Infliximab for pediatric patients with ulcerative colitis: a phase 3, open-label, uncontrolled, multicenter trial in Japan

Hitoshi Tajiri, Katsuhiro Arai, Seiichi Kagimoto, Reiko Kunisaki, Nobuyuki Hida, Noriko Sato, Hiroshi Yamada, Mieko Nagano, Yutaka Susuta, Kunihiko Ozaki, Kazuoki Kondo, Toshifumi Hibi, Hitoshi Tajiri, Katsuhiro Arai, Seiichi Kagimoto, Reiko Kunisaki, Nobuyuki Hida, Noriko Sato, Hiroshi Yamada, Mieko Nagano, Yutaka Susuta, Kunihiko Ozaki, Kazuoki Kondo, Toshifumi Hibi

Abstract

Background: Pediatric ulcerative colitis (UC) is typically more extensive and has a more active disease course than adult UC, and requires early treatment augmentation to achieve and maintain disease remission. The present study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe UC and inadequate response to existing treatment.

Methods: This open-label, uncontrolled, multicenter, Phase 3 trial was conducted at 17 centers in Japan between April 2012 and September 2014. Pediatric patients (aged 6-17 years) diagnosed with moderate-to-severe UC received a treatment protocol comprising 5 mg/kg IFX at Weeks 0, 2, and 6, and Clinical Activity Index (CAI)-based responders at Week 8 also received treatment at 8-week intervals at Weeks 14 and 22, with a final evaluation at Week 30.

Results: A total of 21 patients were treated in this study. IFX therapy rapidly improved clinical symptoms, and this effect was maintained for up to 30 weeks. Overall CAI-based remission rate was 42.9% and overall Pediatric Ulcerative Colitis Activity Index (PUCAI)-based remission rate was 19.0%. Median partial Mayo score was 6.0 at baseline and 4.0 at Week 30 (overall). Among the eight patients who underwent sigmoidoscopy, Mayo response was achieved at Week 30 (overall) in three patients (37.5%). Trough serum IFX concentrations in Week 8 CAI-based responders were maintained throughout the study period. Adverse events and serious adverse events were observed in 95.2 and 14.3% of patients, respectively.

Conclusions: These results support the use of IFX in the treatment of pediatric patients with UC with inadequate response to existing treatment.

Trial registration: ClinicalTrials.gov, registration number: NCT01585155 .

Keywords: Infliximab; Japan; Multicenter trial; Pediatric; Phase 3; Ulcerative colitis.

Conflict of interest statement

HT received consultancy fees from Mitsubishi Tanabe Pharma Corporation. KA received consultancy fees from Mitsubishi Tanabe Pharma Corporation; and speaking fees from AbbVie G.K., EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation and Nippon Kayaku Co., Ltd. RK has financial competing interests with Abbott Japan Co., Ltd., AbbVie G.K., AJINOMOTO CO., Inc., Asahi Kasei Medical Co., Ltd., AstraZeneca, Astellas Pharm Inc., EA Pharma Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., RPM Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd. NH received lecture fees from AbbVie G.K. and Mitsubishi Tanabe Pharma Corporation. NS, HY, MN, YS, KO, and KK are employees of Mitsubishi Tanabe Pharma Corporation. TH received consultancy fees from AbbVie G.K., EA Pharma Co., Ltd., Eli Lilly Japan K.K., JIMRO Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nichi-Iko Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd.; lecture fees from AbbVie G.K., Celltrion Healthcare Co., Ltd., EA Pharma Co., Ltd., Ferring Pharmaceuticals Co., Ltd., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MIYARISAN Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd.; and research grants from AbbVie G.K., EA Pharma Co., Ltd., JIMRO Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd. The other authors have no competing interests.

Figures

Fig. 1
Fig. 1
Overview of the study design. CAI Clinical Activity Index, IFX infliximab. CAI score-based responder: patient who had a decreased (improved) CAI score at Week 8 compared with that measured at the time of registration. CAI score-based non-responder: patient who had an unchanged or increased (worsened) CAI score at Week 8 compared with that measured at the time of registration
Fig. 2
Fig. 2
Flow chart of patients throughout the study. AE adverse event, CAI Clinical Activity Index, IFX infliximab, UC ulcerative colitis
Fig. 3
Fig. 3
Efficacy responses to IFX treatment over time in Japanese patients with UC. (a) Median change in CAI scores. The open circle represents the median CAI score at Week 30 (overall). (b) CAI-based remission. (c) Median change in PUCAI scores. The open square represents the median PUCAI score at Week 30 (overall). (d) PUCAI-based remission and patients who achieved a decrease in PUCAI score of ≥20 over 30 weeks of IFX treatment among patients who achieved a response after 8 weeks of treatment. CAI Clinical Activity Index, IFX infliximab, PUCAI Pediatric Ulcerative Colitis Activity Index, UC ulcerative colitis
Fig. 4
Fig. 4
Trough serum IFX concentration at Week 14 in patients who did/did not achieve CAI remission. CAI Clinical Activity Index, IFX infliximab

