IntroductionCrohn’s disease (CD) is a chronic inflammatory bowel disease with a heterogeneous clinical presentation, relapse rate and treatment response. At present, no markers are available to adequately predict disease course at diagnosis. To prevent overtreatment of patients with a relative mild disease course, a step-up approach starting with corticosteroids is usually applied. Timely introduction of potentially disease modifying drugs and tight control of mucosal inflammation are crucial to prevent disease-related complications in patients with a complex disease course. We hypothesise that episodic treatment with adalimumab monotherapy in combination with close monitoring after drug discontinuation improves long-term outcome and reduces drug-related side effects, while preventing overtreatment.Methods and analysisIn this pragmatic multicentre randomised controlled trial, newly diagnosed CD patients or CD patients with a flare, naïve to thiopurines and biologicals, will be included and randomised 1:1 to open-label episodic (ie, 24 weeks) adalimumab monotherapy or step-up care starting with corticosteroids. The primary outcome is the number of yearly quarters of corticosteroid free clinical (Monitor Inflammatory Bowel Disease At Home score ≤3) and biochemical (C reactive protein within normal range and faecal calprotectin ≤200 µg/g) remission at week 96. Secondary outcomes are total healthcare costs, cumulative corticosteroid dose, proportion of patients with endoscopic remission at week 24, corticosteroid-free clinical remission, time to remission and patient-reported outcome measures on quality of life, (work) disability and treatment adherence. Safety outcomes are drug-related and disease-related adverse events and disease progression on MRI-enterography at week 96.Ethics and disseminationThis study is approved by the Medical Research Ethics Committee of azM/UM in Maastricht dated 21 August 2019 (METC18-076) and is monitored by the Clinical Trial Centre Maastricht according to Good Clinical Practice guidelines. Written informed consent will be obtained from all patients. Study results will be published in international peer-reviewed medical journals.Trial registration numberNCT03917303.
Background Treatment goals for Crohn’s disease (CD) tend to shift from clinical towards endoscopic remission as a potential means to reduce intestinal damage. Additionally, sustained corticosteroid (CS) free remission is warranted to prevent drug related side effects. In clinical trials, long-term efficacy of treatment is assessed by a range of outcome measures at variable time points. Besides clinical activity, it is recommended by the EMA to measure biochemical and endoscopic activity, given the poor correlation between commonly applied clinical activity indices and mucosal inflammation. Finally, STRIDE advices to add a PROM given the frequent perception gap in disease control between patient and health care professionals. Moreover, the relapsing-remitting nature of CD challenges timing of efficacy evaluations. Use of cross-sectional outcomes only on predetermined moments disregards the health status in between these measurements. In this systematic review, we provide an overview of the outcomes employed to assess long-term efficacy of maintenance (drug) therapy or treatment strategies in randomized controlled trials and their open label extensions in CD patients. Methods A systematic search of Pubmed and Embase databases was performed. Giving the emerging treatment goals, the search was restricted to trials published since 2007. Two independent reviewers screened titles and abstracts and selected eligible trials. We assessed whether and when long-term (i.e. >48 weeks) clinical, biochemical and/or endoscopic efficacy outcomes were used. In addition, data on patient perspective and CS use were collected. Results Sixty-seven out of 1947 articles were included (figure 1). Clinical activity indices were used in 66 studies (99%) as long-term efficacy outcome, with 20 studies (30%) taking into account concomitant CS use. C-reactive protein concentration was (part of) an outcome in 29 studies (43%), and faecal calprotectin in 15 studies (22%). Endoscopic activity was evaluated in 30 studies (45%). PROMs were used in 29 studies (43%), with IBDQ being the most frequently used. Seven studies measure long-term clinical, biochemical, endoscopic activity and patient perspective, in three studies a sustained CS free status as part of the outcome was required (table 1). In most studies cross-sectional measures or multiple measurements over time, so-called panel data, were used. Conclusion We established a lack of objective outcome measures of inflammation and patient perspective in clinical trials in CD, consequently missing pivotal data to evaluate current treatment goals. Additionally, cross-sectional outcomes on fixed time points were mostly applied, resulting in loss of efficacy information in chronic relapsing-remitting diseases.
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