The Role of Centralized Reading of Endoscopy in a Randomized Controlled Trial of Mesalamine for Ulcerative Colitis

doi:10.1053/j.gastro.2013.03.025

Gastroenterology

Volume 145, Issue 1, July 2013, Pages 149-157.e2

https://doi.org/10.1053/j.gastro.2013.03.025 Get rights and content

Background & Aims

Interobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations.

Methods

We performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6.

Results

The primary outcome was achieved by 30.0% of patients treated with mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI], −0.7% to 19.4%; P = .069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%–26.0%; P = .011).

Conclusions

Although mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

Section snippets

Patients

This randomized, double-blind, placebo-controlled, multicenter, phase 3 study was conducted in patients with mildly to moderately active UC at 26 centers in Belarus, India, Turkey, and Ukraine (Appendix 1). The study was approved by the independent ethics committee at each center, and all patients provided written informed consent.

Adult patients (18 years or older) with a documented diagnosis of UC were eligible to participate if they met the following criteria: (1) disease extending at least

Patient Disposition and Characteristics

A total of 343 patients were screened for eligibility; 281 met the eligibility criteria and were randomized and received at least one dose of study medication (ITT and safety populations) (Supplementary Figure 1). The first patient enrolled in the study provided informed consent on November 5, 2009, and the last patient completed the last clinic visit on May 19, 2011. Of the 281 patients randomized, 140 received mesalamine and 141 received placebo. There was a single relevant protocol

Discussion

These results provide consistent evidence that treatment with mesalamine 800-mg tablets at a dosage of 4.8 g/day is more effective than placebo for the treatment of patients with mildly to moderately active UC. Although the observed difference between the treatment groups for the primary end point, clinical remission at week 6 in the ITT population, was marginally significant (30.0% vs 20.6%, P =.069), analyses of the prespecified secondary outcome measures consistently favored mesalamine.

