Accepted Manuscript A Systematic Review for the Development of a Core Outcome Set for Ulcerative Colitis Clinical Trials Christopher Ma, Remo Panaccione, Richard N. Fedorak, Claire E. Parker, Tran M. Nguyen, Reena Khanna, Corey A. Siegel, Laurent Peyrin-Biroulet, Geert D’Haens, William J. Sandborn, Brian G. Feagan, Vipul Jairath PII: DOI: Reference:
S1542-3565(17)30991-6 10.1016/j.cgh.2017.08.025 YJCGH 55405
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 4 August 2017 Please cite this article as: Ma C, Panaccione R, Fedorak RN, Parker CE, Nguyen TM, Khanna R, Siegel CA, Peyrin-Biroulet L, D’Haens G, Sandborn WJ, Feagan BG, Jairath V, A Systematic Review for the Development of a Core Outcome Set for Ulcerative Colitis Clinical Trials, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.08.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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A Systematic Review for the Development of a Core Outcome Set for Ulcerative
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Colitis Clinical Trials
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Short Title:
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Systematic Review: Outcomes in UC Clinical Trials
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Authors:
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Christopher Ma1, Remo Panaccione1, Richard N. Fedorak2, Claire E. Parker3, Tran M. Nguyen3,
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Reena Khanna3,4, Corey A. Siegel5, Laurent Peyrin-Biroulet6, Geert D’Haens3,7, William J.
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Sandborn3,8, Brian G. Feagan3,4,9, and Vipul Jairath3,4,9
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Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
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Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
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Robarts Clinical Trials, Western University, London, Ontario, Canada
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Department of Medicine, Western University, London, Ontario, Canada
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Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon,
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New Hampshire, United States
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University, France
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Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, Netherlands
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Division of Gastroenterology, University of California San Diego, La Jolla, California, United
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States
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Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine
Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
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Systematic Review: Outcomes in UC Clinical Trials
Grant Support:
None
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Abbreviations: AE adverse event; COS core outcome set; CRP C-reactive protein; FCP fecal calprotectin; FDA Food and Drug Administration; MCS Mayo Clinic Score; MedDRA Medical Dictionary for Regulatory Activities; PRO patient-reported outcome; RBS rectal bleeding subscore; RCT randomized controlled trial; SFS stool frequency subscore; STRIDE Selecting Therapeutic Targets in Inflammatory Bowel Disease; UC ulcerative colitis; UCDAI Ulcerative Colitis Disease Activity Index
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Corresponding Author: Dr. Vipul Jairath Associate Professor of Medicine Departments of Medicine and Epidemiology and Biostatistics Division of Gastroenterology Western University London, Ontario, Canada N6A 5B6 Phone: 519-685-8500 Fax: 519-663-3658 Email: [email protected]
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Manuscript Word Count:
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Abstract Word Count:
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Number of Tables:
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Number of Figures:
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Number of Supplemental Files:
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Total Word Count (abstract, manuscript, tables/figures legend, references): 5994
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Disclosures Christopher Ma has no conflicts of interest to declare
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Remo Panaccione has received scientific advisory board fees from Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, Prometheus Laboratories, Salix Pharma, Shire, Takeda, 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, 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, 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, Warner Chilcott
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Richard Fedorak has received scientific advisory board fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, VSL#3; consulting fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, VSL#3; and research grant support from Abbott/AbbVie, Alba Therapeutics, BMS, Celltrion, Centocor, Genentech, GSK, Janssen, Merck, Millennium, Novartis, Pfizer, Proctor & Gamble, Roche, VSL#3
Tran Nguyen is an employee of Robarts Clinical Trials
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Claire Parker is an employee of Robarts Clinical Trials
Reena Khanna has received consulting fees from AbbVie, Takeda, and Janssen
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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.
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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.
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Geert D’Haens has received consulting fees from Abbott/Abbvie, ActoGeniX NV, Amgen, AMPharma 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, UCB Pharma; research grants from Abbvie, GSK, Falk, Janssen, Merck, Given Imaging; payments for lectures/speakers bureaux from Abbvie, Jansen, Merck, Takeda, UCB, Shire.
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William Sandborn has served as a consultant to: AbbVie Inc., ActoGeniX NV, AGI Therapeutics, Inc., 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),
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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), 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.
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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, JanssenOrtho, 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; speakers fees from Takeda, Janssen, Shire, Ferring
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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 towards 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. None
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Authorship Contributions CM contributed to study design, data collection, data analysis, manuscript drafting and editing. VJ contributed to study conception, design, data analysis, and manuscript editing. CEP and TMN contributed to data collection and manuscript editing. RP, RNF, RK, CAS, LPB, WJS, and BGJ contributed to manuscript editing. VJ is the guarantor of the article.
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Systematic Review: Outcomes in UC Clinical Trials
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ABSTRACT
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Background and Aims: Advances in drug development for ulcerative colitis (UC) have been
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paralleled by innovations in trial design. Development of a core outcome set (COS) to
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standardize outcome definitions and reporting in clinical trials is desirable. We aim to
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systematically review the efficacy and safety outcomes reported in UC placebo-controlled
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RCTs.
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Methods: We searched MEDLINE, EMBASE, and the Cochrane Library from inception through
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March 1, 2017 for placebo-controlled RCTs in adult patients with UC treated with
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aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules.
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Efficacy and safety outcomes, definitions, and measurement tools were extracted and stratified
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by decade of publication.
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Results: Eighty-three RCTs (68 induction, 15 maintenance) were included, enrolling 17,737
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patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the
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Ulcerative Colitis Disease Activity Index (UCDAI) and the Mayo Clinic Score (MCS) were
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commonly used tools for assessing clinical response/remission. Remarkably, substantial
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variability in the definition of clinical or composite-clinical endpoints was observed with over 50
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definitions of response or remission utilized. Endoscopic, histologic, and fecal/serum biomarker
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outcomes were reported in 83.1% (69/83), 24.1% (20/83), and 24.1% (20/83) of RCTs,
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respectively. A greater proportion of trials published after 2007 reported objective outcomes
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(96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized
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definitions of histologic or biomarker endpoints exists. Patient-reported efficacy and quality of
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life outcomes were described in 25 RCTs (30.1%) and safety outcomes were reported in 77
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RCTs (92.8%).
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Conclusions: Despite recent advances in clinical trials methodology, important heterogeneity in
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reporting and variability in endpoint definitions still remains. A need exists to develop and
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validate a COS for UC clinical trials.
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Key Words: ulcerative colitis, randomized controlled trials, outcomes, efficacy, safety, core
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outcome set, systematic review
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INTRODUCTION
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Approval of new therapies for UC has been informed by data from randomized controlled trials
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(RCTs). Since the first placebo-controlled RCT in UC over 60 years ago1, clinical trials have
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become larger and more sophisticated in their design. In recent years, treatment targets in UC
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have evolved, from symptom-based scoring assessments to normalization of objective
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measures of inflammation such as endoscopic appearance, biomarkers, and histology.2
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However, the US Food and Drug Administration (FDA) has continued to require inclusion of
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patient-reported outcomes (PROs) as clinical trial endpoints to accurately capture the patient’s
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experience.3 Assessment of safety endpoints has also evolved. As novel therapies are designed
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to target specific components of the immune response, treatment-specific short- and long-term
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adverse events (AEs) have been recognized, including the risk of opportunistic infections,
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malignancies, infusion/injection reactions, and the formation of anti-drug antibodies.
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Given the progress that has occurred in this field, it is surprising that no formalized consensus
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has been established regarding what to measure, how to measure, or when to measure efficacy
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and safety endpoints in UC trials. In response to this unmet need, we have proposed the
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collaborative development of a core outcome set (COS) for use in UC RCTs.4 A COS is a
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consensus-derived minimum set of outcomes that should be measured and reported in all
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clinical trials of a given disease.5 COS implementation reduces heterogeneity in outcome
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reporting and enhances quality of evidence synthesis in systematic reviews and meta-analyses.
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Selection of outcomes for development of a COS is a multi-step process, starting with a
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comprehensive review of existing endpoint definitions and measurement tools.4, 5 Accordingly,
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we systematically review the efficacy and safety outcomes reported in placebo-controlled UC
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trials. Specifically, we aim to explore the evolution of endpoint reporting in UC trials over time
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and characterize the key outcome domains of a conceptual framework for COS development. Page 7 of 33
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METHODS
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Search Strategy
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We searched MEDLINE (1948-2017), EMBASE (1947-2017), and the Cochrane Central
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Register of Controlled Trials (1994-2017), without language restrictions, from inception to March
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1, 2017. This was supplemented with hand-searches of conference proceedings from Digestive
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Disease Week and United European Gastroenterology Week (2012-2016). The key search
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terms identify RCTs (including concepts of blinding, randomization, and placebo-control) in
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patients with ulcerative colitis. Key search terms were combined using Boolean operators
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(Supplemental Table 1).
