PMID- 30953540 OWN - NLM STAT- MEDLINE DCOM- 20200406 LR - 20231104 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 21 IP - 1 DP - 2019 Apr 5 TI - 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. PG - 89 LID - 10.1186/s13075-019-1866-2 [doi] LID - 89 AB - BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006). FAU - Wollenhaupt, Jurgen AU - Wollenhaupt J AD - Rheumatologie Hamburg, Struenseehaus, Hamburg, Germany. FAU - Lee, Eun-Bong AU - Lee EB AD - Seoul National University, Seoul, Republic of Korea. FAU - Curtis, Jeffrey R AU - Curtis JR AD - University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Silverfield, Joel AU - Silverfield J AD - Healthpoint Medical Group, Tampa, FL, USA. FAU - Terry, Ketti AU - Terry K AD - Pfizer Inc, Groton, CT, USA. FAU - Soma, Koshika AU - Soma K AD - Pfizer Inc, New York, NY, USA. FAU - Mojcik, Chris AU - Mojcik C AD - Pfizer Inc, New York, NY, USA. FAU - DeMasi, Ryan AU - DeMasi R AD - Pfizer Inc, Collegeville, PA, USA. FAU - Strengholt, Sander AU - Strengholt S AD - Pfizer Inc, Capelle aan den Ijssel, Netherlands. FAU - Kwok, Kenneth AU - Kwok K AD - Pfizer Inc, New York, NY, USA. FAU - Lazariciu, Irina AU - Lazariciu I AD - IQVIA Canada, Montreal, Quebec, Canada. FAU - Wang, Lisy AU - Wang L AD - Pfizer Inc, Groton, CT, USA. Lisy.Wang@pfizer.com. FAU - Cohen, Stanley AU - Cohen S AD - Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX, USA. LA - eng SI - ClinicalTrials.gov/NCT00413699 PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20190405 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Antirheumatic Agents) RN - 0 (Piperidines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (Pyrroles) RN - 87LA6FU830 (tofacitinib) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Antirheumatic Agents/*therapeutic use MH - Arthritis, Rheumatoid/*drug therapy MH - Cardiovascular Diseases/chemically induced MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Female MH - Follow-Up Studies MH - Herpes Zoster/chemically induced MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/chemically induced MH - Piperidines/administration & dosage/adverse effects/*therapeutic use MH - Protein Kinase Inhibitors/administration & dosage/adverse effects/therapeutic use MH - Pyrimidines/administration & dosage/adverse effects/*therapeutic use MH - Pyrroles/administration & dosage/adverse effects/*therapeutic use MH - Time Factors MH - Treatment Outcome PMC - PMC6451219 OTO - NOTNLM OT - Long-term extension OT - Rheumatoid arthritis OT - Tofacitinib COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the Declaration of Helsinki, and the Good Clinical Practice Guidelines, along with applicable local regulatory requirements and laws. The study protocol was approved by the Institutional Review Boards and/or Independent Ethics Committee at each study center. All patients provided written, informed consent. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: JW and SC are consultants for, and have received speaker fees and honoraria from, Pfizer Inc. EBL is a consultant for Pfizer Inc and has received grant/research support from Green Cross Corporation and Hammi Pharm. JRC has received grant/research support and consultant fees from Pfizer Inc. JS has received grant/research support and speaker fees from Pfizer Inc. KT, KS, CM, RD, SS, KW, and LW are employees of, and hold shares in, Pfizer Inc. IL is an employee of IQVIA and a consultant for Pfizer Inc. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/04/07 06:00 MHDA- 2020/04/09 06:00 PMCR- 2019/04/05 CRDT- 2019/04/07 06:00 PHST- 2018/06/08 00:00 [received] PHST- 2019/03/18 00:00 [accepted] PHST- 2019/04/07 06:00 [entrez] PHST- 2019/04/07 06:00 [pubmed] PHST- 2020/04/09 06:00 [medline] PHST- 2019/04/05 00:00 [pmc-release] AID - 10.1186/s13075-019-1866-2 [pii] AID - 1866 [pii] AID - 10.1186/s13075-019-1866-2 [doi] PST - epublish SO - Arthritis Res Ther. 2019 Apr 5;21(1):89. doi: 10.1186/s13075-019-1866-2.