Gluten Challenge Study in Celiac Disease Participants (MK-0000-402)

Study Overview
=================
Brief Summary
-----------------
This is a gluten challenge study to characterize peripheral blood and intestinal gluten specific cluster of differentiation 4 glycoprotein (CD4+) thymus lymphocyte (T cell) subsets in participants with Celiac Disease

Detailed Description
-----------------
This is a multi-site, open-label gluten challenge study to characterize peripheral blood and intestinal gluten specific CD4+ T cell subsets in participants with celiac disease (CeD). Participants will receive 8 grams (g) of gluten daily for 13 consecutive days. Blood samples will be taken at pre-dose, Day 6, and Day 14. Duodenal biopsy samples will also be collected on Day 14. Participants will also complete a symptom diary.

Official Title
-----------------
A Gluten Challenge Study to Characterize Peripheral Blood and Intestinal Gluten-specific CD4+ T Cell Subsets in Patients With Celiac Disease

Conditions
-----------------
Celiac Disease

Intervention / Treatment
-----------------
* Dietary Supplement: Gluten powder 4g


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must have documented diagnosis with celiac disease (CeD) by duodenal/jejunal biopsy at least 6 months prior to entrance into the study. Participant must be on a gluten-free diet (GFD) for at least the past 12 months. Female participants must not be pregnant or breastfeeding. Women of childbearing potential (WOCBP) must use an acceptable contraceptive method or abstain from heterosexual intercourse. Must be Human leukocyte antigen (HLA)-DQ2.5 positive, assessed at screening. If participants have already been genotyped, results from previous testing may be used in lieu of genotyping at screening. Has anti-tissue transglutaminase (anti-tTG) <2x upper limit of normal (ULN) as measured by serology. Be judged to be in good health based on medical history, physical examination (including a targeted neurological exam), versus (vs.) measurements and electrocardiogram (ECG) performed prior to treatment allocation. Have a body mass index (BMI) 18-35 kg/m^2, inclusive. Exclusion Criteria: Has any chronic active gastrointestinal (GI) disease (e.g., clinically active CeD despite being on GFD for past 12 months, Crohn's disease, ulcerative colitis, lymphocytic colitis). Inactive, stable/well-treated lactose intolerance, Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) intolerance, gastroesophageal reflux disease (GERD), and irritable bowel syndrome (IBS) are allowed. Has clinically active endocrine, gastrointestinal (other than CeD), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases. Participants with a remote history of uncomplicated medical events or stable medical diseases with no symptoms and stable treatment for the past >3 months may be enrolled in the study at the discretion of the investigator. Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder within the last 5 years. Participants who have had situational depression may be enrolled in the study at the discretion of the investigator. Participant has an estimated Glomerular Filtration Rate (eGFR) ≤80 mL/min/1.73 m^2 at the screening visit based on the Cockcroft-Gault (CG) equation Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an anaphylactic reaction or systemic allergic reaction to prescription or nonprescription drugs or food. Subject has a history of severe acute symptomatic reactions to sporadic gluten ingestion. Is positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV). Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit. Is on Coumadin™ or other anticoagulants. Is unable to refrain from or anticipates the use of systemic anti-inflammatory, immunosuppressive, or immunomodulatory medications, which may include ibuprofen > 2400 mg/day, naproxen >750 mg/day, prednisone >10 mg/day, or methylprednisolone > 8 mg/day, within 48 hours prior to the start of and throughout the entire gluten challenge. Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit. The window will be derived from the date of the last visit in the previous study. Has a corrected QT (QTc) interval ≥470 msec (for males) or ≥480 msec (for females).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Experimental study to determine blood and duodenal T cell changes following administration of an 8 g gluten challenge daily for 13 days in participants with celiac disease
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gluten challenge<br>Participants will receive a gluten 4 g powder twice daily (BID), for 13 consecutive days | Dietary Supplement: Gluten powder 4g<br>* Gluten powder 4g oral BID<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | Peripheral blood mononuclear cells (PBMC) collected prior to gluten challenge were stained with phycoerythrin (PE)-labeled human leukocyte antigen (HLA)-DQ2.5: gluten tetramers (DQ2.5-glia-α1 and DQ2.5-glia-α2) to identify antigen-specific cluster of differentiation (CD)4-positive thymus lymphocyte (T cells) reactive to gliadin (tetramer+ T cells) by flow cytometry. PBMC were also labeled with a 20-antibody panel for cell surface antigen staining to further define tetramer+ T cell subsets. Antigens included in the analysis were CD25, CD38, CD39, programmed cell death receptor 1 (PD-1), and integrin beta-7 (B7). | Baseline (Day 1, pre-dose) | 
| Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | Peripheral blood mononuclear cells (PBMC) collected on Day 14 following gluten challenge were stained with phycoerythrin (PE)-labeled human leukocyte antigen (HLA)-DQ2.5: gluten tetramers (DQ2.5-glia-α1 and DQ2.5-glia-α2) to identify antigen-specific cluster of differentiation (CD)4-positive thymus lymphocyte (T cells) reactive to gliadin (tetramer+ T cells) by flow cytometry. PBMC were also labeled with a 20-antibody panel for cell surface antigen staining to further define tetramer+ T cell subsets. Antigens included in the analysis were CD25, CD38, CD39, programmed cell death receptor 1 (PD-1), and integrin beta-7 (B7). | Day 14 | 
| Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | Lymphocytes from duodenal biopsies collected on Day 14 following gluten challenge were stained with a phycoerythrin (PE)-labeled human leukocyte antigen (HLA)-DQ2.5: gluten tetramer (DQ2.5-glia-α1) to identify antigen-specific cluster of differentiation (CD)4-positive thymus lymphocyte (T cells) reactive to gliadin (tetramer+ T cells) by flow cytometry. Lymphocytes were also labeled with a 20-antibody panel for cell surface antigen staining to further define tetramer+ T cell subsets. Antigens included in the analysis were CD25, CD38, CD39, programmed cell death receptor 1 (PD-1), and integrin beta-7 (B7). | Day 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Celiac disease