Protocol for Correlating Enteropathic Severity and Small Intestinal CYP3A4 Activity in Patients With Celiac Disease
Protocol for Correlating Enteropathic Severity and Small Intestinal CYP3A4 Activity in Patients With Celiac Disease
Sponsors
Source
All India Institute of Medical Sciences, New Delhi
Oversight Info
Has Dmc
Yes
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.
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.
Overall Status
Completed
Start Date
2010-04-01
Completion Date
2011-09-01
Primary Completion Date
2011-06-01
Phase
Phase 2/Phase 3
Study Type
Interventional
Primary 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
Measure |
Time Frame |
|
Duodenal level of cytochrome CYP3A4 |
72 Hours |
Enrollment
41
Condition
Intervention
Eligibility
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.
Gender
All
Minimum Age
18 Years
Maximum Age
75 Years
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
|
Dr Govind K Makharia, MD, DM, DNB |
Principal Investigator |
All India Institute of Medical Sciences, New Delhi |
Location
Facility |
|
All India Institute of Medical Sciences New Delhi Delhi 110029 India |
Location Countries
Country
India
Verification Date
2011-12-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Principal Investigator
Investigator Affiliation
All India Institute of Medical Sciences, New Delhi
Investigator Full Name
Govind K Makharia
Investigator Title
Dr. Govind K Makharia
Keywords
Has Expanded Access
No
Condition Browse
Intervention Browse
Mesh Term
Simvastatin
Firstreceived Results Date
N/A
Acronym
Cyp
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Diagnostic
Masking
None (Open Label)
Study First Submitted
April 6, 2011
Study First Submitted Qc
April 18, 2011
Study First Posted
April 19, 2011
Last Update Submitted
December 12, 2011
Last Update Submitted Qc
December 12, 2011
Last Update Posted
December 13, 2011
ClinicalTrials.gov processed this data on December 09, 2019
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.