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Among 748 induction and 348 maintenance patients, CDS was lower in ustekinumab vs placebo users at week 8 (141.9 vs 184.3; P < .0001) and week 44 (78.2 vs 151.5; P < .0001). CDS was correlated with the MES (P < .0001) and all clinical components of the partial Mayo score (P < .0001). Stratification by pretreatment CDS revealed ustekinumab was more effective than placebo (P < .0001) with increasing effect in severe vs mild disease (–85.0 vs –55.4; P < .0001). Compared with the MES, CDS was more sensitive to change, requiring 50% fewer participants to demonstrate endoscopic differences between ustekinumab and placebo (Hedges’ g = 0.743 vs 0.460). CDS performance in the JAK-UC replication cohort was similar to UNIFI.
As an automated and quantitative measure of global endoscopic disease severity, the CDS offers artificial intelligence enhancement of traditional MES capability to better evaluate UC in clinical trials and potentially practice.
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Endoscopic assessment of ulcerative colitis (UC) can be performed by using the Mayo Endoscopic Score (MES) or the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). In this meta-analysis, we assessed the pooled diagnostic accuracy parameters of deep machine learning by means of convolutional neural network (CNN) algorithms in predicting UC severity on endoscopic images.
Databases including MEDLINE, Scopus, and Embase were searched in June 2022. Outcomes of interest were the pooled accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Standard meta-analysis methods used the random-effects model, and heterogeneity was assessed using the I²statistics.
Twelve studies were included in the final analysis. The pooled diagnostic parameters of CNN-based machine learning algorithms in endoscopic severity assessment of UC were as follows: accuracy 91.5% (95% confidence interval [CI], 88.3-93.8; I² = 84%), sensitivity 82.8% (95% CI, 78.3-86.5; I² = 89%), specificity 92.4% (95% CI, 89.4-94.6; I² = 84%), PPV 86.6% (95% CI, 82.3-90; I² = 89%), and NPV 88.6% (95% CI, 85.7-91; I² = 78%). Subgroup analysis revealed significantly better sensitivity and PPV with the UCEIS scoring system compared with the MES (93.6% [95% CI, 87.5-96.8; I² = 77%] vs 82% [95% CI, 75.6-87; I² = 89%], P = .003, and 93.6% [95% CI, 88.7-96.4; I² = 68%] vs 83.6% [95% CI, 76.8-88.8; I² = 77%], P = .007, respectively).
CNN-based machine learning algorithms demonstrated excellent pooled diagnostic accuracy parameters in the endoscopic severity assessment of UC. Using UCEIS scores in CNN training might offer better results than the MES. Further studies are warranted to establish these findings in real clinical settings.
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Predictors of Placebo Induction Response and Remission in Ulcerative Colitis
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High placebo response rates in clinical trials of ulcerative colitis (UC) have been reported previously. However, data from patient-level analyses are lacking. We assessed factors associated with clinical and endoscopic placebo response among placebo-treated patients in clinical trials of UC.
We performed a post hoc analysis of pooled clinical trial data from GEMINI-1, ACT-1, ACT-2, PURSUIT, ULTRA-2, OCTAVE-1, and OCTAVE-2. Predictors were assessed in placebo-treated patients for their association with end of induction (week 6 of 8) clinical response (reduction in total Mayo score of ≥3 and ≥30% from baseline with ≥1 point decrease in rectal bleeding subscore [RBS] or absolute RBS ≤1); clinical remission (total Mayo score ≤2 and no subscore >1); endoscopic healing (Mayo endoscopic subscore ≤1); partial Mayo score of 0; patient-reported outcome 2-item remission (RBS of 0 and stool frequency ≤1), resolution of rectal bleeding, and stool frequency normalization. Predictors on univariate analyses with P < .05 were included in multivariate logistic regression models.
Placebo-treated patients with normal serum C-reactive protein and albumin levels were more likely to attain clinical response (71 of 437 [16.3%] vs 49 of 660 [7.4%]; adjusted odds ratio, 2.76; 95% confidence interval, 1.19–5.41; P = .018). Compared with patients with a Mayo endoscopic score of 2, patients with a Mayo endoscopic score of 3 were less likely to attain clinical response (105 of 556 [18.8%] vs 179 of 675 [25.9%]; adjusted odds ratio, 0.33; 95% confidence interval, 0.16–0.68; P = .003). Similar findings were observed for clinical remission and resolution of rectal bleeding.
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Can artificial intelligence replace endoscopists when assessing mucosal healing in ulcerative colitis? A systematic review and diagnostic test accuracy meta-analysis
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Mucosal healing (MH) in inflammatory bowel diseases (IBD) is an important landmark for clinical decision making. Artificial intelligence systems (AI) that automatically deliver the grade of endoscopic inflammation may solve moderate interobserver agreement and the need of central reading in clinical trials.
We performed a systematic review of EMBASE and MEDLINE databases up to 01/12/2022 following PRISMA and the Joanna Briggs Institute methodologies to answer the following question: “Can AI replace endoscopists when assessing MH in IBD?”. The research was restricted to ulcerative colitis (UC), and a diagnostic odds ratio (DOR) meta-analysis was performed. Risk of bias was evaluated with QUADAS-2 tool.
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: Conflicts of interest The authors disclose the following: B. Feagan has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, Abbott Laboratories, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGeniX, and Wyeth; has received consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, Abbott Laboratories, AstraZeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novo Nordisk, GlaxoSmithKline, ActoGeniX, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, gIcare Pharma, and Sigmoid Pharma; and is a member of the speakers bureau for UCB, Abbott Laboratories, and J&J/Janssen. W. J. Sandborn has received consulting fees from Abbott Laboratories, ActoGeniX, AGI Therapeutics, Alba Therapeutics, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Atlantic Healthcare, Aptalis, BioBalance, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine PharmaSciences, Eagle Pharmaceuticals, EnGene, Eli Lilly, EnteroMedics, Exagen Diagnostics, Ferring Pharmaceuticals, Flexion Therapeutics, Funxional Therapeutics, Genzyme, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millennium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, PDL BioPharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb, PurGenesis Technologies, Relypsa, Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering-Plough, Shire, Sigmoid Pharma, Sirtris Pharmaceuticals, SLA Pharma UK, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics, Warner Chilcott UK, and Wyeth; has received research grants from Abbott Laboratories, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Millennium Pharmaceuticals, Novartis, Pfizer, Procter and Gamble, Shire, and UCB Pharma; has received payments for lectures/speakers bureau from Abbott Laboratories, Bristol-Myers Squibb, and Janssen; and holds stock/stock options in EnteroMedics. G. D'Haens has received grant/research support from Merck, Abbott Laboratories, Centocor, Given Imaging, UCB Pharma, and ActoGeniX and has received consulting fees from Boehringer Ingelheim, Cosmo Technologies, EnGene, Ferring Pharmaceuticals, Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, UCB Pharma, Abbott Laboratories, AstraZeneca, Shire, Tillotts Pharma AG, Novo Nordisk, GlaxoSmithKline, ActoGeniX, Pfizer, and Sigmoid Pharma. J. W. D. McDonald, D. King, C. Wong, G. Zou, A. Donner, L. Shackelton, S. Nelson, and M. Vandervoort are employees of Robarts Clinical Trials, which was the research organization that conducted this study. P. Rutgeerts has received consulting fees from Centocor, Merck, UCB, Abbott Laboratories, Millennium/Takeda, Genentech/Hoffmann-La Roche, Neovacs, Merck/Serono, Bristol-Myers Squibb, Robarts Clinical Trials, Tillotts Pharma AG, Pfizer, and Falk Pharma; has received lecture fees from Centocor, Merck, and Abbott Laboratories; and has received research support (university) from Centocor, Merck, UCB, and Abbott Laboratories. P. Munkholm and U. Mittmann have received consulting fees from Tillotts Pharma AG. D. Gilgen is an employee of Tillotts Pharma AG. E.V. Loftus Jr has received consulting fees from Abbott Laboratories, UCB Pharma, Janssen Biotech, Given Imaging, Elan, Hospira, and Eisai and has received research/grant support from Abbott Laboratories, UCB Pharma, Janssen Biotech, Amgen, GlaxoSmithKline, Millennium-Takeda, Braintree Labs, Bristol-Myers Squibb, Pfizer, Genentech, Santarus, and Shire. R. Panaccione has received consulting and/or lecture fees from Abbott Laboratories, Amgen, AstraZeneca, Axcan Pharma (now Aptalis), Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research, Elan Pharmaceuticals, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Millennium Pharmaceuticals (now Takeda), Ocera Therapeutics, Otsuka America Pharmaceutical, Pfizer, Shire, Prometheus Laboratories, Schering-Plough, Synta Pharmaceuticals, Teva, UCB Pharma, and Warner Chilcott. S. Travis is a board member for Abbott Laboratories, Centocor, Schering-Plough, Cosmo Technologies, Elan Pharma, Genentech, Guiliani, GlaxoSmithKline, Merck, Takeda, PDL BioPharma, Pfizer, Shire, UCB Pharma, Asahi, Aspreva, Ferring Pharmaceuticals, Vertex, Warner Chilcott, Vifor, Novartis, Novo Nordisk, Santarus, Genzyme, and Procter & Gamble; has received consulting fees from Abbott Laboratories, Centocor, Schering-Plough, Bristol-Myers Squibb, ChemoCentryx, Cosmo Technologies, Elan Pharma, Genentech, Guiliani, Merck, Takeda, Otsuka Pharmaceuticals, PDL BioPharma, Pfizer, Shire, and Glenmark Pharma; has received grant funding from Ferring, Abbott Laboratories, Schering-Plough, Merck Sharpe & Dohme, Procter & Gamble, Warner Chilcott, and the International Organization of IBD; and has received payment for lectures including service on speakers bureaus for Abbott Laboratories, Schering-Plough, Centocor, Merck, Given Imaging, UCB Pharma, Ferring Pharmaceuticals, Tillotts Pharma AG, Shire, Sanofi Aventis, and Vifor. G. Van Assche has received research support from Merck, Abbott, and Janssen and has received honoraria from Merck, Janssen, Ferring Pharmaceuticals, Elan/Biogen, Bristol-Myers Squibb, Novartis, UCB Pharma, Abbott Laboratories, Shire, Novo Nordisk, and Zealand Pharma. S. Vermeire has received research grants from Abbott Laboratories, MSD, and UCB and lecture fees and advisory board fees from MSD, Abbott Laboratories, UCB, Ferring, Chiesi, Pfizer, and Shire. B. G. Levesque has received consulting fees from Prometheus Laboratories and Santarus; has served on the speakers bureau for Salix; and is an employee of Robarts Clinical Trials, which was the research organization that conducted this study. Robarts Clinical Trials provides central endoscopy reading services for compensation and served as the clinical research organization for this trial. The remaining authors disclose no conflicts.