References

    1. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54. doi: 10.1053/j.gastro.2011.10.001.
    1. Baldassano RN, Piccoli DA. Inflammatory bowel disease in pediatric and adolescent patients. Gastroenterol Clin N Am. 1999;28:445–458. doi: 10.1016/S0889-8553(05)70064-9.
    1. Ishige T, Tomomasa T, Takebayashi T, Asakura K, Watanabe M, Suzuki T, et al. Inflammatory bowel disease in children: epidemiological analysis of the nationwide IBD registry in Japan. J Gastroenterol. 2010;45:911–917. doi: 10.1007/s00535-010-0223-7.
    1. Jakobsen C, Bartek J, Jr, Wewer V, Vind I, Munkholm P, Groen R, et al. Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease--a population-based study. Aliment Pharmacol Ther. 2011;34:1217–1224. doi: 10.1111/j.1365-2036.2011.04857.x.
    1. Ruemmele FM, Turner D. Differences in the management of pediatric and adult onset ulcerative colitis--lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative colitis. J Crohns Colitis. 2014;8:1–4. doi: 10.1016/j.crohns.2013.10.006.
    1. Turner D, Levine A, Escher JC, Griffiths AM, Russell RK, Dignass A, et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nutr. 2012;55:340–361. doi: 10.1097/MPG.0b013e3182662233.
    1. Van Limbergen J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008;135:1114–1122. doi: 10.1053/j.gastro.2008.06.081.
    1. Hibi T. Guidelines for the management of ulcerative colitis in Japan. IBD Res. 2010;4:189–239.
    1. Gisbert JP, González-Lama Y, Maté J. Systematic review: infliximab therapy in ulcerative colitis. Aliment Pharmacol Ther. 2007;25:19–37. doi: 10.1111/j.1365-2036.2006.03131.x.
    1. Hyams J, Damaraju L, Blank M, Johanns J, Guzzo C, Winter HS, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2012;10:391–399. doi: 10.1016/j.cgh.2011.11.026.
    1. Kobayashi T, Suzuki Y, Motoya S, Hirai F, Ogata H, Ito H, et al. First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis-results from a multicenter prospective randomized controlled trial and its post hoc analysis. J Gastroenterol. 2016;51:241–251. doi: 10.1007/s00535-015-1102-z.
    1. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–2476. doi: 10.1056/NEJMoa050516.
    1. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317:1625–1629. doi: 10.1056/NEJM198712243172603.
    1. Turner D, Seow CH, Greenberg GR, Griffiths AM, Silverberg MS, Steinhart AH. A systematic prospective comparison of noninvasive disease activity indices in ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7:1081–1088. doi: 10.1016/j.cgh.2009.06.024.
    1. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ. 1989;298:82–86. doi: 10.1136/bmj.298.6666.82.
    1. Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007;133:423–432. doi: 10.1053/j.gastro.2007.05.029.
    1. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41:1552–1563. doi: 10.1002/1529-0131(199809)41:9<1552::AID-ART5>;2-W.
    1. Adedokun OJ, Sandborn WJ, Feagan BG, Rutgeerts P, Xu Z, Marano CW, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014;147:1296–1307. doi: 10.1053/j.gastro.2014.08.035.
    1. Adedokun OJ, Xu Z, Padgett L, Blank M, Johanns J, Griffiths A, et al. Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase 3 study. Inflamm Bowel Dis. 2013;19:2753–2762. doi: 10.1097/01.MIB.0000435438.84365.f7.
    1. Choi SY, Kang B, Lee JH, Choe YH. Clinical use of measuring trough levels and antibodies against infliximab in patients with pediatric inflammatory bowel disease. Gut Liver. 2017;11:55–61. doi: 10.5009/gnl16041.
    1. Rolandsdotter H, Marits P, Sundin U, Wikström AC, Fagerberg UL, Finkel Y, et al. Serum-infliximab trough levels in 45 children with inflammatory bowel disease on maintenance treatment. Int J Mol Sci. 2017;18:575. doi: 10.3390/ijms18030575.
    1. Tajiri H, Motoya S, Kinjo F, Maemoto A, Matsumoto T, Sato N, et al. Infliximab for pediatric patients with Crohn's disease: a phase 3, open-label, uncontrolled, multicenter trial in Japan. PLoS One. 2018;13:e0201956. doi: 10.1371/journal.pone.0201956.
    1. Hibi T, Sakuraba A, Watanabe M, Motoya S, Ito H, Motegi K, et al. Retrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn's disease. Inflamm Bowel Dis. 2012;18:1480–1487. doi: 10.1002/ibd.21886.

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