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Studies fulfilling the following inclusion criteria were eligible: (1) a placebo-controlled RCT in
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adult UC patients; (2) medical intervention with an aminosalicylate compound, corticosteroid,
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immunosuppressant, biological agent, or small molecule therapy; (3) use of the Mayo Clinic
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Score (MCS6), UC Clinical Disease Activity Index (UCDAI7), or modifications of these indices as
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enrolment criteria; and (4) duration of at least two weeks for induction and four months for
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maintenance trials. We excluded trials of probiotics, antibiotics, complementary therapy, or
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devices and trials of hospitalized patients with fulminant UC.
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Data Extraction
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Citations for potentially relevant studies were screened independently by two investigators (CM,
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TMN). Disagreements were resolved by consensus. The primary data extraction included trial
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reporting of: 1) efficacy outcomes (including clinical/composite-clinical, endoscopic, histologic,
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biomarker, and PROs); and 2) safety outcomes (including occurrence of any AEs, serious AEs
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resulting in hospitalization, drug discontinuation, or persistent/clinically significant disability,
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deaths, and organ-specific AEs). Clinical-composite outcomes were defined by outcomes Page 8 of 33
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including both subjective reported symptoms and objective assessment (e.g. sigmoidoscopy).
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PROs were defined by outcomes directly reported by the patient.
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A comprehensive inventory of efficacy and safety outcomes and definitions was generated.
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These were subsequently organized into outcome subdomains and summarized in tabular form.
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The proportion of studies reporting each outcome was calculated, and stratified by decade of
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publication (1987-1996, 1997-2006, 2007-2017). The evolution of outcome reporting was
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summarized in matrix form with outcome domains listed in rows and frequency of outcome
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reporting plotted in grayscale gradient over a time axis. As this qualitative review evaluates
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outcome measures and definitions rather than measures of efficacy, assessment of study
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quality was not performed. Similarly, a funnel plot incorporating measures of precision and
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effect size is not appropriate for a qualitative review.
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RESULTS
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Search Results and Study Characteristics
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In total, 9860 records were identified (Figure 1). The final analysis incorporated 129 reports of
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83 studies, including patients from 68 induction6-69 and 15 maintenance trials.13, 23, 36, 38, 41, 47, 51, 58,
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65, 70-74
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placebo. Most trials were phase III studies (35 induction, 11 maintenance) and over two-thirds
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were published after 2006 (46 induction trials, 11 maintenance trials). A biological agent was the
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active comparator in 47.0% (39/83) of RCTs.
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In total, 17,737 patients participated with 33.4% of patients (5,918/17,737) randomized to
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Clinical or Composite-Clinical Efficacy Outcomes and Definitions
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Clinical response or improvement was reported in 83.8% (57/68) of induction trials6-12, 14, 15, 17, 19-
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54, 56, 58, 59, 62, 64-69
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remission was reported in 91.2% (62/68) of induction trials6, 9, 11-14, 16-19, 21-23, 25-69 and 93.3%
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(14/15) of maintenance trials.13, 23, 36, 38, 41, 47, 51, 58, 65, 70, 72-74 Combined clinical and endoscopic
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remission was used as a trial endpoint in eleven induction studies.26-28, 37, 48, 55, 57, 60, 61, 63 In
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maintenance trials, five RCTs13, 70-72, 74 reported clinical relapse or worsening as a study
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endpoint.
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and 73.3% (11/15) of maintenance trials.23, 36, 38, 41, 47, 51, 58, 65, 71, 73 Clinical
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Over 50 different definitions of response or remission were used (Supplemental Table 4). The
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UCDAI was used as the assessment tool in 21 induction7-9, 11, 12, 14, 15, 20, 22, 24, 25, 27-29, 35, 37, 42, 44, 48,
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41, 43, 45-47, 49-54, 56-69
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clinical response/remission, including the Rachmilewitz Clinical Activity Index (CAI)60, 69, the
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modified Truelove and Witt’s index20, and the Ulcerative Colitis Clinical Score (UCCS)21 were
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uncommonly utilized.
