Protocol for Correlating Enteropathic Severity and Small Intestinal CYP3A4 Activity in Patients With Celiac Disease
Condition: Celiac Disease
MeSH terms: Celiac Disease
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

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.
    

Intervention name(s): Simvastatin
Intervention type(s): Drug
Intervention description(s): Simvastatin 20 mg single dose on day 1
Intervention MeSH terms: Simvastatin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Biomarker; Pharmacokinetics; Villous; Simvastatin; Celiac disease