Objective Although several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials.
Design MEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA).
Results Of 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy.
Conclusions Current best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.
- COELIAC DISEASE
- CLINICAL TRIALS
- GLUTEN SENSITIVE ENTEROPATHY
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Contributors BGL and VJ were involved in the study concept and design. PH, TH, SD and C-MT were involved in the acquisition of data. PH and VJ were involved in the analysis and interpretation of data. PH and VJ were involved in the drafting of the manuscript. BGL, RK, LMS, GD, WJS, BGF, BL, DAL and VJ were involved in critical revision of the manuscript for important intellectual content. CP provided technical or material support.
Competing interests PH has received consulting fees from Abbvie and Takeda; speakers fees from Ferring, Falk Pharma, Vifor Pharma, Tillotts Pharma, Chiesi, Takeda and Abbvie. BGL is an employee of Robarts Clinical Trials and has received lecture fees from Mitsubishi Tanabe Pharma Corporation. CP is an employee of Robarts Clinical Trials and has no relevant disclosures. RK has received honoraria from AbbVie, Janssen and Takeda Pharma. GDH has received consulting fees from AbbVie, ActoGeniX NV, Amgen, AM-Pharma BV, Boehringer-Ingelheim, ChemoCentryx, Centocor/Jansen Biologics, Cosmo Technologies, Elan/Biogen, EnGene, 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, Teva Pharmaceuticals, Tillotts Pharma AG and UCB Pharma; research grants from AbbVie, GSK, Falk, Janssen, Merck and Given Imaging; and lecture/speakers bureaux fees from AbbVie, Jansen, Merck, Takeda, UCB and Shire. WJS has received grant support from Exact Sciences, the American College of Gastroenterology and the Broad Foundation; grant support and personal fees from Receptos, Amgen, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer and Nutrition Science Partners; and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast, Shire, Ardelyx, Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics, Eisai, Qu Biologics, Toray Industries, Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx, Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen and the University of Western Ontario (owner of Robarts Clinical Trials). DAL has recently accepted an employee position at Takeda and received research support/consultancy fees from Alba Therapeutics, Alvine Pharmaceuticals, INOVA Diagnostics, Genzyme, Coronado Biosciences, Sidney Frank Foundation and Pfizer. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, 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, Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma and Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie and J&J/Janssen. VJ has received scientific advisory board fees from AbbVie and Sandoz; speakers fees from Takeda and Janssen. 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 (USA and Netherlands) expansion in 2012 necessitated establishment of a corporate entity to meet international federal/taxation regulations. All profits from Robarts Clinical Trials are directed towards academic research. The University of Western Ontario is the sole shareholder. None of the authors with affiliation to Robarts Clinical Trials have an equity position in the corporation.
Provenance and peer review Not commissioned; externally peer reviewed.