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

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ClinicalTrials.gov Identifier: NCT01338324
Recruitment Status : Completed
First Posted : April 19, 2011
Last Update Posted : December 13, 2011
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
Brief 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.


Condition or disease Intervention/treatment Phase
Celiac Disease Drug: Simvastatin Phase 2 Phase 3

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 Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Protocol for Correlating Enteropathic Severity and Small Intestinal CYP3A4 Activity in Patients With Celiac Disease
Study Start Date : April 2010
Primary Completion Date : June 2011
Study Completion Date : September 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Celiac Disease
Drug Information available for: Simvastatin
U.S. FDA Resources

Arms and Interventions

Intervention Details:
    Drug: Simvastatin
    Simvastatin 20 mg single dose on day 1

Outcome Measures

Primary Outcome Measures :
  1. Maximum serum concentration (Cmax ) of simvastatin (20 mg, orally dosed after fasting) in subjects with celiac sprue [ Time Frame: 12 hours ]

Secondary Outcome Measures :
  1. Duodenal level of cytochrome CYP3A4 [ Time Frame: 72 Hours ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01338324


Locations
India
All India Institute of Medical Sciences
New Delhi, Delhi, India, 110029
Sponsors and Collaborators
All India Institute of Medical Sciences, New Delhi
University of Zurich
Investigators
Principal Investigator: Dr Govind K Makharia, MD, DM, DNB All India Institute of Medical Sciences, New Delhi
More Information

Responsible Party: Govind K Makharia, Dr. Govind K Makharia, All India Institute of Medical Sciences, New Delhi
ClinicalTrials.gov Identifier: NCT01338324     History of Changes
Other Study ID Numbers: N-1229
First Posted: April 19, 2011    Key Record Dates
Last Update Posted: December 13, 2011
Last Verified: December 2011

Keywords provided by Govind K Makharia, All India Institute of Medical Sciences, New Delhi:
Biomarker
Pharmacokinetics
Villous
Simvastatin
Celiac disease

Additional relevant MeSH terms:
Celiac Disease
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Metabolic Diseases
Malabsorption Syndromes
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors