Infliximab versus intravenous immunoglobulin for refractory Kawasaki disease: a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial

Masaaki Mori, Takuma Hara, Masako Kikuchi, Hiroyuki Shimizu, Tomoyuki Miyamoto, Satoru Iwashima, Tatsuya Oonishi, Kunio Hashimoto, Norimoto Kobayashi, Kenji Waki, Yasuo Suzuki, Yoshikazu Otsubo, Hiroshi Yamada, Chikao Ishikawa, Taichi Kato, Shigeto Fuse, Masaaki Mori, Takuma Hara, Masako Kikuchi, Hiroyuki Shimizu, Tomoyuki Miyamoto, Satoru Iwashima, Tatsuya Oonishi, Kunio Hashimoto, Norimoto Kobayashi, Kenji Waki, Yasuo Suzuki, Yoshikazu Otsubo, Hiroshi Yamada, Chikao Ishikawa, Taichi Kato, Shigeto Fuse

Abstract

We compared the efficacy and safety of infliximab with intravenous immunoglobulin (IVIG), a standard therapy, in a phase 3 trial (NCT01596335) for Japanese patients with Kawasaki disease (KD) showing persistent fever after initial IVIG. Patients with initial IVIG-refractory KD, aged 1-10 years, received a single dose of IV infliximab 5 mg/kg or IV polyethylene glycol-treated human immunoglobulin (VGIH) 2 g/kg on day 0. Primary outcome was defervescence rate within 48 h after the start of treatment. Safety was evaluated through day 56. Overall, 31 patients were randomized (infliximab, n = 16; VGIH, n = 15); 31.3% and 60.0% patients discontinued due to worsening KD. Defervescence rate within 48 h was greater with infliximab (76.7%) than VGIH (37.0%) (p = 0.023), and defervescence was achieved earlier with infliximab (p = 0.0072). Coronary artery lesions occurred in 1 (6.3%) and 3 (20.0%) patients receiving infliximab and VGIH, respectively, up to day 21. Adverse events occurred in 15 (93.8%) and 15 (100.0%) patients in the infliximab and VGIH groups, respectively. No serious adverse events in the infliximab group and one in the VGIH group were observed. Infliximab improved the defervescence rate within 48 h and time to defervescence versus standard therapy, and was well tolerated in patients with IVIG-refractory KD.

Conflict of interest statement

M.M. received personal fees from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and grants from Chugai Pharmaceutical Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Corporation; UCB Japan Co., Ltd.; Towa Pharmaceutical Co., Ltd.; AbbVie G.K.; Japan Blood Products Organization; Ayumi Pharmaceutical Co.; CSL Behring; and Nippon Kayaku Co., Ltd.; and personal fees from AbbVie G.K.; MSD K.K.; Daiichi Sankyo Co., Ltd.; and Taisho Pharmaceutical Co., Ltd. outside the submitted work. T.H. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and personal fees from Mitsubishi Tanabe Pharma Corporation outside the submitted work. M.K. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial. H.S. received grants from Mitsubishi Tanabe Pharma Corporation, during the conduct of the trial and personal fees from Taisho Toyama Pharmaceutical Co., Ltd. outside the submitted work. T.M. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial. S.I. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial. T.O. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and personal fees from Mitsubishi Tanabe Pharma Corporation and TEIJIN PHARMA Limited outside the submitted work. K.H. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and personal fees from Mitsubishi Tanabe Pharma Corporation outside the submitted work. N.K. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and personal fees from Mitsubishi Tanabe Pharma Corporation outside the submitted work. K.W. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial. Y.S. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial. Y.O. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial. H.Y. received personal fees from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and personal fees from Mitsubishi Tanabe Pharma Corporation outside the submitted work. C.I. received personal fees from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and personal fees from Mitsubishi Tanabe Pharma Corporation outside the submitted work. T.K. received grants from Mitsubishi Tanabe Pharma Corporation during the conduct of the trial and personal fees from Actelion Pharmaceuticals Japan, Ltd.; Astellas Pharma Inc.; and Meiji Seika Pharma Co., Ltd. outside the submitted work. S.F. received personal fees from Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Ltd., Nihon Pharmaceutical Co., Ltd.; and Japan Blood Products Organization outside the submitted work.

Figures

Figure 1
Figure 1
Patient disposition. KD, Kawasaki disease; VGIH, polyethylene glycol-treated human immunoglobulin.
Figure 2
Figure 2
Defervescent effect. (A) Defervescence rate (adjusted least squares mean, 95% CI) within 48 h after study drug administration. (B) Kaplan–Meier plot of febrile duration. CI, confidence interval; VGIH, polyethylene glycol-treated human immunoglobulin.
Figure 3
Figure 3
Changes in Z-scores for the internal diameter of the right coronary artery, left main coronary artery, left anterior descending artery, and left circumflex coronary artery in individual patients in each treatment group. VGIH, polyethylene glycol-treated human immunoglobulin.
Figure 4
Figure 4
Pharmacokinetics of infliximab. Mean (standard deviation) serum infliximab concentrations after a single dose.

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