Advertisement

Modeling Endoscopic Improvement after Induction Treatment With Mesalamine in Patients With Mild-to-Moderate Ulcerative Colitis

  • Christopher Ma
    Affiliations
    Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada
    Search for articles by this author
  • Jenny Jeyarajah
    Affiliations
    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada
    Search for articles by this author
  • Leonardo Guizzetti
    Affiliations
    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada
    Search for articles by this author
  • Claire E. Parker
    Affiliations
    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada
    Search for articles by this author
  • Siddharth Singh
    Affiliations
    Division of Gastroenterology, University of California San Diego, La Jolla, California

    Division of Biomedical Informatics, University of California San Diego, La Jolla, California
    Search for articles by this author
  • Parambir S. Dulai
    Affiliations
    Division of Gastroenterology, University of California San Diego, La Jolla, California
    Search for articles by this author
  • Geert R. D’Haens
    Affiliations
    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada

    Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, Netherlands
    Search for articles by this author
  • William J. Sandborn
    Affiliations
    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada

    Division of Gastroenterology, University of California San Diego, La Jolla, California
    Search for articles by this author
  • Brian G. Feagan
    Affiliations
    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada

    Division of Gastroenterology, Western University, London, Ontario, Canada

    Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
    Search for articles by this author
  • Vipul Jairath
    Correspondence
    Reprint requests Address requests for reprints to: Vipul Jairath, MD, PhD, Departments of Medicine and Epidemiology and Biostatistics, Division of Gastroenterology, Western University, London, Ontario, Canada N6A 5B6. fax: (519) 663-3658.
    Affiliations
    Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada

    Division of Gastroenterology, Western University, London, Ontario, Canada

    Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
    Search for articles by this author
Published:December 03, 2020DOI:https://doi.org/10.1016/j.cgh.2020.11.040

      Background & Aims

      Endoscopic improvement is an important treatment target for mild-to-moderate ulcerative colitis (UC). However, early endoscopic evaluation is not always feasible. We aimed to develop a clinical decision support tool to discriminate patients who have achieved endoscopic improvement from those with more severe inflammation following mesalamine induction therapy.

      Methods

      We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 726 adults with mild-to-moderate UC treated with mesalamine. Multivariable logistic regression modeling determined associations between candidate variables and endoscopic improvement (Mayo endoscopic subscore=0-1 according to blinded central reading) at Week 8. Internal model validation was performed using bootstrap resampling. A clinical decision support tool was developed to stratify patients into low, intermediate, and high probability groups for endoscopic improvement.

      Results

      Variables associated with endoscopic improvement at Week 8 included 50% reduction in fecal calprotectin from baseline (odds ratio [OR] 2.64, 95% CI:, 1.81, 3.85), reduction in rectal bleeding (OR 1.79 per point reduction, 95% CI: 1.35, 2.39), and improvement in physician global assessment (OR 2.32 per point improvement, 95% CI: 1.88, 2.85). The baseline Geboes score (OR 0.74 per grade, 95% CI: 0.65, 0.85) and prolonged disease duration (OR 0.95 per year, 95% CI: 0.92, 0.98) were negatively associated with endoscopic improvement. This model strongly discriminated endoscopic improvement in the development dataset (area under the curve [AUC] 0.84, 95% CI: 0.81, 0.87) and during validation (AUC 0.83).

      Conclusions

      We developed and validated a clinical decision support tool that has good discriminative performance for induction of endoscopic improvement in patients with mild-to-moderate UC treated with mesalamine. ClinicalTrials.gov Registration: NCT01903252.

      Keywords

      Abbreviations used in this paper:

      AUC (area under the curve), CI (confidence interval), MCS (Mayo Clinic Score), MES (Mayo endoscopic subscore), OR (odds ratio), PGA (physician’s global assessment), UC (ulcerative colitis)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Fumery M.
        • Singh S.
        • Dulai P.S.
        • et al.
        Natural history of adult ulcerative colitis in population-based cohorts: a systematic review.
        Clin Gastroenterol Hepatol. 2018; 16: 343-356 e3
        • Ko C.W.
        • Singh S.
        • Feuerstein J.D.
        • et al.
        AGA clinical practice guidelines on the management of mild-to-moderate ulcerative colitis.
        Gastroenterology. 2019; 156: 748-764
        • Harbord M.
        • Eliakim R.
        • Bettenworth D.
        • et al.
        Third European evidence-based consensus on diagnosis and management of ulcerative colitis: part 2—current management.
        J Crohns Colitis. 2017; 11: 769-784
        • Lamb C.A.
        • Kennedy N.A.
        • Raine T.
        • et al.
        British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
        Gut. 2019; 68: s1-s106
        • Jeuring S.F.
        • Bours P.H.
        • Zeegers M.P.
        • et al.
        Disease outcome of ulcerative colitis in an era of changing treatment strategies: results from the Dutch population-based IBDSL cohort.
        J Crohns Colitis. 2015; 9: 837-845
        • Vegh Z.
        • Burisch J.
        • Pedersen N.
        • et al.
        Incidence and initial disease course of inflammatory bowel diseases in 2011 in Europe and Australia: results of the 2011 ECCO-EpiCom inception cohort.
        J Crohns Colitis. 2014; 8: 1506-1515
        • Peyrin-Biroulet L.
        • Sandborn W.
        • Sands B.E.
        • et al.
        Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target.
        Am J Gastroenterol. 2015; 110: 1324-1338
        • Limketkai B.N.
        • Singh S.
        • Jairath V.
        • et al.
        US practice patterns and impact of monitoring for mucosal inflammation after biologic initiation in inflammatory bowel disease.
        Inflamm Bowel Dis. 2019; 25: 1828-1837
        • Parasa S.
        • Reddy N.
        • Faigel D.O.
        • et al.
        Global impact of the COVID-19 pandemic on endoscopy: an international survey of 252 centers from 55 countries.
        Gastroenterology. 2020; 159: 1579-1581
        • D’Haens G.R.
        • Sandborn W.J.
        • Zou G.
        • et al.
        Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis.
        Aliment Pharmacol Ther. 2017; 46: 292-302
        • Schroeder K.W.
        • Tremaine W.J.
        • Ilstrup D.M.
        Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study.
        N Engl J Med. 1987; 317: 1625-1629
        • Geboes K.
        • Riddell R.
        • Ost A.
        • et al.
        A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.
        Gut. 2000; 47: 404-409
        • US Food and Drug Administration
        Ulcerative colitis: clinical trial endpoints guidance for industry. In: Department of Health and Human Services (US) FDA, Center for Drug Evaluation and Research (CDER), Rockville, MD.
        (Available at:) (2016, Accessed November 7, 2019)
        • Ma C.
        • Panaccione R.
        • Fedorak R.N.
        • et al.
        Heterogeneity in definitions of endpoints for clinical trials of ulcerative colitis: a systematic review for development of a core outcome set.
        Clin Gastroenterol Hepatol. 2018; 16: 637-647 e13
        • Nagelkerke N.J.D.
        A note on a general definition of the coefficient of determination.
        Biometrika. 1991; 78: 691-692
        • Brier G.W.
        Verification of forecasts expressed in terms of probability.
        Monthly Weather Review. 1950; 78: 1-3
        • Hosmer D.W.
        • Lemeshow S.
        A goodness-of-fit test for the multiple logistic regression model.
        Communications in Statistics. 1980; A10: 1043-1069
        • Harrell F.
        Regression modeling strategies.
        2nd ed. Springer International Publishing, New York, NY2015
        • Sullivan L.M.
        • Massaro J.M.
        • D’Agostino Sr., R.B.
        Presentation of multivariate data for clinical use: the Framingham Study risk score functions.
        Stat Med. 2004; 23: 1631-1660
        • Ma C.
        • Sandborn W.J.
        • D’Haens G.R.
        • et al.
        Discordance between patient-reported outcomes and mucosal inflammation in patients with mild to moderate ulcerative colitis.
        Clin Gastroenterol Hepatol. 2020; 18: 1760-1768 e1
        • Schoepfer A.M.
        • Vavricka S.
        • Zahnd-Straumann N.
        • et al.
        Monitoring inflammatory bowel disease activity: clinical activity is judged to be more relevant than endoscopic severity or biomarkers.
        J Crohns Colitis. 2012; 6: 412-418
        • De Vos M.
        • Dewit O.
        • D’Haens G.
        • et al.
        Fast and sharp decrease in calprotectin predicts remission by infliximab in anti-TNF naive patients with ulcerative colitis.
        J Crohns Colitis. 2012; 6: 557-562
        • Reinisch W.
        • Bressler B.
        • Curtis R.
        • et al.
        Fecal calprotectin responses following induction therapy with vedolizumab in moderate to severe ulcerative colitis: a post hoc analysis of GEMINI 1.
        Inflamm Bowel Dis. 2019; 25: 803-810
        • D’Haens G.
        • Ferrante M.
        • Vermeire S.
        • et al.
        Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease.
        Inflamm Bowel Dis. 2012; 18: 2218-2224
        • Molander P.
        • Bjorkesten C.G.
        • Mustonen H.
        • et al.
        Fecal calprotectin concentration predicts outcome in inflammatory bowel disease after induction therapy with TNFalpha blocking agents.
        Inflamm Bowel Dis. 2012; 18: 2011-2017
        • Brahmania M.
        • Bernstein C.N.
        Physician global assessments or blood tests do not predict mucosal healing in ulcerative colitis.
        Can J Gastroenterol Hepatol. 2014; 28: 325-329
        • Walsh A.J.
        • Ghosh A.
        • Brain A.O.
        • et al.
        Comparing disease activity indices in ulcerative colitis.
        J Crohns Colitis. 2014; 8: 318-325
        • Turner D.
        • Griffiths A.M.
        • Mack D.
        • et al.
        Assessing disease activity in ulcerative colitis: patients or their physicians?.
        Inflamm Bowel Dis. 2010; 16: 651-656
        • Sandborn W.J.
        • Ferrante M.
        • Bhandari B.R.
        • et al.
        Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis.
        Gastroenterology. 2020; 158: 537-549.e10
        • Steyerberg E.W.
        • Harrell Jr., F.E.
        • Borsboom G.J.
        • et al.
        Internal validation of predictive models: efficiency of some procedures for logistic regression analysis.
        J Clin Epidemiol. 2001; 54: 774-781
        • Marchal-Bressenot A.
        • Salleron J.
        • Boulagnon-Rombi C.
        • et al.
        Development and validation of the Nancy histological index for UC.
        Gut. 2017; 66: 43-49
        • Mosli M.H.
        • Feagan B.G.
        • Zou G.
        • et al.
        Reproducibility of histological assessments of disease activity in UC.
        Gut. 2015; 64: 1765-1773
        • Hanauer S.B.
        • Sandborn W.J.
        • Kornbluth A.
        • et al.
        Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial.
        Am J Gastroenterol. 2005; 100: 2478-2485
        • Kruis W.
        • Bar-Meir S.
        • Feher J.
        • et al.
        The optimal dose of 5-aminosalicylic acid in active ulcerative colitis: a dose-finding study with newly developed mesalamine.
        Clin Gastroenterol Hepatol. 2003; 1: 36-43