TY - JOUR
T1 - Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis
T2 - A Systematic Review
AU - Ma, Christopher
AU - van Rhijn, Bram D.
AU - Jairath, Vipul
AU - Nguyen, Tran M.
AU - Parker, Claire E.
AU - Aceves, Seema S.
AU - Furuta, Glenn T.
AU - Gupta, Sandeep K.
AU - Katzka, David A.
AU - Safroneeva, Ekaterina
AU - Schoepfer, Alain M.
AU - Straumann, Alex
AU - Spergel, Jonathan M.
AU - Pai, Rish K.
AU - Feagan, Brian G.
AU - Hirano, Ikuo
AU - Dellon, Evan S.
AU - Bredenoord, Albert J.
N1 - Funding Information:
Funding Christopher Ma is supported by a Clinician Fellowship from the Canadian Association of Gastroenterology and the Canadian Institutes of Health Research .
Funding Information:
Conflicts of interest These authors disclose the following: Vipul Jairath has received consulting fees from AbbVie, Sandoz, Takeda, Janssen, and Robarts Clinical Trials and speaker’s fees from Takeda, Janssen, Shire, Ferring and is the Director for Medical Research & Development at Robarts Clinical Trials. Tran Nguyen is an employee of Robarts Clinical Trials. Claire Parker is an employee of Robarts Clinical Trials. Seema Aceves is a co-inventor of oral viscous budesonide (UCSD patented, licensed to Shire Pharma) and has received consulting fees from Regeneron. Glenn Furuta is the founder of EnteroTrack and has received royalties from UpToDate and consulting fees from Shire. Sandeep Gupta has received consulting fees from Abbott, Allakos, Receptos, and QOL and research support from Shire. David Katzka has received research support from Shire. Ekaterina Safroneeva has received consulting fees from Celgene Corp, Regeneron Pharmaceuticals Inc, and Novartis AG. Alain Schoepfer has received consulting fees and/or speaker fees and/or research grants from Adare Pharmaceuticals, Inc, AstraZeneca, AG, Switzerland, Aptalis Pharma, Inc, Dr. Falk Pharma, GmbH, Glaxo Smith Kline, AG, Nestlé S. A., Receptos, Inc, and Regeneron Pharmaceuticals, Inc. Rish Pai has received consulting fees from Genentech. 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 speakers bureau fees from UCB, AbbVie, and J&J/Janssen; and is the Senior Scientific Director for Robarts Clinical Trials. Ikuo Hirano has received consulting fees from Receptos, Regeneron, Shire, and Roche. Evan Dellon has received research funding from Adare, Meritage, Miraca, Nutricia, Celgene/Receptos, and Shire; has consulted for Adare, Alivio, Allakos, AstraZeneca, Banner, Enumeral, Celgene/Receptos, GSK, Regeneron, and Shire; and has received educational grants from Banner and Holoclara. Albert Bredenoord has received research funding from Nutricia and Bayer and received speaker and/or consulting fees from MMS, Dr Falk Pharma, Regeneron, Astellas, AstraZeneca, Bayer, Norgine, Almirall, and Allergan. The remaining authors disclose no conflicts.
Publisher Copyright:
© 2018 AGA Institute
PY - 2018/11
Y1 - 2018/11
N2 - Background & Aims: Agents are being developed for treatment of eosinophilic esophagitis (EoE). However, it is not clear what outcome measures would best determine the efficacy and safety of these agents in clinical trials. We performed a systematic review of outcomes used in randomized placebo-controlled trials of EoE and we estimate the placebo response and rates of remission. Methods: We searched MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trials Register from inception through February 20, 2018 for randomized controlled trials of pharmacologic therapies for EoE. Efficacy outcome definitions, measurement tools, and the proportion of patients responding to placebo were collected and stratified by based on histologic, endoscopic, and patient-reported outcomes. Results: We analyzed data from 22 placebo-controlled trials, comprising 1112 patients with EoE. Ten additional active registered trials were identified. Most published trials evaluated topical corticosteroid therapy (13/22, 59.1%). Histologic outcomes measuring eosinophil density and patient-reported outcomes were reported in 21/22 published trials (95.5%). No consistently applied definitions of histologic or patient-reported response or remission were identified. Endoscopic outcomes were described in 60% (12/20) of published trials. The EoE Endoscopic Reference Score is the most commonly applied tool for describing changes in endoscopic appearance. The median histologic response to placebo was 3.7% (range, 0%–31.6%) and the median rate of remission in patients given placebo was 0.0% (range, 0%–11.0%). The median patient-reported response to placebo was 14.4% (range, 8.6%–77.8%) and rate of remission in patients given placebo was 26.2% (range, 13.2%–35.7%). Conclusions: In a systematic review of the literature, we found that no standardized definitions of histologic, endoscopic, or patient-reported outcomes are used to determine whether pharmacologic agents produce a response or remission in patients with EoE. A core outcome set is needed to reduce heterogeneity in outcome reporting and facilitate trial interpretation and comparison of results from trials.
AB - Background & Aims: Agents are being developed for treatment of eosinophilic esophagitis (EoE). However, it is not clear what outcome measures would best determine the efficacy and safety of these agents in clinical trials. We performed a systematic review of outcomes used in randomized placebo-controlled trials of EoE and we estimate the placebo response and rates of remission. Methods: We searched MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trials Register from inception through February 20, 2018 for randomized controlled trials of pharmacologic therapies for EoE. Efficacy outcome definitions, measurement tools, and the proportion of patients responding to placebo were collected and stratified by based on histologic, endoscopic, and patient-reported outcomes. Results: We analyzed data from 22 placebo-controlled trials, comprising 1112 patients with EoE. Ten additional active registered trials were identified. Most published trials evaluated topical corticosteroid therapy (13/22, 59.1%). Histologic outcomes measuring eosinophil density and patient-reported outcomes were reported in 21/22 published trials (95.5%). No consistently applied definitions of histologic or patient-reported response or remission were identified. Endoscopic outcomes were described in 60% (12/20) of published trials. The EoE Endoscopic Reference Score is the most commonly applied tool for describing changes in endoscopic appearance. The median histologic response to placebo was 3.7% (range, 0%–31.6%) and the median rate of remission in patients given placebo was 0.0% (range, 0%–11.0%). The median patient-reported response to placebo was 14.4% (range, 8.6%–77.8%) and rate of remission in patients given placebo was 26.2% (range, 13.2%–35.7%). Conclusions: In a systematic review of the literature, we found that no standardized definitions of histologic, endoscopic, or patient-reported outcomes are used to determine whether pharmacologic agents produce a response or remission in patients with EoE. A core outcome set is needed to reduce heterogeneity in outcome reporting and facilitate trial interpretation and comparison of results from trials.
KW - Drug
KW - Endoscopy
KW - Esophagus
KW - Histology
KW - Inflammation
KW - Patient-Reported Outcomes
KW - Placebo
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U2 - 10.1016/j.cgh.2018.06.005
DO - 10.1016/j.cgh.2018.06.005
M3 - Review article
C2 - 29908360
AN - SCOPUS:85053631313
VL - 16
SP - 1714-1729.e3
JO - Clinical Gastroenterology and Hepatology
JF - Clinical Gastroenterology and Hepatology
SN - 1542-3565
IS - 11
ER -