PMID- 33127856 OWN - NLM STAT- MEDLINE DCOM- 20210831 LR - 20210831 IS - 2056-5933 (Electronic) IS - 2056-5933 (Linking) VI - 6 IP - 3 DP - 2020 Oct TI - Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. LID - 10.1136/rmdopen-2020-001395 [doi] LID - e001395 AB - OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA. METHODS: Data were pooled for patients with RA who received >/=1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years [PY]; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest. RESULTS: 7061 patients received tofacitinib (total exposure: 22 875 PY; median [range] exposure: 3.1 [0 to 9.6] years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis [TB]) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months. CONCLUSION: This represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time. TRIAL REGISTRATION NUMBERS: NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661.For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1. CI - (c) Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Cohen, Stanley B AU - Cohen SB AD - Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, Texas, USA. FAU - Tanaka, Yoshiya AU - Tanaka Y AUID- ORCID: 0000-0002-0807-7139 AD - University of Occupational and Environmental Health, Kitakyushu, Japan. FAU - Mariette, Xavier AU - Mariette X AUID- ORCID: 0000-0002-4244-5417 AD - Paris-Saclay University, AP-HP, INSERM, Le Kremlin Bicetre, France. FAU - Curtis, Jeffrey R AU - Curtis JR AUID- ORCID: 0000-0002-8907-8976 AD - University of Alabama at Birmingham, Birmingham, Alabama, USA. FAU - Lee, Eun Bong AU - Lee EB AUID- ORCID: 0000-0003-0703-1208 AD - Seoul National University, Seoul, Korea (the Democratic People's Republic of). FAU - Nash, Peter AU - Nash P AUID- ORCID: 0000-0002-2571-788X AD - Department of Medicine, Griffith University, Brisbane, Australia. FAU - Winthrop, Kevin L AU - Winthrop KL AUID- ORCID: 0000-0002-3892-6947 AD - Oregon Health and Science University, Portland, Oregon, USA. FAU - Charles-Schoeman, Christina AU - Charles-Schoeman C AD - University of California, Los Angeles, California, USA. FAU - Wang, Lisy AU - Wang L AUID- ORCID: 0000-0003-1096-0868 AD - Pfizer Inc, Groton, Connecticut, USA Lisy.Wang@Pfizer.com. FAU - Chen, Connie AU - Chen C AD - Pfizer Inc, New York, New York, USA. FAU - Kwok, Kenneth AU - Kwok K AD - Pfizer Inc, New York, New York, USA. FAU - Biswas, Pinaki AU - Biswas P AD - Pfizer Inc, New York, New York, USA. FAU - Shapiro, Andrea AU - Shapiro A AD - Pfizer Inc, Peapack, New Jersey, USA. FAU - Madsen, Ann AU - Madsen A AD - Pfizer Inc, New York, New York, USA. FAU - Wollenhaupt, Jurgen AU - Wollenhaupt J AD - Struenseehaus Centre for Rheumatology and Clinical Immunology, Hamburg, Germany. LA - eng SI - ClinicalTrials.gov/NCT00853385 SI - ClinicalTrials.gov/NCT02187055 SI - ClinicalTrials.gov/NCT00413660 SI - ClinicalTrials.gov/NCT00847613 SI - ClinicalTrials.gov/NCT01164579 SI - ClinicalTrials.gov/NCT00687193 SI - ClinicalTrials.gov/NCT00856544 SI - ClinicalTrials.gov/NCT00603512 SI - ClinicalTrials.gov/NCT00976599 SI - ClinicalTrials.gov/NCT00960440 SI - ClinicalTrials.gov/NCT01262118 SI - ClinicalTrials.gov/NCT00814307 SI - ClinicalTrials.gov/NCT01039688 SI - ClinicalTrials.gov/NCT00147498 SI - ClinicalTrials.gov/NCT00661661 SI - ClinicalTrials.gov/NCT01359150 SI - ClinicalTrials.gov/NCT01484561 SI - ClinicalTrials.gov/NCT00413699 SI - ClinicalTrials.gov/NCT00550446 SI - ClinicalTrials.gov/NCT02147587 SI - ClinicalTrials.gov/NCT01059864 PT - Clinical Trial, Phase III PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - RMD Open JT - RMD open JID - 101662038 RN - 0 (Piperidines) RN - 0 (Pyrimidines) RN - 0 (Pyrroles) RN - 87LA6FU830 (tofacitinib) SB - IM MH - Adult MH - *Arthritis, Rheumatoid/drug therapy/epidemiology MH - Humans MH - Piperidines MH - Pyrimidines/adverse effects MH - *Pyrroles/adverse effects MH - Treatment Outcome PMC - PMC7722371 OTO - NOTNLM OT - Antirheumatic Agents OT - Arthritis OT - Rheumatoid OT - Therapeutics COIS- Competing interests: SBC has received grant/research support from AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche and Sandoz; and consultancy fees from AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche and Sandoz. YT has received grant/research support from AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Novartis, Pfizer Inc, Sanofi and YL Biologics; and speaker fees and/or honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Novartis, Pfizer Inc, Takeda, Teijin and YL Biologics. XM has received consultancy fees from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Pfizer Inc, Samsung and UCB. JRC has received grant/research support from Amgen, Corrona, Crescendo Bio and Pfizer Inc; and consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Eli Lilly, Janssen, Myriad, Pfizer Inc, Roche/Genentech and UCB. EBL has received consultancy fees from Pfizer Inc. PN has received grant/research support and consultancy fees from, and is part of the speakers' bureau for, AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi and UCB. KLW has received grant/research support and consultancy fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer Inc, Roche and UCB. CC-S has received grant/research support from AbbVie, Bristol-Myers Squibb and Pfizer Inc; and consultancy fees from Gilead, Pfizer Inc and Regeneron-Sanofi. LW, CC, KK, PB, AS and AM are employees and shareholders of Pfizer Inc. JW has received consultancy fees from, and is on the speaker's bureau for, Pfizer Inc. EDAT- 2020/11/01 06:00 MHDA- 2021/09/01 06:00 PMCR- 2020/10/30 CRDT- 2020/10/31 05:30 PHST- 2020/07/13 00:00 [received] PHST- 2020/09/28 00:00 [revised] PHST- 2020/09/29 00:00 [accepted] PHST- 2020/10/31 05:30 [entrez] PHST- 2020/11/01 06:00 [pubmed] PHST- 2021/09/01 06:00 [medline] PHST- 2020/10/30 00:00 [pmc-release] AID - rmdopen-2020-001395 [pii] AID - 10.1136/rmdopen-2020-001395 [doi] PST - ppublish SO - RMD Open. 2020 Oct;6(3):e001395. doi: 10.1136/rmdopen-2020-001395.