Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four–Month, Phase III Study

doi:10.1002/art.40803

Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four–Month, Phase III Study

Internal Medicine

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

Abstract

Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here. Methods: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression. Results: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported. Conclusion: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12–24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

Original language	English
Pages (from-to)	878-891
Number of pages	14
Journal	Arthritis and Rheumatology
Volume	71
Issue number	6
DOIs	https://doi.org/10.1002/art.40803
State	Published - Jun 2019

Bibliographical note

Funding Information:
1Désirée van der Heijde, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands; 2Vibeke Strand, MD: Biopharmaceutical Consultant, Portola Valley, California; 3Yoshiya Tanaka, MD, PhD: University of Occupational and Environmental Health, Kitakyushu, Japan; 4Edward Keystone, MD: Mount Sinai Hospital, Toronto, Ontario, Canada; 5Joel Kremer, MD: Albany Medical College, Albany, New York; 6Cristiano A. F. Zerbini, MD: Centro Paulista de 阀nvestigação Clinica, Sao Paulo, Brazi7lM; ario H. Cardiel, MD: Centro de 阀nvestigacion Clinica de Morelia, Morelia, Mexico8;S tanley Cohen, MD, Roy Fleischmann, MD: Metroplex Clinical Research Center, Dallas, Texas; 9Peter Nash, PhD: Nambour General Hospital, Nambour, Queensland, Australia, and University of Queensland, Brisbane, Queensland, Australia; 10Yeong-Wook Song, MD, PhD: Seoul National University Hospital, Seoul, Republic of Korea; 11Dana Tegzová, MD: 阀nstitute of Rheumatology, Prague, Czech Republic; 12David Gruben, PhD, Gene Wallenstein, PhD, Carol A. Connell, PhD: Pfizer, 阀nc., Groton, Connecticut.

Funding Information:
Pfizer, Inc. personnel developed the study protocol, supervised the conduct of the study, and were involved in data analysis and interpretation. Medical writing support under the guidance of the authors was provided by Rebecca J. Douglas, PhD (CMC Connect, a division of McCann Health Medical Communications Ltd, Macclesfield, UK) and was funded by Pfizer, Inc. in accordance with Good Publication Practice (GPP3) guidelines (Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good publication practice for communicating company-sponsored medical research: GPP3 Ann Intern Med 2015;163:461–4). The authors had the final decision to submit the manuscript for publication.

Publisher Copyright:
© 2019 Pfizer Inc. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

ASJC Scopus subject areas

Immunology and Allergy
Rheumatology
Immunology

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10.1002/art.40803

Cite this

@article{72e228a9fbdc4bdda56b245576fe41b8,

title = "Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four–Month, Phase III Study",

abstract = "Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here. Methods: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression. Results: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported. Conclusion: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12–24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.",

author = "{van der Heijde}, D{\'e}sir{\'e}e and Vibeke Strand and Yoshiya Tanaka and Edward Keystone and Joel Kremer and Zerbini, {Cristiano A.F.} and Cardiel, {Mario H.} and Stanley Cohen and Peter Nash and Song, {Yeong Wook} and Dana Tegzov{\'a} and David Gruben and Gene Wallenstein and Connell, {Carol A.} and Roy Fleischmann and Stephen Hall and David Nicholls and Maureen Rischmueller and Baker, {Milton F.} and Louis Bessette and Cividino, {Alfred A.} and Boulos Haraoui and {Niall Jones}, Henry and Majed Khraishi and J. Thorne and Birbara, {Charles Allen} and Baraf, {Herbert Stuart Block} and Bathon, {Joan Marie} and Brodsky, {Alan Lawrence} and Cush, {John Joseph} and Dikranian, {Ara Hagop} and Erdal Diri and Dura, {Paul Andrew} and Lohr, {Kristine Marie} and Fleischmann, {Roy Mitchell} and Griffin, {Robert Michael} and Halter, {Dale George} and Hargrove, {Jody Kay} and Bouda, {David William} and {Reddy Pasya}, {Suresh Kumar} and Hill, {Geneva Louise} and Jackson, {Raymond Edward} and Kafka, {Shelly Pearl} and Kaine, {Jeffrey Louis} and Katzenstein, {Paul L.} and Kempf, {Kevin James} and Kolba, {Karen Sue} and Kremer, {Joel Marc} and Selden Longley and Mathews, {Steven D.}",