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and four maintenance RCTs70-72, 74; the MCS was used in 38 induction6, 13, 16, 19, 23, 26, 30-34, 36, 38and 11 maintenance RCTs.13, 23, 36, 38, 41, 47, 51, 58, 65, 73 Other tools for assessing
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Studies published prior to 2003 defined response by absolute or relative changes in
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UCDAI/MCS compared to baseline or by improvements in the physician global assessment.8, 10
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This practice has evolved over time, whereby clinical response and remission has become
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defined by a combination of change in MCS/UCDAI with specific subscore cut-offs. RCTs
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published after 2006 typically defined clinical response by a reduction in MCS ≥3 and ≥30%
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compared to baseline, with rectal bleeding subscore (RBS) reduction ≥1 from baseline or
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absolute RBS of 0 or 1. Remission was most commonly defined by MCS ≤2 with no subscores
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>1. In maintenance trials, relapse has been conventionally defined by recurrence or increase in
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rectal bleeding or stool frequency.
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Endoscopic Efficacy Outcomes and Definitions
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Fifty-seven (83.8%) induction14, 16-18, 20, 21, 23-69 and 12 (80.0%) maintenance trials23, 36, 38, 41, 47, 51, 58,
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65, 70, 73, 74
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(55/57) published after 2006 described endoscopic outcomes (Figure 3). Most studies assessed
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mucosal appearance using the endoscopic subscore of the MCS/UCDAI, with mucosal
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appearance rated on a four-point scale (Supplemental Table 5). Mucosal healing was typically
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defined as an MCS/UCDAI ≤1 and endoscopic response defined by a reduction in MCS/UCDAI
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subscore ≥1 from baseline. However, a few authors used more stringent definitions of mucosal
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healing, based on an MCS/UCDAI subscore of 020,
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whereby absence of friability was required for classifying mucosal healing.27,
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endoscopic assessment indices, including the Baron score16,
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Severity (UCEIS)62 were infrequently used.
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reported endoscopic outcomes but this varied by decade of publication: 96% of RCTs
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and UC Endoscopic Index of
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Histologic Efficacy Outcomes and Definitions
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Histologic outcomes have been increasingly reported since 2006 (Figure 3), with heterogeneous
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outcome definitions (Supplemental Table 6). Eighteen (26.5%) induction12, 14, 19, 21, 26, 32, 37, 38, 45, 48Page 11 of 33
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50, 55, 59, 60, 64, 65, 67
and two (13.3%) maintenance studies38, 65 reported histologic response or
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remission outcomes. Multiple different scoring systems have been used to assess histologic
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endpoints, including the Riley/modified Riley Index14, 21, 50, 59, 67, Saverymuttu score37, 48, and
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Robarts Histopathology Index.67 The Geboes score was the most commonly used histology
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assessment tool (8 induction26, 38, 45, 49, 60, 64, 65, 67, 2 maintenance trials38, 65).
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Biomarker outcomes were described in 18 (26.5%) induction18, 25, 33, 34, 36, 39, 46, 49, 50, 52, 53, 56, 61, 62, 64,
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65, 67, 69
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2006 (36.8%) identified either serum or fecal-based biomarkers as a treatment endpoint (Figure
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3). Reductions in fecal calprotectin (FCP)34,
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protein (CRP)18,
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biomarker outcomes.
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and two (13.3%) maintenance trials.41, 65 A greater proportion of studies published after
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25, 33, 34, 36, 39, 46, 50, 52, 53, 56, 61, 62, 64, 65, 67, 69
were the most commonly reported
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and serum C-reactive
Patient-Reported Outcomes and Definitions
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PROs were reported in 20 (29.4%) induction18, 19, 21, 29, 30, 32, 36, 39, 41, 46, 47, 52, 56, 60, 61, 64, 66, 69 and five
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(33.3%) maintenance trials.36, 41, 47, 65, 73 Most studies reporting PROs were published after 2006
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(38.6%, 22/57 RCTs, Figures 2 and 3). Quality of life was frequently assessed using the
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Inflammatory Bowel Disease Questionnaire (IBDQ) with a positive response defined by a 16-
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point increase in IBDQ score or IBDQ score ≥ 170.18, 19, 21, 29, 30, 32, 36, 39, 41, 46, 47, 56, 60, 61, 64, 66, 69
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Other tools for assessing quality of life included the IBD Patient-Reported Treatment Impact
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(IBD PRTI) survey66, the 36-Item Short Form Survey (SF-36)52, 60, and the EuroQoL survey.18
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Rectal bleeding and stool frequency, as reported by the patient, were also described as
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PROs.37,
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They have been combined into a two-item PRO (PRO-2).60 An alternative
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composite endoscopic and patient-reported endpoint using mucosal healing, absence of rectal
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bleeding, and stool frequency
S1542-3565(17)30991-6 10.1016/j.cgh.2017.08.025 YJCGH 55405
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 4 August 2017 Please cite this article as: Ma C, Panaccione R, Fedorak RN, Parker CE, Nguyen TM, Khanna R, Siegel CA, Peyrin-Biroulet L, D’Haens G, Sandborn WJ, Feagan BG, Jairath V, A Systematic Review for the Development of a Core Outcome Set for Ulcerative Colitis Clinical Trials, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.08.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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A Systematic Review for the Development of a Core Outcome Set for Ulcerative
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Colitis Clinical Trials
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Short Title:
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Systematic Review: Outcomes in UC Clinical Trials
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Authors:
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Christopher Ma1, Remo Panaccione1, Richard N. Fedorak2, Claire E. Parker3, Tran M. Nguyen3,
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Reena Khanna3,4, Corey A. Siegel5, Laurent Peyrin-Biroulet6, Geert D’Haens3,7, William J.
