Tofacitinib

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Samuel H Zwillich - One of the best experts on this subject based on the ideXlab platform.

  • Tofacitinib in combination with conventional disease modifying antirheumatic drugs in patients with active rheumatoid arthritis patient reported outcomes from a phase iii randomized controlled trial
    Arthritis Care and Research, 2017
    Co-Authors: Vibeke Strand, Samuel H Zwillich, Sriram Krishnaswami, David Gruben, Joel M Kremer, Gene V Wallenstein
    Abstract:

    Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with Tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). Methods: In a 12-month, Phase 3, randomized controlled trial (ORAL Sync), patients (n=795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to Tofacitinib 5 mg twice daily (BID), Tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included Patient Global Assessment of Arthritis (PtGA), Patient Assessment of Arthritis Pain (Pain), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). Results: At Month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ-DI, all eight SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 10 mg BID, and in PtGA, Pain, HAQ-DI, seven SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 5 mg BID. Improvements were sustained to Month 12. Significantly more Tofacitinib-treated patients reported improvements ≥minimum clinically important differences at Month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for Tofacitinib 10 mg BID). Conclusion: Patients with active RA treated with Tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo. (NCT00856544) This article is protected by copyright. All rights reserved.

  • Tofacitinib versus biologic treatments in patients with active rheumatoid arthritis who have had an inadequate response to tumor necrosis factor inhibitors results from a network meta analysis
    Clinical Therapeutics, 2016
    Co-Authors: M C Vieira, Samuel H Zwillich, Jeroen P Jansen, Brielan Smiechowski, Dean Spurden, Gene V Wallenstein
    Abstract:

    Abstract Purpose Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis compared the efficacy and safety of Tofacitinib with biologic disease-modifying antirheumatic drugs in patients with RA and a prior inadequate response (IR) to tumor necrosis factor inhibitors (TNFi). Methods A systematic literature review identified 5 randomized placebo-controlled trials that evaluated Tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) against placebo in patient populations with RA with a prior IR to TNFi. The definition of TNFi-IR varied across studies, and included patients with an IR or who had failed treatment with TNFi for any reason. A network meta-analysis was conducted comparing study data with regard to American College of Rheumatology response rates and Health Assessment Questionnaire-Disability Index improvement at weeks 12 and 24, rates of treatment withdrawal due to all causes; adverse events (AEs) and lack of efficacy; and rates of AEs, serious AEs, and serious infections. Findings The 5 trials included a total of 2136 patients. Tofacitinib 5 mg twice daily combined with methotrexate was found to have relative risk estimates of American College of Rheumatology responses and change from baseline in Health Assessment Questionnaire-Disability Index score comparable with abatacept, golimumab, rituximab, and tocilizumab combined with conventional synthetic disease-modifying antirheumatic drugs. Withdrawal rates from trials due to all causes and AEs were comparable between treatments, and Tofacitinib had a lower rate of withdrawals due to lack of efficacy. Rates of AEs and HAQ-DI were comparable between Tofacitinib, other active treatments, and placebo. No serious infections were reported with Tofacitinib during the placebo-controlled period (up to week 12) in this study population; rates of serious infection with other active treatments were generally low and similar to placebo. Implications During a 24-week period, Tofacitinib had efficacy and rates of AEs comparable with currently available bDMARDs in the treatment of patients with RA who had a prior IR to TNFi. ClinicalTrials.gov identifiers: ORAL Step, NCT00960440; ATTAIN, NCT00124982; GO-AFTER, NCT00299546; RADIATE, NCT00106522; REFLEX, NCT00462345.

  • Tofacitinib an oral janus kinase inhibitor as monotherapy or with background methotrexate in japanese patients with rheumatoid arthritis an open label long term extension study
    Arthritis Research & Therapy, 2016
    Co-Authors: Hisashi Yamanaka, Naonobu Sugiyama, Hirotoshi Yuasa, Shigeyuki Toyoizumi, Yosuke Morishima, Tomohiro Hirose, Yoshiya Tanaka, Tsutomu Takeuchi, Samuel H Zwillich
    Abstract:

    Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, Tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented.

