Nicolino Ruperto1, Hermine I Brunner2, Olga Synoverska3, Tracy V Ting2, Carlos Abud Mendoza4, Alberto Spindler5, Yulia Vyzhga6, Katherine Marzan7, Lyudmila Grebenkina8, Irit Tirosh9, Lisa Imundo10, Rita Jerath11, Daniel J Kingsbury12, Betul Sozeri13, Sheetal S Vora14, Sampath Prahalad15, Elena Zholobova16, Yonatan Butbul Aviel17, Vyacheslav Chasnyk18, Melissa Lerman19, Kabita Nanda20, Heinrike Schmeling21, Heather Tory22, Yosef Uziel23, Diego O Viola24, Holly B Posner25, Keith S Kanik26, Ann Wouters25, Cheng Chang26, Richard Zhang25, Irina Lazariciu25, Ming-Ann Hsu26, Ricardo M Suehiro27, Alberto Martini28, Daniel J Lovell2. 1. IRCCS Istituto Giannina Gaslini, UOSID Centro Trial, PRINTO, Genova, Italy. Electronic address: nicolaruperto@gaslini.org. 2. College of Medicine, University of Cincinnati, and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 3. Regional Children's Hospital, Ivano-Frankivsk, Ukraine. 4. Regional Unit of Rheumatology and Osteoporosis at Central Hospital, Faculty of Medicine, San Luis Potosí, Mexico. 5. Centro Médico Privado de Reumatologia, Tucumán, Argentina. 6. Vinnytsya National Medical University N Pirogov, Vinnytsya, Ukraine. 7. Division of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 8. Togliatti City Clinical Hospital number 5, Togliatti, Russia. 9. Pediatric Rheumatology Unit and Department of Pediatrics, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 10. Adolescent Rheumatology Columbia University Medical Center, New York, NY, USA. 11. Augusta University Medical Center, Augusta, GA, USA. 12. Augusta University Medical Center, Augusta, GA, USA; Randall Children's Hospital at Legacy Emanuel, Portland, OR, USA. 13. Department of Pediatric Rheumatology, Ümraniye Training and Research Hospital, Istanbul, Turkey. 14. Pediatric Rheumatology, Atrium Health Levine Children's Hospital, Charlotte, NC, USA. 15. Departments of Pediatrics and Human Genetics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA, USA. 16. Institute of Children's Health, University Children's Clinical Hospital, Sechenov University, Moscow, Russia. 17. Pediatric Rheumatology Service, Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel. 18. Saint Petersburg State Pediatric Medical University, Saint-Petersburg, Russia. 19. Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 20. Division of Rheumatology, Seattle Children's Hospital, Seattle, WA, USA. 21. Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada. 22. Division of Rheumatology, Connecticut Children's Medical Center, Hartford, and Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA. 23. Pediatric Rheumatology Unit, Department of Pediatrics, Meir Medical Centre, Kfar Saba, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 24. CAICI Institute, Rosario City, Argentina. 25. Pfizer, New York, NY, USA. 26. Pfizer, Groton, CT, USA. 27. Pfizer, Collegeville, PA, USA. 28. Università degli Studi di Genova, Genova, Italy.
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.
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.
Authors: Alberto Martini; Daniel J Lovell; Salvatore Albani; Hermine I Brunner; Kimme L Hyrich; Susan D Thompson; Nicolino Ruperto Journal: Nat Rev Dis Primers Date: 2022-01-27 Impact factor: 65.038
Authors: Mikhail M Kostik; Rinat K Raupov; Evgeny N Suspitsin; Eugenia A Isupova; Ekaterina V Gaidar; Tatyana V Gabrusskaya; Maria A Kaneva; Ludmila S Snegireva; Tatyana S Likhacheva; Rimma S Miulkidzhan; Artem V Kosmin; Anastasia V Tumakova; Vera V Masalova; Margarita F Dubko; Olga V Kalashnikova; Ivona Aksentijevich; Vyacheslav G Chasnyk Journal: Front Pediatr Date: 2022-02-08 Impact factor: 3.418