Development, Validation and Evaluation of an Adult and Pediatric Eosinophilic Esophagitis Activity Index

Deglutition Disorders Clinical Trial

— EEsAI  

Official title:

Development, Validation and Evaluation of an Adult and Pediatric Eosinophilic Esophagitis Activity Index: A Prospective Multicenter Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00939263
• Other study ID #: 231/08
• Secondary ID: 0901
• Status: Recruiting
• Phase: N/A
• First received: July 13, 2009
• Last updated: September 15, 2015
• Start date: January 2011
• Est. completion date: December 2016

Study information

• Verified date: September 2015
• Source: University Hospital Inselspital, Berne
• Contact: Ekaterina Safroneeva, PhD
• Phone: +41 31 631 59 71
• Email: esafroneeva[@]ispm.unibe.ch
• Is FDA regulated: No
• Health authority: Switzerland: Ethikkommission
• Study type: Observational

Clinical Trial Summary

Eosinophilic Esophagitis (EoE) is a chronic inflammatory disease of the esophagus affecting children and adults. The most frequent symptoms are swallowing difficulties and thoracic pain. The disease has first been described in the 1980s and is found with rapidly increasing frequency mainly in industrialized countries. The factors that lead to EoE are until now incompletely understood, of importance, the disease is found more frequently in men and patients suffering from allergic diseases (e.g., Asthma). So far there exists no activity index to define the severity of EoE; such an index is urgently needed for future clinical trials to determine the efficacy of current and future therapies. The investigators' 3-year project, carried out in cooperation with international EoE experts, aims at the development of an activity index for adult and pediatric EoE patients that will be used in future clinical trials as well as observational studies.

Description:

Background:

1. Introduction Coordinated by the Swiss Eosinophilic Esophagitis Research Group and in close collaboration with The International Gastrointestinal Eosinophil Researchers (TIGERS), we plan to conduct a series of related studies in order to develop an Activity Index (AI) for adult and pediatric patients with Eosinophilic Esophagitis (EoE).

EoE is an emerging disease, with rapidly growing clinical relevance and research activities. A validated assessment instrument is therefore urgently needed.

The purpose of this project is to develop within a representative group of pediatric and adult EoE-experienced gastroenterologists and EoE-experienced pathologists an AI for this chronic inflammatory esophageal disease. The project is investigator initiated, but funding from different sources will be necessary. The project will be conducted in compliance with this protocol, with the ICH guideline E6 on Good Clinical Practice, the FDA perspectives on patient-reported outcomes to support medical product labeling claims (1,2), and the applicable regulatory requirements.

As EoE is a new disorder we include below a comprehensive description of the disease.

1.1. Characterization of Eosinophilic Esophagitis Definition: EoE is rapidly emerging as a distinctive disorder in pediatric and adult gastroenterology. EoE is a chronic-inflammatory esophageal disease, characterized clinicopathologically by the presence of esophagus-related symptoms and by a dense esophageal eosinophilia, both of which persist despite prolonged treatment with proton pump inhibitors (3). Epidemiology: EoE is diagnosed 2-3 times more frequently in males than in females.

The disease is found mainly in industrialized countries such as the United States, Canada, Europe and Australia. EoE is likely to be a 'young' disease: it had not been seen prior to the early 1980, and there is strong evidence to suggest that its prevalence is increasing (4)(5). A population-based study performed in Switzerland suggested an increase in prevalence from 2 per 100000 to 40 per 100000 inhabitants over a 19-year period (6). Clinical Symptoms: As in many other diseases, symptom presentation differs significantly between children and adults. In infants and toddlers, food refusal is a common symptom of EoE. Children often suffer from GERD-like symptoms, vomiting and abdominal pain. Dysphagia and food impaction are reported increasingly with proceeding age. Adolescents and adults present mostly with dysphagia for solids and food impaction (5-7). Endoscopy/Histology: Esophago-gastro-duodenoscopy (EGD) is the first diagnostic step in the evaluation of an individual with suspected EoE. A broad spectrum of endoscopic features associated with EoE have been described, but the endoscopic suspicion needs confirmation by histology. The key diagnostic criterion for diagnosing EoE is an increased number of intraepithelial eosinophils in patients with lack of responsiveness to high-dose proton pump inhibition or normal pH-monitoring of the distal esophagus. In a consensus conference a cut-off value of =15 Eos/HPF (peak eosinophilic count in 400 fold magnification) in any biopsy was recommended as diagnostic criterion (3). Treatment: The optimal treatment for EoE is not yet clear, as experience has been limited largely to case series and small controlled trials. So far topically and systemically administered corticosteroids, several types of allergen-reduced diets, immunosuppressants and IL-5 blocking agents have been shown to be efficacious (8-11).

1.2. Rationale for the planned Studies In the clinical setting the current status of a given disease is often reported as "mild", "moderate" and "severe", and the course of the disease over time is described with terms such as "stable", "progressive", "in remission" or "flare-up". None of these terms has so far been clearly defined for EoE. However, an increasing number of phase 3 therapeutic multi-center trials and natural history studies in patients with EoE will be performed in the near future. In order to set up standardized study protocols and to compare results between different studies a standardized definition of disease activity is a necessity. Taken together, for clinical and for research purposes it is indispensable to define the terms mentioned above by a suitable, reproducible and validated score, which reflects the disease activity as precisely as possible. The necessity for such a score has repeatedly been discussed by the TIGERS and has been underscored by several publications (12).

