Shunsuke Furuta1, Daiki Nakagomi2, Yoshihisa Kobayashi3, Masaki Hiraguri4, Takao Sugiyama5, Koichi Amano6, Takeshi Umibe7, Hajime Kono8, Kazuhiro Kurasawa9, Yasuhiko Kita10, Ryutaro Matsumura11, Yuko Kaneko12, Keita Ninagawa13, Keiju Hiromura14, Shin-Ichiro Kagami15, Yosuke Inaba16, Hideki Hanaoka16, Kei Ikeda1, Hiroshi Nakajima1. 1. Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan. 2. Third Department of Internal Medicine, University of Yamanashi, Chuo, Japan. 3. Department of Internal Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan. 4. Allergy and Clinical Immunology Center, Japanese Red Cross Narita Hospital, Narita, Japan. 5. Department of Rheumatology, Shimoshizu Hospital, National Hospital Organization, Yotsukaido, Japan. 6. Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan. 7. Department of Internal Medicine, Matsudo City Hospital, Matsudo, Japan. 8. Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan. 9. Department of Rheumatology, Dokkyo Medical University, Tochigi, Japan. 10. Department of Rheumatology, Yokohama Rosai Hospital, Yokohama, Japan. 11. Department of Rheumatology, National Hospital Organization Chiba-East Hospital, Chiba, Japan. 12. Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. 13. Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. 14. Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan. 15. Research Center for Allergy and Clinical Immunology, Asahi General Hospital, Chiba, Japan. 16. Clinical Research Center, Chiba University Hospital, Chiba, Japan.
Abstract
Importance: The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. Objective: To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. Design, Setting, and Participants: This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. Interventions: Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). Main Outcomes and Measures: The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. Results: Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04). Conclusions and Relevance: Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. Trial Registration: ClinicalTrials.gov Identifier: NCT02198248.
RCT Entities:
Importance: The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. Objective: To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. Design, Setting, and Participants: This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. Interventions: Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). Main Outcomes and Measures: The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. Results: Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04). Conclusions and Relevance: Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. Trial Registration: ClinicalTrials.gov Identifier: NCT02198248.
Authors: Balazs Odler; Martin Windpessl; Marcell Krall; Maria Steiner; Regina Riedl; Carina Hebesberger; Martin Ursli; Emanuel Zitt; Karl Lhotta; Marlies Antlanger; Daniel Cejka; Philipp Gauckler; Martin Wiesholzer; Marcus Saemann; Alexander R Rosenkranz; Kathrin Eller; Andreas Kronbichler Journal: Front Immunol Date: 2021-10-29 Impact factor: 7.561
Authors: Yingqi Xiao; Gordon Guyatt; Linan Zeng; David Rw Jayne; Peter A Merkel; Reed Ac Siemieniuk; Jared E Dookie; Tayler A Buchan; Muhammad Muneeb Ahmed; Rachel J Couban; Alfred Mahr; Michael Walsh Journal: BMJ Open Date: 2022-02-25 Impact factor: 2.692