  • Tofacitinib versus methotrexate in rheumatoid arthritis
    The New England Journal of Medicine, 2014
    Co-Authors: Roy Fleischmann, Sriram Krishnaswami, David Gruben, Bethanie Wilkinson, Stephen Hall, Gene V Wallenstein, John D Bradley, Tamas Koncz, Chuanbo Zang, Samuel H Zwillich
    Abstract:

    We randomly assigned 958 patients to receive 5 mg or 10 mg of Tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the pa tient’s assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). Results Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the Tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg Tofacitinib group and <0.1 point in the 10-mg Tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving Tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received Tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received Tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. Conclusions In patients who had not previously received methotrexate or therapeutic doses of methotrexate, Tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of Tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.)

  • open label Tofacitinib and double blind atorvastatin in rheumatoid arthritis patients a randomised study
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: Iain B Mcinnes, Andrea Zuckerman, Zhen Luo, Carol A Connell, Yeong Wook Song, Hoyoun Kim, Sangheon Lee, David Mandel, Julia M Brosnan, Samuel H Zwillich
    Abstract:

    Objectives To evaluate the efficacy and safety of atorvastatin versus placebo in modifying lipids in patients with rheumatoid arthritis (RA) receiving the oral Janus kinase inhibitor, Tofacitinib. Methods A randomised, placebo controlled, multicentre phase 2 study, open-label for Tofacitinib and blinded for atorvastatin. Patients received Tofacitinib 10 mg twice daily for 12 weeks; at week 6, patients were randomly assigned 1:1 to receive oral atorvastatin 10 mg once daily or placebo for 6 weeks. Main outcome measures were lipid moieties, American College of Rheumatology (ACR) response rates, disease activity score in 28 joint counts and safety. Results 111 patients meeting ACR 1987 RA criteria with active disease were enrolled. Tofacitinib-induced elevation of mean total, low-density lipoprotein (LDL) and high-density lipoprotein-cholesterol, triglycerides and apolipoprotein A-1 concentrations were sustained in placebo recipients to week 12; atorvastatin added at week 6 significantly reduced Tofacitinib-associated increases in total and LDL-cholesterol, triglycerides and apolipoprotein B to below week 0 levels. Co-administration of atorvastatin resulted in a significant reduction of LDL-cholesterol versus placebo (primary endpoint; p Conclusions Tofacitinib-associated elevated total and LDL-cholesterol and triglycerides were rapidly and significantly reduced by atorvastatin. Further investigation is required to explore the significance of reductions in RA disease activity in patients receiving Tofacitinib and atorvastatin. (http://www.ClinicalTrials.gov identifier NCT01059864; Pfizer protocol A3921109).

Gene V Wallenstein - One of the best experts on this subject based on the ideXlab platform.

  • Tofacitinib in combination with conventional disease modifying antirheumatic drugs in patients with active rheumatoid arthritis patient reported outcomes from a phase iii randomized controlled trial
    Arthritis Care and Research, 2017
    Co-Authors: Vibeke Strand, Samuel H Zwillich, Sriram Krishnaswami, David Gruben, Joel M Kremer, Gene V Wallenstein
    Abstract:

    Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with Tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). Methods: In a 12-month, Phase 3, randomized controlled trial (ORAL Sync), patients (n=795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to Tofacitinib 5 mg twice daily (BID), Tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included Patient Global Assessment of Arthritis (PtGA), Patient Assessment of Arthritis Pain (Pain), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). Results: At Month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ-DI, all eight SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 10 mg BID, and in PtGA, Pain, HAQ-DI, seven SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 5 mg BID. Improvements were sustained to Month 12. Significantly more Tofacitinib-treated patients reported improvements ≥minimum clinically important differences at Month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for Tofacitinib 10 mg BID). Conclusion: Patients with active RA treated with Tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo. (NCT00856544) This article is protected by copyright. All rights reserved.