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Sandborn3,8, Brian G. Feagan3,4,9, and Vipul Jairath3,4,9
11 Affiliations:
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Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
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Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
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Robarts Clinical Trials, Western University, London, Ontario, Canada
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Department of Medicine, Western University, London, Ontario, Canada
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Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon,
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New Hampshire, United States
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University, France
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Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, Netherlands
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Division of Gastroenterology, University of California San Diego, La Jolla, California, United
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States
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Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine
Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
ACCEPTED MANUSCRIPT Ma et al.
Systematic Review: Outcomes in UC Clinical Trials
Grant Support:
None
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Abbreviations: AE adverse event; COS core outcome set; CRP C-reactive protein; FCP fecal calprotectin; FDA Food and Drug Administration; MCS Mayo Clinic Score; MedDRA Medical Dictionary for Regulatory Activities; PRO patient-reported outcome; RBS rectal bleeding subscore; RCT randomized controlled trial; SFS stool frequency subscore; STRIDE Selecting Therapeutic Targets in Inflammatory Bowel Disease; UC ulcerative colitis; UCDAI Ulcerative Colitis Disease Activity Index
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Corresponding Author: Dr. Vipul Jairath Associate Professor of Medicine Departments of Medicine and Epidemiology and Biostatistics Division of Gastroenterology Western University London, Ontario, Canada N6A 5B6 Phone: 519-685-8500 Fax: 519-663-3658 Email: [email protected]
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Manuscript Word Count:
2901
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Abstract Word Count:
268
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Number of Tables:
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Number of Figures:
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Number of Supplemental Files:
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Total Word Count (abstract, manuscript, tables/figures legend, references): 5994
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Disclosures Christopher Ma has no conflicts of interest to declare
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Remo Panaccione has received scientific advisory board fees from Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, Prometheus Laboratories, Salix Pharma, Shire, Takeda, 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, 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, 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, Warner Chilcott
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Richard Fedorak has received scientific advisory board fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, VSL#3; consulting fees from Abbott/AbbVie, Celltrion, Ferring, Janssen, Shire, VSL#3; and research grant support from Abbott/AbbVie, Alba Therapeutics, BMS, Celltrion, Centocor, Genentech, GSK, Janssen, Merck, Millennium, Novartis, Pfizer, Proctor & Gamble, Roche, VSL#3
Tran Nguyen is an employee of Robarts Clinical Trials
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Claire Parker is an employee of Robarts Clinical Trials
Reena Khanna has received consulting fees from AbbVie, Takeda, and Janssen
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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.
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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.
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Geert D’Haens has received consulting fees from Abbott/Abbvie, ActoGeniX NV, Amgen, AMPharma 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, UCB Pharma; research grants from Abbvie, GSK, Falk, Janssen, Merck, Given Imaging; payments for lectures/speakers bureaux from Abbvie, Jansen, Merck, Takeda, UCB, Shire.
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William Sandborn has served as a consultant to: AbbVie Inc., ActoGeniX NV, AGI Therapeutics, Inc., 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),
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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), 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.
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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, JanssenOrtho, 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; speakers fees from Takeda, Janssen, Shire, Ferring
Writing Assistance:
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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 towards 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. None
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Authorship Contributions CM contributed to study design, data collection, data analysis, manuscript drafting and editing. VJ contributed to study conception, design, data analysis, and manuscript editing. CEP and TMN contributed to data collection and manuscript editing. RP, RNF, RK, CAS, LPB, WJS, and BGJ contributed to manuscript editing. VJ is the guarantor of the article.
