Celiac Disease Clinical Trial
Official title:
Protocol for Correlating Enteropathic Severity and Small Intestinal CYP3A4 Activity in Patients With Celiac Disease
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.
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.
;
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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