Abstract
Background & Aims: Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD. Methods: We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication. Results: Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts’ Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials. Conclusions: In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.
Original language | English (US) |
---|---|
Pages (from-to) | 1407-1419.e22 |
Journal | Clinical Gastroenterology and Hepatology |
Volume | 16 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2018 |
Keywords
- Effects
- IBD
- Inflammatory Bowel Disease
- RCT
- Treatment
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease : A Systematic Review. / Ma, Christopher; Hussein, Isra M.; Al-Abbar, Yousef J. et al.
In: Clinical Gastroenterology and Hepatology, Vol. 16, No. 9, 09.2018, p. 1407-1419.e22.Research output: Contribution to journal › Review article › peer-review
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TY - JOUR
T1 - Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease
T2 - A Systematic Review
AU - Ma, Christopher
AU - Hussein, Isra M.
AU - Al-Abbar, Yousef J.
AU - Panaccione, Remo
AU - Fedorak, Richard N.
AU - Parker, Claire E.
AU - Nguyen, Tran M.
AU - Khanna, Reena
AU - Siegel, Corey A.
AU - Peyrin-Biroulet, Laurent
AU - Pai, Rish K.
AU - Vande Casteele, Niels
AU - D'Haens, Geert R.
AU - Sandborn, William J.
AU - Feagan, Brian G.
AU - Jairath, Vipul
N1 - Funding Information: Funding Christopher Ma is supported by the Canadian Institutes of Health Research and the Canadian Association of Gastroenterology. Systematic reviews and meta-analyses Funding Information: Conflicts of interest These authors disclose the following: Remo Panaccione has received scientific advisory board fees from Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, Prometheus Laboratories, Salix Pharma, Shire, Takeda, and Warner Chilcott; consulting fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Elan/Biogen, Eisai, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus Therapeutics and Diagnostics, Schering-Plough, Shire, Takeda, UCB Pharma, and Warner Chilcott; research grants from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, Shire, Schering-Plough, Takeda, UCB Pharma, and Warner Chilcott; and speaker’s bureau fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, Schering-Plough, Shire, Takeda, UCB Pharma, and Warner Chilcott. Richard Fedorak has received scientific advisory board fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, and VSL#3; consulting fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, and VSL#3; and research grant support from Abbott/AbbVie, Alba Therapeutics, BMS, Celltrion, Centocor, Genentech, GSK, Janssen, Merck, Millennium, Novartis, Pfizer, Proctor & Gamble, Roche, and VSL#3. Claire Parker is an employee of Robarts Clinical Trials. Tran Nguyen is an employee of Robarts Clinical Trials. Reena Khanna has received scientific advisory board fees from AbbVie, Janssen, Pfizer, and Takeda; consulting fees from AbbVie, Janssen, Takeda, and Robarts Clinical Trials; and payments for lectures/speakers bureau from AbbVie, Janssen, Shire, and Takeda. Corey Siegal has received consulting fees from AbbVie, Amgen, Celgene, Lilly, Janssen, Sandoz, Pfizer, Prometheus, and Takeda; payments for lectures/speakers bureau from AbbVie, Janssen, Pfizer, and Takeda; and received grant support from AbbVie, Janssen, Pfizer, and Takeda. Laurent Peyrin-Biroulet has received honoraria from Merck, AbbVie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC-Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, and Samsung Bioepis. Rish Pai has received consulting fees from Genetech. Niels Vande Casteele has received consulting fees from MSD, Janssen, Pfizer, UCB, and Takeda and speaker’s bureau fees from AbbVie. Geert D’Haens has received consulting fees from Abbott/AbbVie, ActoGeniX NV, Amgen, AM-Pharma BV, Boehringer-Ingelheim, ChemoCentryx, Centocor/Jansen Biologics, Cosmo Technologies, Elan/Biogen, EnGene Inc, Ferring Pharmaceuticals, Gilead Sciences, Given Imaging, GSK, Merck Research Laboratories, Merck Serono, Millenium Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, PDL Biopharma, Pfizer, Receptos, Salix Pharmaceuticals, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Teva Pharmaceuticals, Tillotts Pharma AG, and UCB Pharma; research grants from AbbVie, GSK, Falk, Janssen, Merck, and Given Imaging; and payments for lectures/speakers bureau from AbbVie, Jansen, Merck, Takeda, UCB, and Shire. William Sandborn has served as a consultant to AbbVie Inc, ActoGeniX NV, AGI Therapeutics, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc, Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer-Ingelheim Inc, Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research Inc, Elan Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals, Flexion Therapeutics, Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc), Janssen (previously Centocor), KaloBios Pharmaceuticals, Inc, Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co, Ltd, Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Inc, Receptos, Relypsa, Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Inc, Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co, Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited (VBL), and Warner Chilcott UK Limited; has received speaker’s fees from AbbVie Inc, Bristol Meyers Squibb, and Janssen (previously Centocor); and financial support for research from AbbVie Inc, Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma. 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 bureaux fees from UCB, AbbVie, and J&J/Janssen. Vipul Jairath has received consulting fees from AbbVie, Sandoz, Takeda, Janssen, Robarts Clinical Trials; and speakers fees from Takeda, Janssen, Shire, and Ferring. The remaining authors disclose no conflicts. Robarts Clinical Trials began in 1986 as an academic research unit within the Robarts Research Institute, which is affiliated with University Hospital and the University of Western Ontario. A subsequent international (United States of America and Netherlands) expansion in 2012 necessitated establishment of a corporate entity to meet international federal/taxation regulations. All profits from Robarts Clinical Trials, Inc are directed toward academic research. The University of Western Ontario is the sole owner and shareholder of Robarts Clinical Trials Inc. None of the authors with affiliation to Robarts Clinical Trials, Inc have an equity position or any shares in the corporation. Publisher Copyright: © 2018 AGA Institute
PY - 2018/9
Y1 - 2018/9
N2 - Background & Aims: Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD. Methods: We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication. Results: Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts’ Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials. Conclusions: In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.
AB - Background & Aims: Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD. Methods: We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication. Results: Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts’ Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials. Conclusions: In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.
KW - Effects
KW - IBD
KW - Inflammatory Bowel Disease
KW - RCT
KW - Treatment
UR - http://www.scopus.com/inward/record.url?scp=85051144025&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051144025&partnerID=8YFLogxK
U2 - 10.1016/j.cgh.2018.02.051
DO - 10.1016/j.cgh.2018.02.051
M3 - Review article
C2 - 29596987
AN - SCOPUS:85051144025
VL - 16
SP - 1407-1419.e22
JO - Clinical Gastroenterology and Hepatology
JF - Clinical Gastroenterology and Hepatology
SN - 1542-3565
IS - 9
ER -