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ABSTRACT
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Background and Aims: Advances in drug development for ulcerative colitis (UC) have been
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paralleled by innovations in trial design. Development of a core outcome set (COS) to
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standardize outcome definitions and reporting in clinical trials is desirable. We aim to
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systematically review the efficacy and safety outcomes reported in UC placebo-controlled
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RCTs.
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Methods: We searched MEDLINE, EMBASE, and the Cochrane Library from inception through
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March 1, 2017 for placebo-controlled RCTs in adult patients with UC treated with
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aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules.
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Efficacy and safety outcomes, definitions, and measurement tools were extracted and stratified
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by decade of publication.
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Results: Eighty-three RCTs (68 induction, 15 maintenance) were included, enrolling 17,737
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patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the
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Ulcerative Colitis Disease Activity Index (UCDAI) and the Mayo Clinic Score (MCS) were
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commonly used tools for assessing clinical response/remission. Remarkably, substantial
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variability in the definition of clinical or composite-clinical endpoints was observed with over 50
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definitions of response or remission utilized. Endoscopic, histologic, and fecal/serum biomarker
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outcomes were reported in 83.1% (69/83), 24.1% (20/83), and 24.1% (20/83) of RCTs,
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respectively. A greater proportion of trials published after 2007 reported objective outcomes
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(96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized
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definitions of histologic or biomarker endpoints exists. Patient-reported efficacy and quality of
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life outcomes were described in 25 RCTs (30.1%) and safety outcomes were reported in 77
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RCTs (92.8%).
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Conclusions: Despite recent advances in clinical trials methodology, important heterogeneity in
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reporting and variability in endpoint definitions still remains. A need exists to develop and
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validate a COS for UC clinical trials.
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Key Words: ulcerative colitis, randomized controlled trials, outcomes, efficacy, safety, core
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outcome set, systematic review
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INTRODUCTION
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Approval of new therapies for UC has been informed by data from randomized controlled trials
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(RCTs). Since the first placebo-controlled RCT in UC over 60 years ago1, clinical trials have
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become larger and more sophisticated in their design. In recent years, treatment targets in UC
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have evolved, from symptom-based scoring assessments to normalization of objective
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measures of inflammation such as endoscopic appearance, biomarkers, and histology.2
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However, the US Food and Drug Administration (FDA) has continued to require inclusion of
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patient-reported outcomes (PROs) as clinical trial endpoints to accurately capture the patient’s
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experience.3 Assessment of safety endpoints has also evolved. As novel therapies are designed
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to target specific components of the immune response, treatment-specific short- and long-term
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adverse events (AEs) have been recognized, including the risk of opportunistic infections,
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malignancies, infusion/injection reactions, and the formation of anti-drug antibodies.
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Given the progress that has occurred in this field, it is surprising that no formalized consensus
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has been established regarding what to measure, how to measure, or when to measure efficacy
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and safety endpoints in UC trials. In response to this unmet need, we have proposed the
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collaborative development of a core outcome set (COS) for use in UC RCTs.4 A COS is a
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consensus-derived minimum set of outcomes that should be measured and reported in all
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clinical trials of a given disease.5 COS implementation reduces heterogeneity in outcome
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reporting and enhances quality of evidence synthesis in systematic reviews and meta-analyses.
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Selection of outcomes for development of a COS is a multi-step process, starting with a
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comprehensive review of existing endpoint definitions and measurement tools.4, 5 Accordingly,
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we systematically review the efficacy and safety outcomes reported in placebo-controlled UC
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trials. Specifically, we aim to explore the evolution of endpoint reporting in UC trials over time
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and characterize the key outcome domains of a conceptual framework for COS development. Page 7 of 33
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METHODS
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Search Strategy
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We searched MEDLINE (1948-2017), EMBASE (1947-2017), and the Cochrane Central
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Register of Controlled Trials (1994-2017), without language restrictions, from inception to March
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1, 2017. This was supplemented with hand-searches of conference proceedings from Digestive
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Disease Week and United European Gastroenterology Week (2012-2016). The key search
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terms identify RCTs (including concepts of blinding, randomization, and placebo-control) in
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patients with ulcerative colitis. Key search terms were combined using Boolean operators
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(Supplemental Table 1).
