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

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.

Study Overview

• Status: Completed
• Conditions: Celiac Disease
• Intervention / Treatment: Drug: Simvastatin

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 110029
      • All India Institute of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum serum concentration (Cmax ) of simvastatin (20 mg, orally dosed after fasting) in subjects with celiac sprue	12 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
Duodenal level of cytochrome CYP3A4	72 Hours

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences, New Delhi
• Collaborators: University of Zurich
• Investigators: Principal Investigator: Dr Govind K Makharia, MD, DM, DNB, All India Institute of Medical Sciences, New Delhi

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: April 6, 2011
• First Submitted That Met QC Criteria: April 18, 2011
• First Posted (Estimate): April 19, 2011

Study Record Updates

• Last Update Posted (Estimate): December 13, 2011
• Last Update Submitted That Met QC Criteria: December 12, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: Biomarker; Pharmacokinetics; Simvastatin; Celiac disease; Villous
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Gastrointestinal Diseases; Intestinal Diseases; Malabsorption Syndromes; Celiac Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: N-1229