Clinical Trials

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.