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229 Study Eligibility Criteria
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Studies fulfilling the following inclusion criteria were eligible: (1) a placebo-controlled RCT in
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adult UC patients; (2) medical intervention with an aminosalicylate compound, corticosteroid,
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immunosuppressant, biological agent, or small molecule therapy; (3) use of the Mayo Clinic
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Score (MCS6), UC Clinical Disease Activity Index (UCDAI7), or modifications of these indices as
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enrolment criteria; and (4) duration of at least two weeks for induction and four months for
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maintenance trials. We excluded trials of probiotics, antibiotics, complementary therapy, or
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devices and trials of hospitalized patients with fulminant UC.
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Data Extraction
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Citations for potentially relevant studies were screened independently by two investigators (CM,
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TMN). Disagreements were resolved by consensus. The primary data extraction included trial
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reporting of: 1) efficacy outcomes (including clinical/composite-clinical, endoscopic, histologic,
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biomarker, and PROs); and 2) safety outcomes (including occurrence of any AEs, serious AEs
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resulting in hospitalization, drug discontinuation, or persistent/clinically significant disability,
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deaths, and organ-specific AEs). Clinical-composite outcomes were defined by outcomes Page 8 of 33
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including both subjective reported symptoms and objective assessment (e.g. sigmoidoscopy).
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PROs were defined by outcomes directly reported by the patient.
248 Data Synthesis and Analysis
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A comprehensive inventory of efficacy and safety outcomes and definitions was generated.
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These were subsequently organized into outcome subdomains and summarized in tabular form.
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The proportion of studies reporting each outcome was calculated, and stratified by decade of
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publication (1987-1996, 1997-2006, 2007-2017). The evolution of outcome reporting was
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summarized in matrix form with outcome domains listed in rows and frequency of outcome
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reporting plotted in grayscale gradient over a time axis. As this qualitative review evaluates
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outcome measures and definitions rather than measures of efficacy, assessment of study
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quality was not performed. Similarly, a funnel plot incorporating measures of precision and
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effect size is not appropriate for a qualitative review.
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RESULTS
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Search Results and Study Characteristics
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In total, 9860 records were identified (Figure 1). The final analysis incorporated 129 reports of
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83 studies, including patients from 68 induction6-69 and 15 maintenance trials.13, 23, 36, 38, 41, 47, 51, 58,
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65, 70-74
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placebo. Most trials were phase III studies (35 induction, 11 maintenance) and over two-thirds
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were published after 2006 (46 induction trials, 11 maintenance trials). A biological agent was the
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active comparator in 47.0% (39/83) of RCTs.
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In total, 17,737 patients participated with 33.4% of patients (5,918/17,737) randomized to
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Clinical or Composite-Clinical Efficacy Outcomes and Definitions
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Clinical response or improvement was reported in 83.8% (57/68) of induction trials6-12, 14, 15, 17, 19-
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54, 56, 58, 59, 62, 64-69
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remission was reported in 91.2% (62/68) of induction trials6, 9, 11-14, 16-19, 21-23, 25-69 and 93.3%
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(14/15) of maintenance trials.13, 23, 36, 38, 41, 47, 51, 58, 65, 70, 72-74 Combined clinical and endoscopic
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remission was used as a trial endpoint in eleven induction studies.26-28, 37, 48, 55, 57, 60, 61, 63 In
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maintenance trials, five RCTs13, 70-72, 74 reported clinical relapse or worsening as a study
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endpoint.
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and 73.3% (11/15) of maintenance trials.23, 36, 38, 41, 47, 51, 58, 65, 71, 73 Clinical
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Over 50 different definitions of response or remission were used (Supplemental Table 4). The
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UCDAI was used as the assessment tool in 21 induction7-9, 11, 12, 14, 15, 20, 22, 24, 25, 27-29, 35, 37, 42, 44, 48,
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41, 43, 45-47, 49-54, 56-69
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clinical response/remission, including the Rachmilewitz Clinical Activity Index (CAI)60, 69, the
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modified Truelove and Witt’s index20, and the Ulcerative Colitis Clinical Score (UCCS)21 were
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uncommonly utilized.
