Discontinuation of infliximab therapy in patients with Crohn's disease in sustained complete remission (the STOP IT study): protocol for a double-blind, randomised, placebo-controlled, multicentre trial

Abstract

IntroductionInfliximab (IFX), a monoclonal chimeric antibody against tumour necrosis factor (TNF) α, is effective for induction and maintenance of remission in moderate to severe Crohn's disease. Discontinuation of IFX maintenance therapy in patients in remission should be considered in order to reduce the potential long-term side effects and lower costs.Methods and analysisThis is a prospective, double-blind, randomised, placebo-controlled, multicentre study of patients with luminal Crohn’s disease who have been treated with IFX for at least 1 year and are in sustained complete clinical, biochemical and endoscopic remission (ie, Crohn's Disease Activity Index (CDAI) score <150, complete mucosal healing and biochemical markers of inflammation within the normal range). These patients are randomised to receive placebo infusions or continue IFX maintenance therapy. The primary end point is the proportion of patients in maintained remission after 48 weeks (def. CDAI <150).Ethics and disseminationIt is estimated that the knowledge gained about how to optimally handle patients with Crohn’s disease in complete long-term sustained remission on IFX is proportionate to the risks and inconveniences related to participation in this study. Prolonged exposure to IFX may cause severe side effects and increased risk of malignancies. Conversely, IFX discontinuation should not unnecessarily create a high risk of relapse. Thus, empirical evidence is needed concerning the safety of discontinuing IFX once a patient exhibits sustained remission. Study results will be published in an English language scientific medical journal. The study is approved by the Danish Medicines Agency (EudraCT-number: 2012-002702-51) and the Regional Ethics Committee of Region Hovedstaden Denmark (Approval-number: H-4-2012-099). The project is reported to the Danish Data Protection Agency (ID-number: 2007-58-0015/HEH.750.89-27), registered at Clinicaltrials.gov, and monitored by independent GCP units for the University of Copenhagen, Odense and Aarhus. The current approved protocol is V.3.2, dated 1 June 2014.Trial registration numberhttp://clinicaltrials.gov/show/NCT01817426.

De‐escalating medical therapy in Crohn’s disease patients who are in deep remission: A RAND appropriateness panel

“…The appropriateness of de‐escalation of medical therapy in CD patients was rated uncertain in more than 60% of scenarios in our study. Hopefully some of this uncertainty will be addressed by ongoing studies such as SPARE and STOP IT, which are prospectively evaluating the benefits of discontinuing infliximab or IM in patients with CD who achieve deep remission on combination therapy. SPARE will prospectively evaluate relapse and remission rates using objective clinical endpoints after pre‐specified de‐escalation strategies .…”

“…[1][2][3] Extrapolating from these data, clinical and biochemical factors associated with the risk of relapse have been identified, 1,[14][15][16] and algorithms for de-escalation have been proposed. 17 However, prospective trials of anti-TNF/IM withdrawal in patients on combination therapy are still ongoing, 18,19 and prospective trials of IM monotherapy withdrawal to date have assessed only thiopurines, [10][11][12][13] potentially limiting applicability of study results to real-world clinical practice where both thiopurines and methotrexate are used.…”

De-escalation of immunomodulator and biological therapy in inflammatory bowel disease

“…The efficacy of each treatment group to maintain remission will be assessed. Further data on the discontinuation of infliximab in Crohn's disease will be provided by the STOP IT trial, 90 while the BIOSTOP trial (EudraCT number 2016-001409-18) will assess the effects of anti-TNF withdrawal in patients with ulcerative colitis and explore the feasibility of drug holidays, as the protocol allows for the anti-TNF to be restarted in the event of relapse.…”

Personalising therapy: de‐escalation in Crohn's disease patients who are in deep remission

“…Furthermore, when considering withdrawing, anti-TNF levels may be important and important factor which was not taken into account in this study but this is subject to an ongoing randomised controlled trial. 4 What is also not covered in this paper is whether expert opinion will be different if there was a clear strategy to monitor patients to allow early identification of relapse so that therapy can be re-introduced in a timely fashion as in most cases reintroduction of therapy is successful. 5 This has resulted in the concept of allowing for drug holidays in some patients.…”

“…In this study a 6‐month period of remission was suggested but one may debate whether this should be a longer period of sustained remission before consideration therapy withdrawal. Furthermore, when considering withdrawing, anti‐TNF levels may be important and important factor which was not taken into account in this study but this is subject to an ongoing randomised controlled trial …”