Clinical trial NCT00931892: Serum Markers in Gluten Challenge
Official title: Circulating Markers of Celiac Disease Activity During Gluten Challenge - a Pilot Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Celiac Disease
Keywords: celiac disease
gluten challenge
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2009-07-02
Enrollment: 21
Sex: ALL
Minimum age (years): 17
Maximum age (years): 72
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: 1. The purpose of this research study is to evaluate non-invasive markers of celiac disease activity in subjects that are on a gluten-free diet, in remission from celiac disease who undergo gluten challenge.
2. The secondary aims of this protocol are to identify novel mediators important in the pathophysiology of celiac disease and to evaluate changes in metabolism with gluten exposure.

Detailed description: The diagnosis of celiac disease carries with it important ramifications. Celiac disease is a systemic immunologic disorder in which the sentinel lesion is an enteropathy triggered by polypeptides derived primarily from the gliadin proteins found in wheat, rye and barley. Ingestion of the offending proteins leads to inflammation and intestinal mucosal damage, which results in a spectrum of abdominal symptoms, increased intestinal permeability, malabsorption, occult gastrointestinal bleeding and diarrhea. Systemic manifestations of celiac disease include a myriad of conditions including malignancy and autoimmune disease.

The only accepted treatment for celiac disease is lifelong adherence to a gluten free diet. Adherence to this diet, simply put avoiding all foods containing even small amounts of wheat, rye and barley, has been shown to lead to improvement in the majority of related problems and normalization of all standard diagnostic tests. Because of this many individuals who present for evaluation of possible celiac disease but who are already on a gluten free diet cannot be tested accurately as there is currently no way of differentiating between healthy individuals and individuals with well treated celiac disease. The standard practice in such cases is to perform a 'Gluten Challenge' whereby the patient eats the equivalent of 2 slices of bread per day for six to eight weeks before returning for evaluation with serologic testing and endoscopy with duodenal biopsy. The use of the gluten challenge in clinical practice is limited by patient symptoms and resistance to such a long test period, after which it may take a number of weeks for the intestine to heal and the symptoms to resolve. Autoantibodies to tissue transglutaminase or antibodies to deamidated gliadin, while being excellent tools to predict celiac disease in patients who have been on a long-term gluten containing diet, display low sensitivities to detect short-term and/or recent gluten exposure. For this reason, it would be very useful if novel circulating markers could be identified that indicate the presence of celiac disease and in particular would provide an early and less invasive marker of a positive response to gluten challenge.

Eligibility criteria: Inclusion Criteria:

1. Age between 17 and 72 years, inclusive.
2. Subject must have been diagnosed with celiac disease by duodenal / jejunal biopsy at least 6 months prior to entrance into the study.
3. Subject has Anti-Tissue Transglutaminase (anti-tTG) ≤ 20 EU as measured by serology.
4. Subject must be on a gluten-free diet for at least the past 6 months.
5. Female subjects should be either post-menopausal (amenorrhea for at least 24 consecutive months), surgically sterile, or women of child-bearing potential (WOCP) with a negative urine beta human chorionic gonadotropin (HCG) pregnancy test prior to entering the study and who are using or agree to use acceptable methods of contraception. Abstinence is an acceptable means of avoiding pregnancy as long as the subject agrees to use contraception if they become sexually active. Acceptable contraceptives include intrauterine devices (IUDs), hormonal contraceptives (oral, depo, patch or injectable) in use for one month prior to screening and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.
6. Subject must sign an Institutional Review Board approved informed consent and agree to complete required clinic visits.
7. BMI between 18.5 and 38, inclusive.

Exclusion Criteria:

1. Subject has Anti-Tissue Transglutaminase (anti-tTG) \> 20 EU as measured by serology.
2. Subject has other food intolerances or food allergies (other than celiac disease) that would interfere with the conduct of the study).
3. Subject has a history of severe acute symptomatic reactions to sporadic gluten ingestion
4. Subject has any chronic active GI disease other than celiac disease (e.g. Crohn's disease, IBS).
5. Subjects with symptomatic neurological or psychiatric disease(s) that would interfere with the conduct of the study.
6. Subject has clinically significant abnormal laboratory test results at the screening visit or as determined by the Principal Investigator
7. Subject is pregnant or breast feeding.
8. Subject (premenopausal females) is sexually active without contraception.
9. Subject should not have been on steroids in the past 3 months.
10. Subject is deemed inappropriate by the Principal Investigator.

Primary outcomes:
measure: Crypt Depth to Villous Height Ratio
timeFrame: Screening (Day -7 to -14), Day 3, Day 14
Secondary outcomes:
measure: Count of Intraepithelial Lymphocytes Per 100 Enterocytes in Duodenal Biopsy Samples
timeFrame: Screening (Day -7 to -14), Day 3, Day 14
measure: Measures of Intestinal Permeability (Urinary Lactulose to Mannitol Ratio)
timeFrame: Screening (Day -7 to -14), Day 0, Day 3, Day 7, Day 14, Day 28
measure: Measures of Immune Activation
timeFrame: Screening (Day -7 to -14), Day 0, Day 3, Day 7, Day 14, Day 28
measure: Assessment of Protein Expression in Intestinal Biopsies
timeFrame: Screening (Day -7 to -14), Day 3, Day 14
measure: Symptomatic Response to Gluten Exposure Determined by Celiac Symptom Index Questionnaire
timeFrame: Screening (Day -7 to -14), Day 0, Day 3, Day 7, Day 14, Day 28
measure: Assessment of Protein Expression in Intestinal Biopsies Using Marsh Scores
timeFrame: Screening (Day -7 to -14), Day 3, Day 14
measure: Symptomatic Response to Gluten Exposure Determined by Gastrointestinal Symptom Rating Scale
timeFrame: Screening (Day -7 to -14), Day 0, Day 3, Day 7, Day 14, Day 28
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Ciaran P Kelly, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Beth Israel Deaconess Medical Center
name: Daniel A Leffler, MD, MS
role: STUDY_DIRECTOR
References:
citation: Svedlund J, Sjodin I, Dotevall G. GSRS--a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1988 Feb;33(2):129-34. doi: 10.1007/BF01535722.
citation: Adelman DC, Murray J, Wu TT, Maki M, Green PH, Kelly CP. Measuring Change In Small Intestinal Histology In Patients With Celiac Disease. Am J Gastroenterol. 2018 Mar;113(3):339-347. doi: 10.1038/ajg.2017.480. Epub 2018 Feb 20.
citation: Leffler DA, Dennis M, Edwards George J, Jamma S, Cook EF, Schuppan D, Kelly CP. A validated disease-specific symptom index for adults with celiac disease. Clin Gastroenterol Hepatol. 2009 Dec;7(12):1328-34, 1334.e1-3. doi: 10.1016/j.cgh.2009.07.031. Epub 2009 Aug 7.
citation: Leffler D, Schuppan D, Pallav K, Najarian R, Goldsmith JD, Hansen J, Kabbani T, Dennis M, Kelly CP. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut. 2013 Jul;62(7):996-1004. doi: 10.1136/gutjnl-2012-302196. Epub 2012 May 22.