  • Tofacitinib versus biologic treatments in patients with active rheumatoid arthritis who have had an inadequate response to tumor necrosis factor inhibitors results from a network meta analysis
    Clinical Therapeutics, 2016
    Co-Authors: M C Vieira, Samuel H Zwillich, Jeroen P Jansen, Brielan Smiechowski, Dean Spurden, Gene V Wallenstein
    Abstract:

    Abstract Purpose Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis compared the efficacy and safety of Tofacitinib with biologic disease-modifying antirheumatic drugs in patients with RA and a prior inadequate response (IR) to tumor necrosis factor inhibitors (TNFi). Methods A systematic literature review identified 5 randomized placebo-controlled trials that evaluated Tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) against placebo in patient populations with RA with a prior IR to TNFi. The definition of TNFi-IR varied across studies, and included patients with an IR or who had failed treatment with TNFi for any reason. A network meta-analysis was conducted comparing study data with regard to American College of Rheumatology response rates and Health Assessment Questionnaire-Disability Index improvement at weeks 12 and 24, rates of treatment withdrawal due to all causes; adverse events (AEs) and lack of efficacy; and rates of AEs, serious AEs, and serious infections. Findings The 5 trials included a total of 2136 patients. Tofacitinib 5 mg twice daily combined with methotrexate was found to have relative risk estimates of American College of Rheumatology responses and change from baseline in Health Assessment Questionnaire-Disability Index score comparable with abatacept, golimumab, rituximab, and tocilizumab combined with conventional synthetic disease-modifying antirheumatic drugs. Withdrawal rates from trials due to all causes and AEs were comparable between treatments, and Tofacitinib had a lower rate of withdrawals due to lack of efficacy. Rates of AEs and HAQ-DI were comparable between Tofacitinib, other active treatments, and placebo. No serious infections were reported with Tofacitinib during the placebo-controlled period (up to week 12) in this study population; rates of serious infection with other active treatments were generally low and similar to placebo. Implications During a 24-week period, Tofacitinib had efficacy and rates of AEs comparable with currently available bDMARDs in the treatment of patients with RA who had a prior IR to TNFi. ClinicalTrials.gov identifiers: ORAL Step, NCT00960440; ATTAIN, NCT00124982; GO-AFTER, NCT00299546; RADIATE, NCT00106522; REFLEX, NCT00462345.

  • effects of the oral janus kinase inhibitor Tofacitinib on patient reported outcomes in patients with active rheumatoid arthritis results of two phase 2 randomised controlled trials
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Gene V Wallenstein, Keith S Kanik, David Gruben, Bethanie Wilkinson, Roy Fleischmann, Juan Gomez Reino, Mark C. Genovese, Stanley N Cohen, Maurizio Cutolo, Joel M Kremer
    Abstract:

    OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of Tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received Tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received Tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all Tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for Tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for Tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with Tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the Tofacitinib groups were observed at Weeks 12 and 24. CONCLUSIONS: In patients with active RA, Tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  • effects of the oral janus kinase inhibitor Tofacitinib on patient reported outcomes in patients with active rheumatoid arthritis results of two phase 2 randomised controlled trials
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Gene V Wallenstein, Keith S Kanik, David Gruben, Bethanie Wilkinson, Roy Fleischmann, Juan Gomez Reino, Mark C. Genovese, Stanley N Cohen, Maurizio Cutolo, Joel M Kremer
    Abstract:

    OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of Tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received Tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received Tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all Tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for Tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for Tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with Tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the Tofacitinib groups were observed at Weeks 12 and 24. CONCLUSIONS: In patients with active RA, Tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  • Tofacitinib versus methotrexate in rheumatoid arthritis
    The New England Journal of Medicine, 2014
    Co-Authors: Roy Fleischmann, Sriram Krishnaswami, David Gruben, Bethanie Wilkinson, Stephen Hall, Gene V Wallenstein, John D Bradley, Tamas Koncz, Chuanbo Zang, Samuel H Zwillich
    Abstract:

    We randomly assigned 958 patients to receive 5 mg or 10 mg of Tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the pa tient’s assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). Results Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the Tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg Tofacitinib group and <0.1 point in the 10-mg Tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving Tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received Tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received Tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. Conclusions In patients who had not previously received methotrexate or therapeutic doses of methotrexate, Tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of Tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.)

David Gruben - One of the best experts on this subject based on the ideXlab platform.

