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

https://doi.org/10.1016/j.cgh.2020.11.040Get rights and content

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.

Section snippets

Data and Participants

We used data from an active-comparator, multicenter, randomized, non-inferiority trial of mesalamine (Clinicaltrials.gov NCT01903252). The study design and trial outcomes have been previously reported.10 Adults with mild-to-moderate UC, defined by a total Mayo Clinic Score11 (MCS) ≥5, rectal bleeding subscore ≥1, and Mayo endoscopic subscore (MES) ≥2 at baseline were randomized to receive 3.2 g oral mesalamine, administered as either two 1600 mg tablets once daily or four 400 mg tablets twice

Patients

A total of 726 patients were included, and 436 patients (60.1%) achieved endoscopic improvement at week 8. Mean disease duration was 5.3 years (standard deviation ±6.5 years), and mean baseline fecal calprotectin was 1108 μg/g (±1546 μg/g). Mean rectal bleeding subscore was 1.5 (±0.5), and mean baseline Geboes score was 4.3 (±1.3).

Modeling Endoscopic Improvement

Univariable associations with endoscopic improvement are summarized in Supplementary Table 1. Multivariable logistic regression analyses are presented in Table 1.

Discussion

Although targeting endoscopic endpoints is associated with improved long-term outcomes in patients with UC, repeated lower endoscopy to evaluate disease activity is time-intensive, costly, and invasive for patients. Furthermore, many practices are facing restricted endoscopy availability because of coronavirus disease 2019, leading to a situation where many patients with mild-to-moderate UC will not undergo repeat endoscopy to measure treatment response to mesalamine. Although existing

CRediT Authorship Contributions

Christopher Ma, MD, MPH (Conceptualization: Lead; Data curation: Supporting; Methodology: Lead; Supervision: Equal; Writing – original draft: Lead; Writing – review & editing: Lead)

Jenny Jeyarajah (Conceptualization: Supporting; Formal analysis: Lead; Writing – review & editing: Supporting)

Leonardo Guizzetti (Formal analysis: Lead; Writing – review & editing: Supporting)

Claire E. Parker (Writing – original draft: Supporting; Writing – review & editing: Supporting)

Siddharth Singh (Writing –

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    Conflicts of interest The authors disclose the following: Christopher Ma has received consulting fees from AbbVie, AVIR Pharma Inc, Janssen, Pfizer, Robarts Clinical Trials, and Takeda; and speaker’s fees from AbbVie, Janssen, Pfizer, and Takeda. Jenny Jeyarajah is an employee of Robarts Clinical Trials, Inc. Leonardo Guizzetti is an employee of Robarts Clinical Trials, Inc. Claire Parker is an employee of Robarts Clinical Trials, Inc. Siddharth Singh has received research grants from AbbVie and consulting fees from AbbVie, Takeda, Pfizer, and AMAG Pharmaceuticals. Parambir Dulai is supported by an American Gastroenterology Association Research Scholar Award and has received research support and/or consulting fees from AbbVie, Takeda, Pfizer, Janssen, Buhlmann, Polymedco, and Prometheus. Geert D’Haens has received consulting fees from AbbVie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmo, Covidien/Medtronics, Dr. Falk Pharma, Engene, Ferring, Galapagos, Gilead, GlaxoSmithKline, Hospira, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millennium/Takeda, Mitsubishi Pharma, MSD, Mundipharma, Novo Nordisk, Pfizer Inc, Prometheus Laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor; research grants from AbbVie, Falk, Ferring, MSD, Mundipharma, and Takeda; and lecture and/or speaker bureau fees from AbbVie, Ferring, Johnson and Johnson, Millennium/Takeda, MSD, Mundipharma, Norgine, Pfizer Inc, Shire, Tillotts, and Vifor. William Sandborn has received research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, Celgene/Receptos, Pfizer, Prometheus Laboratories (now Prometheus Biosciences); consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Progenity, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals; and stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences. Spouse: Opthotech - consultant, stock options; Progenity - consultant, stock; Oppilan Pharma - employee, stock options; Escalier Biosciences - employee, stock options; Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories) - employee, stock options; Ventyx Biosciences – employee, stock options; Vimalan Biosciences – employee, stock options. Brian Feagan has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals Inc; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc, Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc, and Sigmoid Pharma; and speaker’s fees from UCB, AbbVie, and J&J/Janssen. Vipul Jairath has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, Celltrion; and speaker’s fees from Takeda, Janssen, Shire, Ferring, AbbVie, and Pfizer.

    Funding The randomized trial was funded in full by Tillotts Pharma, AG. Tillotts Pharma, AG had no role in the design, analysis, or writing of this manuscript. William Sandborn was supported in part by NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515).

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