Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial
- PMID: 34767764
- DOI: 10.1016/S0140-6736(21)01255-1
Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial
Abstract
Background: Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
Methods: This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Findings: Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
Interpretation: The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Funding: Pfizer.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests NR has received honoraria for consultancy fees or speaker bureaus from Ablynx, AstraZeneca/MedImmune, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, EMD Serono, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, R-Pharm, Sanofi, Servier, Sinergie, and Sobi. The IRCCS Istituto Giannina Gaslini, where NR works as a full-time public employee, has received contributions from the following pharmaceutical companies in the past 3 years: Bristol-Myers Squibb, Eli Lilly, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, and Sobi; this funding has been reinvested for the research activities of the hospital in a fully independent manner, without any involvement of third parties. HIB has received research grants from Bristol-Myers Squibb, MedImmune, Novartis, and Pfizer; is an employee of Cincinnati Children's Hospital Medical Center; has received consulting fees or other remuneration from AbbVie, AstraZeneca/MedImmune, Bayer, Biocon, Boehringer Ingelheim, Janssen, Lilly, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and R-Pharm; and is a member of speaker bureaus for GlaxoSmithKline, Novartis, and Roche. OS is a member of a speaker bureau for Sanofi. AS is a member of a speaker bureau for Eli Lilly. KM has received research grants from Novartis and Pfizer. SP has received consulting fees or other remuneration from Novartis. EZ is a member of speaker bureaus for AbbVie, Novartis, Pfizer, and Roche. ML has received research grants from Amgen. KN has received research grants from Abbott, AbbVie, Amgen, Bristol-Myers Squibb, Patient-Centered Outcomes Research Institute, and Roche. HS has received research grants from Bristol-Myers Squibb, Janssen, Pfizer, Roche, Sanofi, and USB Bioscience. YU is a member of a speaker bureau for Pfizer. DOV has received research grants from Bristol-Myers Squibb, GlaxoSmithKline, Janssen, and Pfizer; and is a member of speaker bureaus for AbbVie and Bristol-Myers Squibb. HBP, KSK, AW, CC, RZ, M-AH, and RMS are employees and stockholders of Pfizer. IL is an employee of IQVIA, who were paid contractors to Pfizer in the development of this manuscript and in providing statistical support. AM has received consulting fees or other remuneration from Aurinia, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Janssen, and Pfizer. DJL's institution, the Cincinnati Children's Hospital Medical Center, has received research grants from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Roche, and UCB; and has received consulting fees or other remuneration from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Roche, Takeda, and UCB for the work of DJL. DJL is a Data Safety and Monitoring Board chairperson for Forest Research and the National Institutes of Health. All otjer authors declare no competing interests.
Comment in
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Tofacitinib in juvenile idiopathic arthritis.Lancet. 2021 Nov 27;398(10315):1943-1945. doi: 10.1016/S0140-6736(21)01444-6. Epub 2021 Nov 9. Lancet. 2021. PMID: 34767763 No abstract available.
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Tofacitinib a promising oral therapy for JIA.Nat Rev Rheumatol. 2022 Feb;18(2):63. doi: 10.1038/s41584-021-00737-5. Nat Rev Rheumatol. 2022. PMID: 34907349 No abstract available.
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Tofacitinib for juvenile idiopathic arthritis.Lancet. 2022 May 14;399(10338):1865-1866. doi: 10.1016/S0140-6736(22)00836-4. Lancet. 2022. PMID: 35569464 No abstract available.