  • Tofacitinib in combination with conventional disease modifying antirheumatic drugs in patients with active rheumatoid arthritis patient reported outcomes from a phase iii randomized controlled trial
    Arthritis Care and Research, 2017
    Co-Authors: Vibeke Strand, Samuel H Zwillich, Sriram Krishnaswami, David Gruben, Joel M Kremer, Gene V Wallenstein
    Abstract:

    Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with Tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). Methods: In a 12-month, Phase 3, randomized controlled trial (ORAL Sync), patients (n=795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to Tofacitinib 5 mg twice daily (BID), Tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included Patient Global Assessment of Arthritis (PtGA), Patient Assessment of Arthritis Pain (Pain), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). Results: At Month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ-DI, all eight SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 10 mg BID, and in PtGA, Pain, HAQ-DI, seven SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 5 mg BID. Improvements were sustained to Month 12. Significantly more Tofacitinib-treated patients reported improvements ≥minimum clinically important differences at Month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for Tofacitinib 10 mg BID). Conclusion: Patients with active RA treated with Tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo. (NCT00856544) This article is protected by copyright. All rights reserved.

  • effects of the oral janus kinase inhibitor Tofacitinib on patient reported outcomes in patients with active rheumatoid arthritis results of two phase 2 randomised controlled trials
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Gene V Wallenstein, Keith S Kanik, David Gruben, Bethanie Wilkinson, Roy Fleischmann, Juan Gomez Reino, Mark C. Genovese, Stanley N Cohen, Maurizio Cutolo, Joel M Kremer
    Abstract:

    OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of Tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received Tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received Tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all Tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for Tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for Tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with Tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the Tofacitinib groups were observed at Weeks 12 and 24. CONCLUSIONS: In patients with active RA, Tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  • effects of the oral janus kinase inhibitor Tofacitinib on patient reported outcomes in patients with active rheumatoid arthritis results of two phase 2 randomised controlled trials
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Gene V Wallenstein, Keith S Kanik, David Gruben, Bethanie Wilkinson, Roy Fleischmann, Juan Gomez Reino, Mark C. Genovese, Stanley N Cohen, Maurizio Cutolo, Joel M Kremer
    Abstract:

    OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of Tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received Tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received Tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all Tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for Tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for Tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with Tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the Tofacitinib groups were observed at Weeks 12 and 24. CONCLUSIONS: In patients with active RA, Tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  • Tofacitinib versus methotrexate in rheumatoid arthritis
    The New England Journal of Medicine, 2014
    Co-Authors: Roy Fleischmann, Sriram Krishnaswami, David Gruben, Bethanie Wilkinson, Stephen Hall, Gene V Wallenstein, John D Bradley, Tamas Koncz, Chuanbo Zang, Samuel H Zwillich
    Abstract:

    We randomly assigned 958 patients to receive 5 mg or 10 mg of Tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the pa tient’s assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). Results Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the Tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg Tofacitinib group and <0.1 point in the 10-mg Tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving Tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received Tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received Tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. Conclusions In patients who had not previously received methotrexate or therapeutic doses of methotrexate, Tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of Tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.)

  • Tofacitinib in combination with nonbiologic disease modifying antirheumatic drugs in patients with active rheumatoid arthritis a randomized trial
    Annals of Internal Medicine, 2013
    Co-Authors: Joel M Kremer, Sriram Krishnaswami, David Gruben, Roy Fleischmann, Mark C. Genovese, Gene V Wallenstein, John D Isaacs, Stephen B Hall, E Martinmola, Samuel H Zwillich
    Abstract:

    BACKGROUND Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE To evaluate the efficacy and safety of Tofacitinib in combination with nonbiologic DMARDs. DESIGN 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING 114 centers in 19 countries. PATIENTS 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION Patients were randomly assigned 4:4:1:1 to oral Tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to Tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg Tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the Tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg Tofacitinib, 10-mg Tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the Tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the Tofacitinib groups. LIMITATIONS Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than Tofacitinib plus methotrexate was limited. CONCLUSION Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE Pfizer.

Jeffrey R. Curtis - One of the best experts on this subject based on the ideXlab platform.

