallepalli, Jyothi R.
AU - Mathews, Steven D.
AU - Metyas, Samy K.
AU - Mizutani, Wesley T.
AU - Najam, Sabeen
AU - Nascimento, Joao M.
AU - Pang, Shirley W.
AU - Patel, Rakesh C.
AU - Poiley, Jeffrey E.
AU - Ramirez, Carlos E.
AU - Reddy, Riteesha
AU - Rehman, Qaiser
AU - Schnitz, William M.
AU - Scoville, Craig D.
AU - Shergy, William J.
AU - Silverfield, Joel C.
AU - Singhal, Atul K.
AU - Smallwood-Sherrer, Yvonne R.
AU - Songcharoen, Suthin N.
AU - Stack, Michael T.
AU - Stohl, William
AU - Su, Tien I.K.
AU - Udell, James
AU - Waraich, Saleem
AU - Weidmann, Charles E.
AU - Wei, Nathan
AU - Wiesenhutter, Craig W.
AU - Winkler, Anne E.
AU - Zagar, Karen E.
AU - Berman, Alberto
AU - Mysler, Eduardo F.
AU - Hidalgo, Rodolfo A.Pardo
AU - Venarotti, Horacio O.
AU - Sariego, Irmgadt Annelise Goecke
AU - Calabresse, Renato E.Jimenez
AU - Ruiz-Tagle, Juan Ignacio Vargas
AU - Vargas, Luis Fernando M.Bellatin
AU - Berrocal, Alfredo E.
AU - Portocarrero, Manuel Gustavo Leon
AU - Jesus, Felix
AU - Pena, Romero
N1 - Publisher Copyright: © 2017 Elsevier Ltd
PY - 2017/7/29
Y1 - 2017/7/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85020770079&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(17)31618-5
DO - 10.1016/S0140-6736(17)31618-5
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 28629665
AN - SCOPUS:85020770079
VL - 390
SP - 457
EP - 468
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10093
ER -