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and four maintenance RCTs70-72, 74; the MCS was used in 38 induction6, 13, 16, 19, 23, 26, 30-34, 36, 38and 11 maintenance RCTs.13, 23, 36, 38, 41, 47, 51, 58, 65, 73 Other tools for assessing
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Studies published prior to 2003 defined response by absolute or relative changes in
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UCDAI/MCS compared to baseline or by improvements in the physician global assessment.8, 10
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This practice has evolved over time, whereby clinical response and remission has become
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defined by a combination of change in MCS/UCDAI with specific subscore cut-offs. RCTs
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published after 2006 typically defined clinical response by a reduction in MCS ≥3 and ≥30%
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compared to baseline, with rectal bleeding subscore (RBS) reduction ≥1 from baseline or
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absolute RBS of 0 or 1. Remission was most commonly defined by MCS ≤2 with no subscores
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>1. In maintenance trials, relapse has been conventionally defined by recurrence or increase in
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rectal bleeding or stool frequency.
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Endoscopic Efficacy Outcomes and Definitions
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Fifty-seven (83.8%) induction14, 16-18, 20, 21, 23-69 and 12 (80.0%) maintenance trials23, 36, 38, 41, 47, 51, 58,
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65, 70, 73, 74
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(55/57) published after 2006 described endoscopic outcomes (Figure 3). Most studies assessed
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mucosal appearance using the endoscopic subscore of the MCS/UCDAI, with mucosal
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appearance rated on a four-point scale (Supplemental Table 5). Mucosal healing was typically
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defined as an MCS/UCDAI ≤1 and endoscopic response defined by a reduction in MCS/UCDAI
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subscore ≥1 from baseline. However, a few authors used more stringent definitions of mucosal
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healing, based on an MCS/UCDAI subscore of 020,
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whereby absence of friability was required for classifying mucosal healing.27,
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endoscopic assessment indices, including the Baron score16,
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Severity (UCEIS)62 were infrequently used.
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reported endoscopic outcomes but this varied by decade of publication: 96% of RCTs
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, or modifications to the subscore
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and UC Endoscopic Index of
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Histologic Efficacy Outcomes and Definitions
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Histologic outcomes have been increasingly reported since 2006 (Figure 3), with heterogeneous
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outcome definitions (Supplemental Table 6). Eighteen (26.5%) induction12, 14, 19, 21, 26, 32, 37, 38, 45, 48Page 11 of 33
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50, 55, 59, 60, 64, 65, 67
and two (13.3%) maintenance studies38, 65 reported histologic response or
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remission outcomes. Multiple different scoring systems have been used to assess histologic
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endpoints, including the Riley/modified Riley Index14, 21, 50, 59, 67, Saverymuttu score37, 48, and
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Robarts Histopathology Index.67 The Geboes score was the most commonly used histology
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assessment tool (8 induction26, 38, 45, 49, 60, 64, 65, 67, 2 maintenance trials38, 65).
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317 Biomarker Outcomes and Definitions
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Biomarker outcomes were described in 18 (26.5%) induction18, 25, 33, 34, 36, 39, 46, 49, 50, 52, 53, 56, 61, 62, 64,
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65, 67, 69
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2006 (36.8%) identified either serum or fecal-based biomarkers as a treatment endpoint (Figure
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3). Reductions in fecal calprotectin (FCP)34,
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protein (CRP)18,
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biomarker outcomes.
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and two (13.3%) maintenance trials.41, 65 A greater proportion of studies published after
39, 41, 49, 50, 52, 62, 64, 65, 67, 69
25, 33, 34, 36, 39, 46, 50, 52, 53, 56, 61, 62, 64, 65, 67, 69
were the most commonly reported
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and serum C-reactive
Patient-Reported Outcomes and Definitions
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PROs were reported in 20 (29.4%) induction18, 19, 21, 29, 30, 32, 36, 39, 41, 46, 47, 52, 56, 60, 61, 64, 66, 69 and five
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(33.3%) maintenance trials.36, 41, 47, 65, 73 Most studies reporting PROs were published after 2006
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(38.6%, 22/57 RCTs, Figures 2 and 3). Quality of life was frequently assessed using the
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Inflammatory Bowel Disease Questionnaire (IBDQ) with a positive response defined by a 16-
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point increase in IBDQ score or IBDQ score ≥ 170.18, 19, 21, 29, 30, 32, 36, 39, 41, 46, 47, 56, 60, 61, 64, 66, 69
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Other tools for assessing quality of life included the IBD Patient-Reported Treatment Impact
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(IBD PRTI) survey66, the 36-Item Short Form Survey (SF-36)52, 60, and the EuroQoL survey.18
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Rectal bleeding and stool frequency, as reported by the patient, were also described as
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PROs.37,
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They have been combined into a two-item PRO (PRO-2).60 An alternative
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composite endoscopic and patient-reported endpoint using mucosal healing, absence of rectal
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bleeding, and stool frequency
