LB0003 Tofacitinib with and without methotrexate versus adalimumab with methotrexate for the treatment of rheumatoid arthritis: results from oral strategy, a phase 3b/4 randomised trial
Authors: R Fleischmann, E Mysler, S Hall, A Kivitz, R Moots, Z Luo, S Tatulych, R DeMasi, K Soma, R Zhang, L Takiya, C Mojcik, S Krishnaswami, S Menon, J Smolen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Tofacitinib is an oral JAK inhibitor for the treatment of RA. There is no direct comparison of tofacitinib monotherapy vs tofacitinib +MTX in MTX inadequate responders (IR) and limited data comparing tofacitinib (±MTX) vs adalimumab (ADA) +MTX in patients (pts) with RA. <h3>Objectives</h3> To compare efficacy and safety of tofacitinib monotherapy, tofacitinib+MTX, and ADA+MTX in a head-to-head, non-inferiority trial in MTX-IR pts. <h3>Methods</h3> In this randomised, triple-dummy, active-controlled, 1-year, Phase 3b/4 trial (ORAL Strategy; NCT02187055), pts had active RA (≥4 tender/painful joints on motion and ≥4 swollen joints [28-joint count] at baseline [BL]) inadequately controlled with MTX. Pts were randomised 1:1:1 to receive tofacitinib 5 mg twice daily (5 mg mono BID), tofacitinib 5 mg BID +MTX (5 mg BID+MTX) or subcutaneous ADA 40 mg every other week +MTX (ADA+MTX); MTX dose: 15–25 mg/wk. The primary endpoint was ACR50 at Month (Mo) 6. Non-inferiority between treatments was declared if the lower bound of 98.34% two-sided confidence intervals of the difference of ACR50 response at Mo 6 was larger than -13% (based on meta analysis of ADA trials<sup>1</sup>), and superiority if it was larger than 0%. Other endpoints included: ACR20/50/70 and least-squares mean changes from BL in SDAI, DAS28-4(ESR) and HAQ-DI at Mos 6 and 12. Safety was assessed throughout the trial. <h3>Results</h3> 1146 pts were randomised and treated (5 mg mono BID: n=384; 5 mg BID+MTX: n=376; ADA+MTX: n=386). Demographics and BL disease characteristics were similar across groups. Most pts were female (82.7–83.1%), white (75.9–77.1%), with a mean age of 49.7–50.7 years, median disease duration of 5.4–6.1 years and mean HAQ-DI score of 1.6. Across groups, 80.2–81.6% of pts completed the study. ACR50 response rate at Mo 6 was 38.3% for 5 mg mono BID, 46.0% for 5 mg BID+MTX and 43.8% for ADA+MTX. Non-inferiority was demonstrated for 5 mg BID+MTX vs ADA+MTX (P&lt;0.0001) but not for 5 mg mono BID vs ADA+MTX (P=0.0512) or 5 mg mono BID vs 5 mg BID+MTX (P=0.2101) which, although numerically different, were not statistically different (Figure). Tofacitinib monotherapy achieved the efficacy expected of an effective immunomodulator in this pt population. Secondary efficacy analyses were generally consistent with the primary analysis (Table). Adverse event (AE), serious AE and discontinuation due to AE rates were generally clinically similar across groups, though numerically fewer pts had increased alanine aminotransferase with 5 mg mono BID vs 5 mg BID+MTX or ADA+MTX. <h3>Conclusions</h3> Tofacitinib 5 mg BID+MTX was as effective as ADA+MTX in MTX-IR pts with RA. However, clinical outcomes of all 3 regimens, including tofacitinib 5 mg BID monotherapy, were comparable. There were no new or unexpected safety issues. <h3>References</h3> Machado et al. Rev Bras Reumatol 2013;53:419–430. <h3>Acknowledgements</h3> This study was funded by Pfizer Inc. Editorial support provided by D Binks of CMC. <h3>Disclosure of Interest</h3> R. Fleischmann Grant/research support from: Abbott, Amgen, Astellas, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Genentech, Eli Lilly, Janssen, Novartis, Pfizer Inc, Regeneron Pharmaceuticals Inc., Sanofi Aventis, Roche, UCB, Consultant for: Abbott, Akros, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sanofi Aventis, UCB, E. Mysler Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medimmune, Pfizer Inc and Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medimmune, Pfizer Inc and Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medimmune, Pfizer Inc and Roche, S. Hall Consultant for: Pfizer Inc, Celgene, Roche, AbbVie, Eli Lilly, Janssen, A. Kivitz Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Genentech and Pfizer Inc, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Genentech and Pfizer Inc, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Pfizer Inc, R. Moots Grant/research support from: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer, Roche, Sandoz, UCB Pharma, Consultant for: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer, Roche, Sandoz, UCB Pharma, Speakers bureau: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer, Roche, Sandoz, UCB Pharma, Z. Luo Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Tatulych Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Zhang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Mojcik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Smolen Grant/research support from: AbbVie, Janssen, Lilly, MSD, Pfizer Inc, and Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB