Celiac Disease
Conditions
Keywords
Celiac disease
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.
Interventions
DIETARY_SUPPLEMENTGluten powder 4g
Gluten powder 4g oral BID
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention 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
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Participant must have documented diagnosis with celiac disease (CeD) by duodenal/jejunal biopsy at least 6 months prior to entrance into the study. 2. Participant must be on a gluten-free diet (GFD) for at least the past 12 months. 3. Female participants must not be pregnant or breastfeeding. Women of childbearing potential (WOCBP) must use an acceptable contraceptive method or abstain from heterosexual intercourse. 4. 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. 5. Has anti-tissue transglutaminase (anti-tTG) \<2x upper limit of normal (ULN) as measured by serology. 6. 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. 7. Have a body mass index (BMI) 18-35 kg/m\^2, inclusive.
Exclusion criteria
1. 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. 2. 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. 3. 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. 4. 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 5. 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. 6. Subject has a history of severe acute symptomatic reactions to sporadic gluten ingestion. 7. Is positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV). 8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit. 9. Is on Coumadin™ or other anticoagulants. 10. 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. 11. 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. 12. Has a corrected QT (QTc) interval ≥470 msec (for males) or ≥480 msec (for females).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | Baseline (Day 1, pre-dose) | 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). |
| Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | Day 14 | 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). |
| Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | Day 14 | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gluten Challenge Participants with celiac disease received 8 g gluten powder (4 g twice daily) orally for 13 consecutive days. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Gluten Challenge |
|---|---|
| Age, Continuous | 35.9 Years STANDARD_DEVIATION 15.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 16 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
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).
Time frame: Day 14
Population: The analysis population includes participants who were compliant with study procedures and had available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α1-gliadin tetramer+ | 0.00707 Percentage of T cells | Standard Deviation 0.0051 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α1-gliadin tetramer+, CD25+ | 0.00054 Percentage of T cells | Standard Deviation 0.00071 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α1-gliadin tetramer+, CD38+ | 0.00276 Percentage of T cells | Standard Deviation 0.00161 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α1-gliadin tetramer+, CD39+ | 0.00049 Percentage of T cells | Standard Deviation 0.00075 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α1-gliadin tetramer+, PD1+ | 0.00091 Percentage of T cells | Standard Deviation 0.00113 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α1-gliadin tetramer+, Integrin B7+ | 0.00361 Percentage of T cells | Standard Deviation 0.00198 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α2-gliadin tetramer+ | 0.01315 Percentage of T cells | Standard Deviation 0.01199 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α2-gliadin tetramer+, CD25+ | 0.00177 Percentage of T cells | Standard Deviation 0.00391 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α2-gliadin tetramer+, CD38+ | 0.00495 Percentage of T cells | Standard Deviation 0.00698 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α2-gliadin tetramer+, CD39+ | 0.00018 Percentage of T cells | Standard Deviation 0.0007 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α2-gliadin tetramer+, PD1+ | 0.00186 Percentage of T cells | Standard Deviation 0.00378 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood After Gluten Challenge | α2-gliadin tetramer+, Integrin B7+ | 0.00609 Percentage of T cells | Standard Deviation 0.0047 |
Primary
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).
Time frame: Baseline (Day 1, pre-dose)
Population: The analysis population includes participants who were compliant with study procedures and had available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α1-gliadin tetramer+ | 0.00364 Percentage of T cells | Standard Deviation 0.00278 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α1-gliadin tetramer+, CD25+ | 0.00016 Percentage of T cells | Standard Deviation 0.00029 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α1-gliadin tetramer+, CD38+ | 0.00049 Percentage of T cells | Standard Deviation 0.0008 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α1-gliadin tetramer+, CD39+ | 0.00005 Percentage of T cells | Standard Deviation 0.00021 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α1-gliadin tetramer+, PD1+ | 0.00007 Percentage of T cells | Standard Deviation 0.0002 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α1-gliadin tetramer+, Integrin B7+ | 0.00161 Percentage of T cells | Standard Deviation 0.00162 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α2-gliadin tetramer+ | 0.01115 Percentage of T cells | Standard Deviation 0.00988 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α2-gliadin tetramer+, CD25+ | 0.00058 Percentage of T cells | Standard Deviation 0.00092 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α2-gliadin tetramer+, CD38+ | 0.00080 Percentage of T cells | Standard Deviation 0.00151 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α2-gliadin tetramer+, CD39+ | 0.00006 Percentage of T cells | Standard Deviation 0.00024 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α2-gliadin tetramer+, PD1+ | 0.00010 Percentage of T cells | Standard Deviation 0.00037 |
| Gluten Challenge | Percentage of α1- and α2-gliadin-reactive CD4+ T Cells in Peripheral Blood Before Gluten Challenge | α2-gliadin tetramer+, Integrin B7+ | 0.00335 Percentage of T cells | Standard Deviation 0.00423 |
Primary
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).
Time frame: Day 14
Population: The analysis population includes participants who were compliant with study procedures and had available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gluten Challenge | Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | α1-gliadin tetramer+ | 0.29347 Percentage of T cells | Standard Deviation 0.26689 |
| Gluten Challenge | Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | α1-gliadin tetramer+, CD25+ | 0.00263 Percentage of T cells | Standard Deviation 0.00401 |
| Gluten Challenge | Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | α1-gliadin tetramer+, CD38+ | 0.19977 Percentage of T cells | Standard Deviation 0.19001 |
| Gluten Challenge | Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | α1-gliadin tetramer+, CD39+ | 0.21248 Percentage of T cells | Standard Deviation 0.24696 |
| Gluten Challenge | Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | α1-gliadin tetramer+, PD1+ | 0.26563 Percentage of T cells | Standard Deviation 0.2651 |
| Gluten Challenge | Percentage of α1-gliadin-reactive CD4+ T Cells in Duodenal Biopsies After Gluten Challenge | α1-gliadin tetramer+, Integrin B7+ | 0.24281 Percentage of T cells | Standard Deviation 0.24192 |