: Funding Supported by Tillotts Pharma AG.

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Original ResearchFull Report: Clinical—Alimentary TractThe Role of Centralized Reading of Endoscopy in a Randomized Controlled Trial of Mesalamine for Ulcerative Colitis

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients

Patient Disposition and Characteristics

Discussion

J Crohns Colitis

Gastroenterology

Clin Gastroenterol Hepatol

Am J Med

Am J Gastroenterol

Gastroenterology

J Stat Plan Inference

Gastroenterology

Magn Reson Imaging

Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee

Am J Gastroenterol

Guidelines for the management of inflammatory bowel disease in adults

Gut

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis

Cochrane Database Syst Rev

Efficacy of delayed-release oral mesalamine in patients who received previous ulcerative colitis treatment

Gastroenterology

Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis

Gastroenterology

Rapid symptom resolution with delayed release mesalamine 4.8g/d compared to 2.4 g/d in moderately active ulcerative colitis patients with a history of more difficult to treat disease

Am J Gastroenterol

Effect of extended MMX mesalamine therapy for acute, mild-to-moderate ulcerative colitis

Inflamm Bowel Dis

Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis

Inflamm Bowel Dis

Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial

Gut

The challenge of compliance and persistence: focus on ulcerative colitis

J Manag Care Pharm

Original Research
Full Report: Clinical—Alimentary Tract
The Role of Centralized Reading of Endoscopy in a Randomized Controlled Trial of Mesalamine for Ulcerative Colitis