Objective

The planned research program has the aim to develop and validate an AI for EoE (EEsAI) for adult (adEEsAI) and pediatric (pedEEsAI) patients, which can be used in future clinical trials and observational studies. According to the characterization of EoE, the AI will likely contain clinical and histopathological items. Laboratory and endoscopical parameters may be part of the score, but in a subsidiary role.

Methods:

The development and validation of a disease activity index is a research program involving several related studies. Broadly speaking, it involves 3 main steps: Step I Item Generation and Reduction through a Delphi process with an international expert group (Development phase A). Step II Item Weighting and Activity Index Derivation, using data from a first cohort of adult and a first cohort of pediatric patients (Development phase B).

Step III Evaluation of the Activity Index using data from a second independent cohort of adult and pediatric patients respectively. This involves also assessment of test-retest reliability and responsiveness of the score, using longitudinal data from the same patients.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 650
• Est. completion date: December 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• every patient with the diagnosis Eosinophilic Esophagitis

• pediatric and adult EoE patients

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Deglutition Disorders
• Eosinophilia
• Eosinophilic Esophagitis
• Esophageal Diseases
• Esophagitis

Intervention

Other:
• assessment of disease activity using the EEsAI
disease activity index

Locations

Country	Name	City	State
Canada	Clinical Epidemiology & Biostatistics : Mc Master University	Hamilton	Ontario
Canada	Ste-Justine Hospital : University of Montreal	Montréal	Quebec
Switzerland	Department of Gastroenterology, Inselspital/Bern University Hospital	Bern
Switzerland	Institute for Social and Preventive Medicine, University of Bern	Bern
Switzerland	Pädiatrische Gastroenterologie Medizinische Universitäts-Kinderklinik Bern	Bern
Switzerland	University Hospital Lausanne (CHUV)	Lausanne
Switzerland	Department of Gastroenterology and Hepatology, Kantonsspital Lucerne	Lucerne
Switzerland	Institute for Pathology, Kantonsspital Lucerne	Lucerne
Switzerland	Praxis Römerhof, Römerstr. 7, Olten	Olten
Switzerland	Ostschweizer Kinderspital	St. Gallen
United Kingdom	Northumbria Healthcare Foundation Trust North Tyneside Hospital	North Shields
United States	The Children`s Hospital : University of Colorado Denver	Aurora	Colorado
United States	Institute for Clinical Research and Health Policy Studies: Tufts Medical Center	Boston	Massachusetts
United States	Division of Allergy and Inflammation : Harvard Medical School Boston	Brookline	Massachusetts
United States	Division of Gastroenterology : Northwestern University Chicago	Chicago	Illinois
United States	Gastroenterology, hepatology and nutrition : Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Gastroenterology, Hepatology and Nutrition : University of Cincinnati	Cincinnati	Ohio
United States	Inova Fairfax Hospital for Children	Fairfax	Virginia
United States	Riley Hospital for Children : Indiana University School of Medicine	Indianapolis	Indiana
United States	Gastroenterology and Hepatology : Mayo Clinic, Jacksonville	Jacksonville	Florida
United States	Pediatrics : Mount Sinai School of Medicine	New York	New York
United States	Children`s Hospital of Philadelphia : University of Philadelphia	Philadelphia	Pennsylvania
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Department of Pediatrics : University of California	San Diego	California
United States	Gastroenterology and Hepatology : Mayo Clinic, Scottsdale	Scottsdale	Arizona

Sponsors (10)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	Indiana University School of Medicine, Kantonsspital Olten, Luzerner Kantonsspital, Mayo Clinic Rochester, Minnesota, USA, Northwestern University, Philadelphia University, University of Bern, University of Cincinnati, University of Colorado, Denver

Countries where clinical trial is conducted

United States,  Canada,  Switzerland,  United Kingdom, 

References & Publications (8)

Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, Bonis P, Hassall E, Straumann A, Rothenberg ME; First International Gastrointestinal Eosinophil Research Symposium (FIGERS) Subcommittees. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007 Oct;133(4):1342-63. Epub 2007 Aug 8. Review. — View Citation

Guyatt GH, Deyo RA, Charlson M, Levine MN, Mitchell A. Responsiveness and validity in health status measurement: a clarification. J Clin Epidemiol. 1989;42(5):403-8. — View Citation

Liacouras CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, Flick J, Kelly J, Brown-Whitehorn T, Mamula P, Markowitz JE. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol. 2005 Dec;3(12):1198-206. — View Citation

Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004 Aug 26;351(9):940-1. — View Citation

Patrick DL, Burke LB, Powers JH, Scott JA, Rock EP, Dawisha S, O'Neill R, Kennedy DL. Patient-reported outcomes to support medical product labeling claims: FDA perspective. Value Health. 2007 Nov-Dec;10 Suppl 2:S125-37. Review. — View Citation

Straumann A, Simon HU. Eosinophilic esophagitis: escalating epidemiology? J Allergy Clin Immunol. 2005 Feb;115(2):418-9. — View Citation

Straumann A, Spichtin HP, Grize L, Bucher KA, Beglinger C, Simon HU. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology. 2003 Dec;125(6):1660-9. — View Citation

U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research; U.S. Department of Health and Human Services FDA Center for Biologics Evaluation and Research; U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006 Oct 11;4:79. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Development of an EE Activity Index		12 months	No
Secondary	Evaluation and validation of the activity index		2 years	No