  • risk for herpes zoster in Tofacitinib treated rheumatoid arthritis patients with and without concomitant methotrexate and glucocorticoids
    Arthritis Care and Research, 2019
    Co-Authors: Jeffrey R. Curtis, Sasha Bernatsky, Huifeng Yun, Fenglong Xie, Shuo Yang, Lang Chen, Kevin L Winthrop
    Abstract:

    Objective: Increased incidence of herpes zoster (HZ) has been observed with JAK inhibitors such as Tofacitinib. However, whether concomitant methotrexate (MTX) and/or glucocorticoids confer additional (additive or multiplicative) risk is unclear. We evaluated HZ risk in Tofacitinib users with and without MTX and glucocorticoids. Methods: Within MarketScan and Medicare data (2011-2016), we identified all patients with rheumatologist-diagnosed rheumatoid arthritis initiating treatment with Tofacitinib (index date); demographics and baseline covariates were evaluated in the year prior to the index date. HZ was ascertained using International Classification of Diseases, Ninth Revision or Tenth Revision codes with antiviral drug use (±7 days). Multivariable Cox regression was used to evaluate hazard ratios (HRs) for HZ in Tofacitinib users with and without current concomitant MTX and glucocorticoids, controlling for baseline covariates. Results: We studied 8,030 new Tofacitinib users (83.3% women). The mean ± SD age was 60.3 ± 12.6 years. HZ incidence in Tofacitinib users was numerically lowest in the absence of glucocorticoids (3.4 per 100 patient-years with MTX; 3.7 per 100 patient-years without MTX). An approximately 2-fold increased incidence of HZ was observed for Tofacitinib users receiving either glucocorticoids alone (6.0 per 100 patient-years) or both MTX plus glucocorticoids (6.5 per 100 patient-years). The adjusted HR for HZ in Tofacitinib users was unchanged (HR 0.99 [95% confidence interval (95% CI) 0.64-1.54]) when given only with MTX, but was increased (HR 1.96 [95% CI 1.33-2.88]) for Tofacitinib plus glucocorticoids. Older age and female sex were also risk factors, while prior vaccination was associated with a strong trend for lower risk. Conclusion: In Tofacitinib users, HZ occurred at a rate of approximately 4% per year and was further doubled with glucocorticoid exposure. Concomitant MTX did not confer additional risk. Zoster vaccination may decrease risk.

  • safety and efficacy of Tofacitinib for up to 9 5 years in the treatment of rheumatoid arthritis final results of a global open label long term extension study
    Arthritis Research & Therapy, 2019
    Co-Authors: J Wollenhaupt, Koshika Soma, Jeffrey R. Curtis, Ryan Demasi, Joel Silverfield, Eun Bong Lee, Ketti Terry, Chris Mojcik, Sander Strengholt, Kenneth Kwok
    Abstract:

    Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of Tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA). Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of Tofacitinib and received open-label Tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to Tofacitinib or background therapy were permitted at investigators’ discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients’ average total daily dose. The primary objective was to determine the long-term safety and tolerability of Tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy. Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total Tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all Tofacitinib; efficacy data are reported up to month 96 for Tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained. Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions. NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006)

  • worldwide 3 year post marketing surveillance experience with Tofacitinib in rheumatoid arthritis
    Rheumatology and Therapy, 2018
    Co-Authors: Stanley N Cohen, Jeffrey R. Curtis, Ryan Demasi, Yan Chen, Haiyun Fan, Arif Soonasra, Roy Fleischmann
    Abstract:

    Post-marketing surveillance (PMS) is an integral part of monitoring adverse events (AEs) following approval of new drugs. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). An analysis of PMS reports was conducted to evaluate the safety of Tofacitinib in a post-marketing setting. Worldwide Tofacitinib PMS data received in the Pfizer safety database from November 6, 2012 (first marketing authorization of Tofacitinib) to November 5, 2015 were analyzed. Serious AEs (SAEs) of interest were reviewed and reporting rates (RRs) were calculated by dividing the number of SAEs by the estimated 100 patient-years of exposure. Patient exposure was calculated based on estimated worldwide sales and an estimated daily regimen of Tofacitinib 5 mg twice daily. During the 3-year reporting period, worldwide post-marketing exposure to Tofacitinib since approval was estimated to be 34,223 patient-years. In total, 9291 case reports (82.9% non-serious) were received and 25,417 AEs, 102 fatal cases, and 4352 SAEs were reported. The RRs (per 100 patient-years) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 2.57 for infections, 0.91 for gastrointestinal disorders, 0.60 for respiratory disorders, 0.45 for neoplasms, 0.43 for cardiac disorders, and 0.12 for hepatobiliary disorders. Although there are limitations to these data, no new safety risks were revealed in this real-world setting compared with the safety profile identified in the Tofacitinib RA clinical development program. Any risks identified through the Tofacitinib development program and PMS will continue to be monitored through pharmacovigilance surveillance. Pfizer Inc.

