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Impact of various central endoscopy reading models on treatment outcome in Crohn’s disease using data from the randomized, controlled, exploratory cohort arm of the BERGAMOT trial

      Background and Aims

      Endoscopic assessment of mucosal appearance by independent central reading has become the standard method to assess Crohn’s disease activity in clinical trials. The performance characteristics of various endoscopy reading models have yet to be systematically evaluated.

      Methods

      This substudy included patients with Crohn’s disease in the exploratory induction cohort of the BERGAMOT trial (NCT02394028) randomly assigned to etrolizumab or placebo. Endoscopies conducted at baseline and week 14 were independently scored using the Simple Endoscopic Score for Crohn’s Disease (SES-CD) by a local reader (LR) and 2 central readers (CRs). Five endoscopy reading models were compared: single LR, single CR, average of 2 CRs, and 2 models incorporating the LR and 1 or 2 CRs depending on alignment between the LR and the CR, defined according to a sliding scale applied to a range of scores.

      Results

      Five hundred thirty-five videos were scored. Models involving 2 readers demonstrated lower placebo rates (3.4%) than the single LR (11.9%) and the single CR (6.8%) models. Treatment effect size based on endoscopic improvement (≥50% reduction in SES-CD from baseline) was highest with the 2 models incorporating the LR and 1 or 2 CRs (Δ = 16.2%). Further, in the etrolizumab arm, models with 2 readers demonstrated the lowest variability for the SES-CD.

      Conclusions

      Central endoscopy reading models in Crohn’s disease have an impact on placebo response rates and effect size. Incorporating the LR appears to be important because models using both CRs and LRs resulted in the greatest treatment effect size for endoscopic improvement with etrolizumab, lower placebo rates, and reduced variability.

      Abbreviations:

      CR (central reader), CRM (central reader model), CDAI (Crohn’s Disease Activity Index), CDEIS (Crohn's Disease Endoscopic Index of Severity), LR (local reader), SES-CD (Simple Endoscopic Score for Crohn’s Disease)
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      References

        • Van Assche G.
        • Dignass A.
        • Panes J.
        • et al.
        The second European evidence-based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis.
        J Crohns Colitis. 2010; 4: 7-27
        • Lichtenstein G.R.
        • Loftus E.V.
        • Isaacs K.L.
        • et al.
        ACG clinical guideline: management of Crohn's disease in adults.
        Am J Gastroenterol. 2018; 113: 481-517
        • Peyrin-Biroulet L.
        • Panes J.
        • Sandborn W.J.
        • et al.
        Defining disease severity in inflammatory bowel diseases: current and future directions.
        Clin Gastroenterol Hepatol. 2016; 14: 348-354.e317
        • Williet N.
        • Sandborn W.J.
        • Peyrin-Biroulet L.
        Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2014; 12: 1246-1256.e1683
        • European Medicines Agency
        Guideline on the development of new medicinal products for the treatment of Crohn’s Disease.
        (Available at:)
        • Feagan B.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Performance of Crohn's disease clinical trial endpoints based upon different cutoffs for patient reported outcomes or endoscopic activity: analysis of EXTEND data.
        Inflamm Bowel Dis. 2018; 24: 932-942
        • McLeod C.
        • Norman R.
        • Litton E.
        • et al.
        Choosing primary endpoints for clinical trials of health care interventions.
        Contemp Clin Trials Commun. 2019; 16: 100486
        • Ford A.C.
        • Luthra P.
        • Hanauer S.B.
        • et al.
        Placebo response rate in clinical trials of fistulizing Crohn's disease: systematic review and meta-analysis.
        Clin Gastroenterol Hepatol. 2014; 12: 1981-1990
        • Reinisch W.
        • Colombel J.F.
        • D'Haens G.
        • et al.
        Characterisation of mucosal healing with adalimumab treatment in patients with moderately to severely active Crohn's disease: results from the EXTEND trial.
        J Crohns Colitis. 2017; 11: 425-434
        • Rutgeerts P.
        • Reinisch W.
        • Colombel J.F.
        • et al.
        Agreement of site and central readings of ileocolonoscopic scores in Crohn's disease: comparison using data from the EXTEND trial.
        Gastrointest Endosc. 2016; 83: 188-197.e181-e183
        • Panes J.
        • Feagan B.G.
        • Hussain F.
        • Levesque B.G.
        • Travis S.P.
        Central endoscopy reading in inflammatory bowel diseases.
        J Crohns Colitis. 2016; 10: S542-S547
        • Sandborn W.
        • Panes J.
        • Jones J.
        • et al.
        Etrolizumab as induction therapy in moderate to severe Crohn's disease: results from BERGAMOT cohort 1.
        Am J Gastroenterol. 2018; 113 (Poster P-011): S3
        • 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: 505-512
        • Gottlieb K.
        • Hussain F.
        Voting for image scoring and assessment (VISA)--theory and application of a 2 + 1 reader algorithm to improve accuracy of imaging endpoints in clinical trials.
        BMC Med Imaging. 2015; 15: 6
        • Gottlieb K.
        • Travis S.
        • Feagan B.
        • et al.
        Central reading of endoscopy endpoints in inflammatory bowel disease trials.
        Inflamm Bowel Dis. 2015; 21: 2475-2482
        • Feagan B.G.
        • Sandborn W.J.
        • D'Haens G.
        • et al.
        The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.
        Gastroenterology. 2013; 145: 149-157.e142
        • Hebuterne X.
        • Lemann M.
        • Bouhnik Y.
        • et al.
        Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.
        Gut. 2013; 62: 201-208

      Linked Article

      • Routine incorporation of the local read in Crohn’s disease clinical trials? Not so fast
        Gastrointestinal EndoscopyVol. 93Issue 1
        • Preview
          Over the past few years, endoscopic assessment of disease activity by use of the Simple Endoscopic Score for Crohn’s disease (SES-CD) has routinely been used to assess eligibility for Crohn’s disease (CD) clinical trials and as a coprimary efficacy endpoint.1 Variability in scoring with the use of multiple readers is inevitable with complex instruments such as the SES-CD.1 Training and standardized scoring rules can reduce variance and improve interrater agreement.2,3 However, this does not eliminate the potential for bias when scoring is performed by the participant’s caregiver or site investigator–local reader (LR), who has concomitant knowledge of clinical symptoms and foreknowledge of the time sequence of treatments.
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