Protocol for Correlating Enteropathic Severity and Small Intestinal CYP3A4 Activity in Patients With Celiac Disease

Celiac Disease Clinical Trial

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Official title:

Protocol for Correlating Enteropathic Severity and Small Intestinal CYP3A4 Activity in Patients With Celiac Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01338324
• Other study ID #: N-1229
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: April 6, 2011
• Last updated: December 12, 2011
• Start date: April 2010
• Est. completion date: September 2011

Study information

• Verified date: December 2011
• Source: All India Institute of Medical Sciences, New Delhi
• Contact: n/a
• Is FDA regulated: No
• Health authority: India: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The small bowel biopsy is the cornerstone of for the diagnosis of celiac disease. In addition to being the gold standard for the initial diagnosis of celiac disease, periodic biopsies are also recommended on an ongoing basis for this life-long disease. However, biopsy evaluation is invasive and expensive. Therefore, there is a need for simple, non-invasive tests that can be performed on celiac patients with subclinical disease.

The present study is based on the hypothesis that the expression and activity of cytochrome P450 CYP3A4 in the small intestinal mucosa is a sensitive measure of enteropathy. Therefore small intestinal CYP3A4 activity will be markedly different in celiac disease patients with active disease as compared to patients in remission. Small intestinal CYP3A4 activity will be measured in three ways:

(i) Cmax of oral simvastatin, a widely used drug that is predominantly metabolized by small intestinal CYP3A4; (ii) AUC of oral simvastatin; and (iii) Measurement of CYP3A4 activity in two small bowel biopsies.

Description:

The proposed study is based on the hypothesis that the expression and activity of cytochrome P450 CYP3A4 in the small intestinal mucosa is a sensitive measure of enteropathy. Therefore small intestinal CYP3A4 activity will be markedly different in celiac disease patients with active disease as compared to patients in remission. Small intestinal CYP3A4 activity will be measured in three ways:

(iv) Cmax of oral simvastatin, a widely used medication that is predominantly metabolized by small intestinal CYP3A4; (v) AUC of oral simvastatin; and (vi) Measurement of CYP3A4 activity in two small bowel biopsies.

Objectives Primary Objectives

• To test the hypothesis that a positive correlation exists between villus height: crypt depth (Vh:Cd) ratio and the specific activity of CYP3A4 in small intestinal biopsy samples derived from subjects with celiac disease.

• To test the hypothesis that an inverse correlation exists between small intestinal villus height: crypt depth (Vh:Cd) ratio and the maximum serum concentration (Cmax) of simvastatin (20 mg, orally dosed after fasting) in subjects with celiac disease

Secondary Objectives:

• To test the hypothesis that an inverse correlation exists between small intestinal villus height: crypt depth (Vh:Cd) ratio and the serum area-under-the-curve (AUC) of simvastatin (20 mg, orally dosed after fasting) in subjects with celiac disease

• To test the hypothesis that a positive correlation exists between small intestinal villus height : crypt depth (Vh:Cd) ratio and the relative expression level of CYP3A4 protein in subjects with celiac disease.

• To test the hypothesis that an inverse correlation exists between small intestinal villus height : crypt depth (Vh:Cd) ratio and the concentration of simvastatin (20 mg, orally dosed after fasting) in a 6-hour urine collection from subjects with celiac disease.

• To test the hypothesis that a positive correlation exists between villus height : crypt depth (Vh:Cd) ratio and the specific activity of CYP3A4 in small intestinal biopsy samples derived from subjects with celiac disease who have followed a gluten-free diet for > 1 year.

• To test the hypothesis that an inverse correlation exists between small intestinal villus height: crypt depth (Vh:Cd) ratio and the maximum serum concentration (Cmax) of simvastatin (20 mg, orally dosed after fasting) in subjects with celiac disease who have followed a gluten-free diet for > 1 year.

• To test the hypothesis that an inverse correlation exists between small intestinal villus height: crypt depth (Vh:Cd) ratio and the serum area-under-the-curve (AUC) of simvastatin (20 mg, orally dosed after fasting) in subjects with celiac disease who have followed a gluten-free diet for > 1 year.

• To test the hypothesis that a positive correlation exists between serum anti-transglutaminase antibody levels and the specific activity of CYP3A4 in small intestinal biopsy samples derived from subjects with celiac disease.

• To test the hypothesis that a positive correlation exists between the average daily consumption of dietary gluten and the specific activity of CYP3A4 in small intestinal biopsy samples derived from subjects with celiac disease.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: September 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Cohort A: Suspected celiac sprue patients who have:

(i) Positive Anti-transglutaminase IgA levels.

(ii) Either a first-degree relative with diagnosed celiac sprue or at least one of the following symptoms:

iron deficiency, osteopenia, chronic diarrhea.

2. Cohort B: Diagnosis of celiac disease confirmed by medical history,

(i)Histology of small intestinal mucosa on small bowel biopsy and elevated serum concentrations of anti-transglutaminase antibodies.

(ii)Followed gluten-free diet for at least 1 year.

3. If the subject is female, she is eligible to enter and participate in this study if she is physiologically incapable of becoming pregnant or has a negative urine pregnancy test at screening.

Exclusion Criteria:

1. Smoking

2. Any gastrointestinal or hepatic disease besides celiac sprue.

3. Clinically significant renal disease.

4. Use of any prescription or non-prescription drugs (including vitamins and herbal supplements) must be discontinued 30 days prior to study.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Celiac Disease

Intervention

Drug:
• Simvastatin
Simvastatin 20 mg single dose on day 1

Locations

Country	Name	City	State
India	All India Institute of Medical Sciences	New Delhi	Delhi

Sponsors (2)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, New Delhi	University of Zurich

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum serum concentration (Cmax ) of simvastatin (20 mg, orally dosed after fasting) in subjects with celiac sprue		12 hours	No
Secondary	Duodenal level of cytochrome CYP3A4		72 Hours	No