  • herpes zoster and Tofacitinib clinical outcomes and the risk of concomitant therapy
    Arthritis & Rheumatism, 2017
    Co-Authors: Kevin L Winthrop, Lisy Wang, Hernan Valdez, Tomohiro Hirose, Yoshiya Tanaka, Jeffrey R. Curtis, Kunihiro Yamaoka, Chudy I Nduaka, S Lindsey, A Mendelsohn
    Abstract:

    Objective Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with Tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with Tofacitinib. Methods HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long-term extension studies of Tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. Results Across all studies (6,192 patients; 16,839 patient-years), HZ was reported in 636 Tofacitinib-treated patients (IR 4.0, 95% CI 3.7–4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0–2.9) in Eastern Europe to 8.0 (95% CI 6.6–9.6) in Japan and 8.4 (95% CI 6.4–10.9) in Korea. Within phase III studies, HZ IRs varied according to Tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with Tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07–2.01]) and highest for Tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72–7.68]). Age, GC use, Tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. Conclusion Patients receiving treatment with Tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving Tofacitinib monotherapy without GCs.

  • long term safety of Tofacitinib for the treatment of rheumatoid arthritis up to 8 5 years integrated analysis of data from the global clinical trials
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Stanley Cohen, Christina Charlesschoeman, Krishan Thirunavukkarasu, Peter Nash, Yoshiya Tanaka, Jeffrey R. Curtis, Kevin L Winthrop, Eun Bong Lee, Xavier Mariette, Ryan Demasi
    Abstract:

    Objectives: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of Tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA. Methods: Data were pooled for all Tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest. Results: 6194 patients received Tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration Tofacitinib exposure. Conclusion: This analysis of Tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous Tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous Tofacitinib reports.

Joel M Kremer - One of the best experts on this subject based on the ideXlab platform.

  • incidence of venous and arterial thromboembolic events reported in the Tofacitinib rheumatoid arthritis psoriasis and psoriatic arthritis development programmes and from real world data
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Philip J Mease, Christina Charlesschoeman, Joel M Kremer, Stanley N Cohen, Lara Fallon, John Woolcott, Huifeng Yun, Jeffrey D Greenberg, Wendi Malley, Alina Onofrei
    Abstract:

    Objectives Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, Tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving Tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for Tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the Tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within. Methods This post-hoc analysis used data from separate Tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years’ exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed. Results 12 410 Tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all Tofacitinib cohorts’ average Tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09–0.27) and 0.15 (0.09–0.22)); PE (0.12 (0.06–0.22) and 0.13 (0.08–0.21)); ATE (0.32 (0.22–0.46) and 0.38 (0.28–0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00–0.36) and 0.06 (0.02–0.15)); PE (0.13 (0.02–0.47) and 0.09 (0.04–0.19)); ATE (0.52 (0.22–1.02) and 0.22 (0.13–0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00–0.28) and 0.13 (0.00–0.70)); PE (0.08 (0.00–0.43) and 0.00 (0.00–0.46)); ATE (0.31 (0.08–0.79) and 0.38 (0.08–1.11)). IRs were similar between Tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including Tofacitinib-naive/biologic disease-modifying antirheumatic drug-treated and Tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the Tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with Tofacitinib were identified in the FAERS database. Conclusions DVT, PE and ATE IRs in the Tofacitinib RA, PsO and PsA programmes were similar across Tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with Tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32–0.87)), versus patients with baseline cardiovascular risk factors treated with Tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13–0.41)).

