Sirolimus for Eosinophil-Associated Gastrointestinal Disorders

Eosinophilic Esophagitis Clinical Trial

Official title: A Phase 1, Open-Label Study of Sirolimus in Eosinophil-Associated Gastrointestinal Disorders

Status Terminated

Clinical Trial Summary

Background:

• Eosinophil-associated gastrointestinal disorders (EGID) are a group of related disorders that affect the esophagus, stomach, and bowel. There are two major types of EGID, eosinophilic esophagitis and eosinophilic gastroenteritis. They are caused by the body's immune system being activated by food allergens, which then damages the gut wall. People with EGID have large numbers of eosinophils (a type of white blood cell) in their gut. EGID can cause difficulty swallowing, abdominal pain, or nausea.

• At present, there are no drugs specifically approved to treat EGID. Most adults who have EGID receive steroid therapy to manage the symptoms. However, long-term steroid use may cause other problems in the body. Researchers want to see if low-dose sirolimus can be used to treat EGID. Sirolimus is a drug used to prevent rejection of transplanted organs. It may be able to keep the body's immune cells from being activated by food allergens and decrease the eosinophils.

Objectives:

• To see if low dose sirolimus is safe and decreases blood or gut eosinophils in EGID.

Eligibility:

• Individuals between 18 to 65 years of age who have EGID.

• Participants must also have an elevated blood eosinophil count and positive blood tests for IgE antibodies to foods.

Design:

• Participants who are on medicine for EGID or related symptoms must be on a stable dose for 1 month before screening and stay on that dose throughout the study.

• Participants will be screened with a medical history and physical exam, and review their symptoms. They will provide blood and urine samples. They will also have heart and lung function tests. Some participants may have allergy skin tests.

• At the first study visit, participants will have 2 days of inpatient tests. They will repeat the tests from the screening visit. They will also have a full analysis of the esophagus, stomach, and small intestine. On the second day, they will start to take sirolimus as a liquid with orange juice or water.

• Participants will continue to take sirolimus at home. They will record their doses and any symptoms. They will also have a visit to provide blood samples about 2 weeks after the first study visit.

• At the second study visit (about a month after the first visit), participants will repeat the tests from the screening visit. The sirolimus dose may be adjusted as needed.

• Participants will take sirolimus for at least another 28 days. Depending on the dose of the drug and the blood test results, some participants may need to take it for up to 112 days. Those who take the drug for a longer period will have additional study visits with tests.

• There will be another study visit when participants stop taking the drug. The last visit will be a final follow-up visit.

Clinical Trial Description

Eosinophil-Associated Gastrointestinal Disorders (EGID) are a group of related disorders characterized by gastrointestinal symptoms and eosinophilic infiltration of the gastrointestinal wall. The 2 major forms of EGID, eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EG), differ in regard to the site of inflammation (esophagus vs. stomach/small bowel). Both EoE and EG are highly associated with coexisting allergic disease, and a large fraction of EGID patients are sensitized to multiple food allergens. Existing data strongly support the concept that EGID is a food-allergen-driven, eosinophilic, inflammatory gut disease. Multiple lines of evidence support a major role for Th2 cells and the cytokines they express (IL-4, IL-5, and IL-13) in EGID pathogenesis.

There are presently no drugs with a labeled indication for EGID. Most adult patients are managed long-term with corticosteroid therapy, which raises concerns about toxicity. Sirolimus is an immunomodulator approved for use in preventing transplant rejection. It specifically inhibits Th2 cell proliferation in vitro, suggesting it may have activity in EGID.

This study is a phase I open-label design intending to target a sirolimus whole blood concentration of 6 ng/mL for a duration of 56 days. Twenty adult EGID subjects 10 with EoE and 10 with EG with evidence of Th2-mediated IgE sensitization and peripheral blood eosinophil counts (Bullet)800 cells/ L will be recruited to participate. Subjects will begin sirolimus at a dose of 1.2 mg/m2/day. Blood sirolimus level will be checked at 14- to 28-day intervals, and the dose will be serially adjusted in each subject as needed to target the 6- ng/mL target trough concentration. Blood will be drawn at each visit to monitor drug levels and safety labs. ;

Related Conditions & MeSH terms

• Digestive System Diseases
• Enteritis
• Eosinophilia
• Eosinophilic Esophagitis
• Eosinophilic Gastroenteritis
• Esophagitis
• Gastritis
• Gastroenteritis
• Gastrointestinal Diseases

• NCT number: NCT01814059
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Terminated
• Phase: Phase 1
• Start date: March 7, 2013
• Completion date: May 12, 2015