note = "Funding Information: 1D{\'e}sir{\'e}e van der Heijde, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands; 2Vibeke Strand, MD: Biopharmaceutical Consultant, Portola Valley, California; 3Yoshiya Tanaka, MD, PhD: University of Occupational and Environmental Health, Kitakyushu, Japan; 4Edward Keystone, MD: Mount Sinai Hospital, Toronto, Ontario, Canada; 5Joel Kremer, MD: Albany Medical College, Albany, New York; 6Cristiano A. F. Zerbini, MD: Centro Paulista de 阀nvestiga{\c c}{\~a}o Clinica, Sao Paulo, Brazi7lM; ario H. Cardiel, MD: Centro de 阀nvestigacion Clinica de Morelia, Morelia, Mexico8;S tanley Cohen, MD, Roy Fleischmann, MD: Metroplex Clinical Research Center, Dallas, Texas; 9Peter Nash, PhD: Nambour General Hospital, Nambour, Queensland, Australia, and University of Queensland, Brisbane, Queensland, Australia; 10Yeong-Wook Song, MD, PhD: Seoul National University Hospital, Seoul, Republic of Korea; 11Dana Tegzov{\'a}, MD: 阀nstitute of Rheumatology, Prague, Czech Republic; 12David Gruben, PhD, Gene Wallenstein, PhD, Carol A. Connell, PhD: Pfizer, 阀nc., Groton, Connecticut. Funding Information: Pfizer, Inc. personnel developed the study protocol, supervised the conduct of the study, and were involved in data analysis and interpretation. Medical writing support under the guidance of the authors was provided by Rebecca J. Douglas, PhD (CMC Connect, a division of McCann Health Medical Communications Ltd, Macclesfield, UK) and was funded by Pfizer, Inc. in accordance with Good Publication Practice (GPP3) guidelines (Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good publication practice for communicating company-sponsored medical research: GPP3 Ann Intern Med 2015;163:461–4). The authors had the final decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2019 Pfizer Inc. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.",

year = "2019",

month = jun,

doi = "10.1002/art.40803",

language = "English",

volume = "71",

pages = "878--891",

number = "6",

}

TY - JOUR

T1 - Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis

T2 - Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four–Month, Phase III Study

AU - van der Heijde, Désirée

AU - Strand, Vibeke

AU - Tanaka, Yoshiya

AU - Keystone, Edward

AU - Kremer, Joel

AU - Zerbini, Cristiano A.F.

AU - Cardiel, Mario H.

AU - Cohen, Stanley

AU - Nash, Peter

AU - Song, Yeong Wook

AU - Tegzová, Dana

AU - Gruben, David

AU - Wallenstein, Gene

AU - Connell, Carol A.

AU - Fleischmann, Roy

AU - Hall, Stephen

AU - Nicholls, David

AU - Rischmueller, Maureen

AU - Baker, Milton F.

AU - Bessette, Louis

AU - Cividino, Alfred A.

AU - Haraoui, Boulos

AU - Niall Jones, Henry

AU - Khraishi, Majed

AU - Thorne, J.

AU - Birbara, Charles Allen

AU - Baraf, Herbert Stuart Block

AU - Bathon, Joan Marie

AU - Brodsky, Alan Lawrence

AU - Cush, John Joseph

AU - Dikranian, Ara Hagop

AU - Diri, Erdal

AU - Dura, Paul Andrew

AU - Lohr, Kristine Marie

AU - Fleischmann, Roy Mitchell

AU - Griffin, Robert Michael

AU - Halter, Dale George

AU - Hargrove, Jody Kay

AU - Bouda, David William

AU - Reddy Pasya, Suresh Kumar

AU - Hill, Geneva Louise

AU - Jackson, Raymond Edward

AU - Kafka, Shelly Pearl

AU - Kaine, Jeffrey Louis

AU - Katzenstein, Paul L.

AU - Kempf, Kevin James

AU - Kolba, Karen Sue

AU - Kremer, Joel Marc

AU - Longley, Selden

AU - Mathews, Steven D.

N1 - Funding Information: 1Désirée van der Heijde, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands; 2Vibeke Strand, MD: Biopharmaceutical Consultant, Portola Valley, California; 3Yoshiya Tanaka, MD, PhD: University of Occupational and Environmental Health, Kitakyushu, Japan; 4Edward Keystone, MD: Mount Sinai Hospital, Toronto, Ontario, Canada; 5Joel Kremer, MD: Albany Medical College, Albany, New York; 6Cristiano A. F. Zerbini, MD: Centro Paulista de 阀nvestigação Clinica, Sao Paulo, Brazi7lM; ario H. Cardiel, MD: Centro de 阀nvestigacion Clinica de Morelia, Morelia, Mexico8;S tanley Cohen, MD, Roy Fleischmann, MD: Metroplex Clinical Research Center, Dallas, Texas; 9Peter Nash, PhD: Nambour General Hospital, Nambour, Queensland, Australia, and University of Queensland, Brisbane, Queensland, Australia; 10Yeong-Wook Song, MD, PhD: Seoul National University Hospital, Seoul, Republic of Korea; 11Dana Tegzová, MD: 阀nstitute of Rheumatology, Prague, Czech Republic; 12David Gruben, PhD, Gene Wallenstein, PhD, Carol A. Connell, PhD: Pfizer, 阀nc., Groton, Connecticut. Funding Information: Pfizer, Inc. personnel developed the study protocol, supervised the conduct of the study, and were involved in data analysis and interpretation. Medical writing support under the guidance of the authors was provided by Rebecca J. Douglas, PhD (CMC Connect, a division of McCann Health Medical Communications Ltd, Macclesfield, UK) and was funded by Pfizer, Inc. in accordance with Good Publication Practice (GPP3) guidelines (Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good publication practice for communicating company-sponsored medical research: GPP3 Ann Intern Med 2015;163:461–4). The authors had the final decision to submit the manuscript for publication. Publisher Copyright: © 2019 Pfizer Inc. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

PY - 2019/6

Y1 - 2019/6

N2 - Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here. Methods: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression. Results: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported. Conclusion: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12–24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

AB - Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here. Methods: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression. Results: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported. Conclusion: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12–24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

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Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four–Month, Phase III Study

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