  • Tofacitinib in combination with conventional disease modifying antirheumatic drugs in patients with active rheumatoid arthritis patient reported outcomes from a phase iii randomized controlled trial
    Arthritis Care and Research, 2017
    Co-Authors: Vibeke Strand, Samuel H Zwillich, Sriram Krishnaswami, David Gruben, Joel M Kremer, Gene V Wallenstein
    Abstract:

    Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared patient-reported outcomes (PROs) in patients with RA treated with Tofacitinib or placebo in combination with conventional disease-modifying antirheumatic drugs (DMARDs). Methods: In a 12-month, Phase 3, randomized controlled trial (ORAL Sync), patients (n=795) with active RA and previous inadequate response to therapy with ≥1 conventional or biologic DMARD were randomized 4:4:1:1 to Tofacitinib 5 mg twice daily (BID), Tofacitinib 10 mg BID, placebo advanced to 5 mg BID, or placebo to 10 mg BID, in combination with stable background DMARD therapy. PROs included Patient Global Assessment of Arthritis (PtGA), Patient Assessment of Arthritis Pain (Pain), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), and sleep (Medical Outcomes Study Sleep [MOS Sleep]). Results: At Month 3, statistically significant improvements from baseline versus placebo were reported in PtGA, Pain, HAQ-DI, all eight SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 10 mg BID, and in PtGA, Pain, HAQ-DI, seven SF-36 domains, FACIT-F, and MOS Sleep with Tofacitinib 5 mg BID. Improvements were sustained to Month 12. Significantly more Tofacitinib-treated patients reported improvements ≥minimum clinically important differences at Month 3 versus placebo in all PROs, except the SF-36 role-emotional domain (significant for Tofacitinib 10 mg BID). Conclusion: Patients with active RA treated with Tofacitinib combined with background conventional DMARD therapy reported sustained, significant, and clinically meaningful improvements in PROs versus placebo. (NCT00856544) This article is protected by copyright. All rights reserved.

  • effects of the oral janus kinase inhibitor Tofacitinib on patient reported outcomes in patients with active rheumatoid arthritis results of two phase 2 randomised controlled trials
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Gene V Wallenstein, Keith S Kanik, David Gruben, Bethanie Wilkinson, Roy Fleischmann, Juan Gomez Reino, Mark C. Genovese, Stanley N Cohen, Maurizio Cutolo, Joel M Kremer
    Abstract:

    OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of Tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received Tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received Tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all Tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for Tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for Tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with Tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the Tofacitinib groups were observed at Weeks 12 and 24. CONCLUSIONS: In patients with active RA, Tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  • effects of the oral janus kinase inhibitor Tofacitinib on patient reported outcomes in patients with active rheumatoid arthritis results of two phase 2 randomised controlled trials
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Gene V Wallenstein, Keith S Kanik, David Gruben, Bethanie Wilkinson, Roy Fleischmann, Juan Gomez Reino, Mark C. Genovese, Stanley N Cohen, Maurizio Cutolo, Joel M Kremer
    Abstract:

    OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of Tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received Tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received Tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36. RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all Tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for Tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for Tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with Tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the Tofacitinib groups were observed at Weeks 12 and 24. CONCLUSIONS: In patients with active RA, Tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  • Tofacitinib in combination with nonbiologic disease modifying antirheumatic drugs in patients with active rheumatoid arthritis a randomized trial
    Annals of Internal Medicine, 2013
    Co-Authors: Joel M Kremer, Sriram Krishnaswami, David Gruben, Roy Fleischmann, Mark C. Genovese, Gene V Wallenstein, John D Isaacs, Stephen B Hall, E Martinmola, Samuel H Zwillich
    Abstract:

    BACKGROUND Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE To evaluate the efficacy and safety of Tofacitinib in combination with nonbiologic DMARDs. DESIGN 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING 114 centers in 19 countries. PATIENTS 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION Patients were randomly assigned 4:4:1:1 to oral Tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to Tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg Tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the Tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg Tofacitinib, 10-mg Tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the Tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the Tofacitinib groups. LIMITATIONS Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than Tofacitinib plus methotrexate was limited. CONCLUSION Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE Pfizer.

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