Gastroenterology. 2024 Jan;166(1):88-102. doi: 10.1053/j.gastro.2023.08.051. Epub 2023 Sep 11.

Benjamin Lebwohl ¹, Christopher Ma ², Stephen M Lagana ³, Rish K Pai ⁴, K Adam Baker ⁵, Alexa Zayadi ⁵, Malcolm Hogan ⁵, Gerd Bouma ⁶, Christophe Cellier ⁷, Jeffrey D Goldsmith ⁸, Knut E A Lundin ⁹, Maria I Pinto-Sanchez ¹⁰, Marie E Robert ¹¹, Alberto Rubio-Tapia ¹², David S Sanders ¹³, David F Schaeffer ¹⁴, Carol E Semrad ¹⁵, Jocelyn A Silvester ¹⁶, Elena F Verdú ¹⁰, Ritu Verma ¹⁷, Tsung-Teh Wu ¹⁸, Brian G Feagan ¹⁹, Eileen Crowley ²⁰, Vipul Jairath ¹⁹, Joseph A Murray ²¹

Author information

¹Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York. Electronic address: bl114@cumc.columbia.edu.

²Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; Alimentiv Inc, London, Ontario, Canada. Electronic address: christopher.ma@ucalgary.ca.

³Department of Pathology and Cell Biology, Columbia University, New York, New York.

⁴Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona.

⁵Alimentiv Inc, London, Ontario, Canada.

⁶Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, The Netherlands.

⁷Department of Gastroenterology, University of Paris-Cité, Georges-Pompidou European Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.

⁸Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.

⁹Norwegian Coeliac Disease Research Centre, University of Oslo Faculty of Medicine, Oslo, Norway; Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway.

¹⁰Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

¹¹Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

¹²Celiac Disease Program, Division of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio.

¹³Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, United Kingdom.

¹⁴Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada.

¹⁵Department of Gastroenterology, University of Chicago, Chicago, Illinois.

¹⁶Harvard Celiac Research Program, Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts; Celiac Disease Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

¹⁷Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago, Chicago, Illinois.

¹⁸Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

¹⁹Alimentiv Inc, London, Ontario, Canada; Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.

²⁰Alimentiv Inc, London, Ontario, Canada; Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital Western Ontario, London Health Sciences Centre, Western University, London, Ontario, Canada.

²¹Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Abstract

Background & aims: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking.

Methods: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale.

Results: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points.

Conclusions: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.