Top-down Infliximab Study in Kids with Crohn's disease (TISKids): an international multicentre randomised controlled trial

M A Cozijnsen, M van Pieterson, J N Samsom, J C Escher, L de Ridder, M A Cozijnsen, M van Pieterson, J N Samsom, J C Escher, L de Ridder

Abstract

Introduction: Crohn's disease (CD) is a chronic inflammatory disease predominantly affecting the gastrointestinal tract. CD usually requires lifelong medication and is accompanied by severe complications, such as fistulae and strictures, resulting in surgery. Infliximab (IFX) is very effective for treating paediatric patients with CD, but is currently only registered for therapy refractory patients-the so-called step-up strategy. We hypothesise that using IFX first-line, that is, top-down, will give more mucosal healing, fewer relapses, less complications, need for surgery and hospitalisation.

Methods and analysis: This international multicentre open-label randomised controlled trial includes children, aged 3-17 years, with new-onset, untreated CD with moderate-to-severe disease activity (weighted Paediatric Crohn's Disease Activity Index (wPCDAI)>40). Eligible patients will be randomised to top-down or step-up treatment. Top-down treatment consists of 5 IFX infusions combined with azathioprine (AZA). After these 5 infusions, patients will continue AZA. Patients randomised to step-up will receive standard induction treatment, either oral prednisolone or exclusive enteral nutrition, combined with AZA as maintenance treatment. The primary outcome is clinical remission (wPCDAI<12.5) at 52 weeks without need for additional CD-related therapy or surgery. Total follow-up is 5 years. Secondary outcomes include clinical disease activity, mucosal healing by endoscopy (at week 10 and optionally week 52), faecal calprotectin, growth, quality of life, medication use and adverse events.

Ethics and dissemination: Conducted according to the Declaration of Helsinki and Good Clinical Practice. Medical-ethical approval will be obtained for each site.

Trial registration number: NCT02517684; Pre-results.

Keywords: COST-EFFECTIVENESS; CROHN'S DISEASE; INFLIXIMAB; PAEDIATRIC GASTROENTEROLOGY; STEROID-SPARING EFFICACY.

Conflict of interest statement

JCE is part of the Scientific Advisory Committee of Janssen and Abbvie and received a research grant from Merck Sharp & Dohme (MSD). LdR reports a presentation on an Abbvie sponsored meeting.

Figures

Figure 1
Figure 1
Study design. EEN, exclusive enteral nutrition; IFX, infliximab; opt, optional; wPCDAI, weighted Paediatric Crohn's Disease Activity Index.

References

    1. Levine A, Koletzko S, Turner D, et al. . ESPGHAN revised Porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014;58:795–806.
    1. Benchimol EI, Fortinsky KJ, Gozdyra P, et al. . Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423–39.
    1. Van Limbergen J, Russell RK, Drummond HE, et al. . Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008;135:1114–22.
    1. Pigneur B, Seksik P, Viola S, et al. . Natural history of Crohn's disease: comparison between childhood- and adult-onset disease. Inflamm Bowel Dis 2010;16:953–61.
    1. Ruemmele FM, Veres G, Kolho KL, et al. . Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis 2014;8:1179–207.
    1. Vatn MH. Mucosal healing: impact on the natural course or therapeutic strategies. Dig Dis 2009;27:470–5.
    1. Lichtenstein GR, Feagan BG, Cohen RD, et al. . Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621–30.
    1. Lichtenstein GR. Approach to steroid-dependent and steroid-refractory Crohn's disease. J Pediatr Gastroenterol Nutr 2001;33(Suppl 1):S27–35.
    1. Markowitz J, Hyams J, Mack D, et al. . Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease. Clin Gastroenterol Hepatol 2006;4:1124–9.
    1. Hyams J, Crandall W, Kugathasan S, et al. . Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007;132:863–73.
    1. Vande Casteele N, Ferrante M, Van Assche G, et al. . Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology 2015;148: 1320–9.e3
    1. Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919–27.
    1. Cozijnsen MA, Escher JC, Griffiths A, et al. . Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2015;21:951–61.
    1. Church PC, Guan J, Walters TD, et al. . Infliximab maintains durable response and facilitates catch-up growth in luminal pediatric Crohn's disease. Inflamm Bowel Dis 2014;20:1177–86.
    1. Cozijnsen MA, de Ridder L. Infliximab more effective in therapy-naive than in therapy-refractory patients. J Pediatr Gastroenterol Nutr 2015;61:e15
    1. Lionetti P, Bronzini F, Salvestrini C, et al. . Response to infliximab is related to disease duration in paediatric Crohn's disease. Aliment Pharmacol Ther 2003;18:425–31.
    1. Kugathasan S, Werlin SL, Martinez A, et al. . Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease. Am J Gastroenterol 2000;95:3189–94.
    1. Rutgeerts P, Diamond RH, Bala M, et al. . Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endosc 2006;63:433–42.
    1. D'Haens G, Baert F, van Assche G, et al. . Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371:660–7.
    1. Fan R, Zhong J, Wang ZT, et al. . Evaluation of “top-down” treatment of early Crohn's disease by double balloon enteroscopy. World J Gastroenterol 2014;20:14479–87.
    1. Lee JS, Lee JH, Lee JH, et al. . Efficacy of early treatment with infliximab in pediatric Crohn's disease. World J Gastroenterol 2010;16:1776–81.
    1. Lee YM, Kang B, Lee Y, et al. . Infliximab “top-down” strategy is superior to “step-up” in maintaining long-term remission in the treatment of pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2015;60:737–43.
    1. Kim MJ, Lee JS, Lee JH, et al. . Infliximab therapy in children with Crohn's disease: a one-year evaluation of efficacy comparing ‘top-down’ and ‘step-up’ strategies. Acta Paediatr 2011;100: 451–5.
    1. Walters TD, Kim MO, Denson LA, et al. . Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children with Crohn's disease. Gastroenterology 2014;146:383–91.
    1. Turner D, Griffiths AM, Walters TD, et al. . Mathematical weighting of the pediatric Crohn's disease activity index (PCDAI) and comparison with its other short versions. Inflamm Bowel Dis 2012;18:55–62.
    1. Castor Electronic Data Capture, Ciwit BV, Amsterdam, The Netherlands, 2016.
    1. Otley A, Smith C, Nicholas D, et al. . The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002;35:557–63.
    1. Loonen HJ, Grootenhuis MA, Last BF, et al. . Measuring quality of life in children with inflammatory bowel disease: the impact-II (NL). Qual Life Res 2002;11:47–56.
    1. Daperno M, D'Haens G, Van Assche G, et al. . Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc 2004;60:505–12.

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