T Cell Receptor (TCR) Sequencing and Transcriptional Profiling in Adult Celiac Disease Patients Undergoing Gluten Challenge

Study Overview
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Brief Summary
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The primary objectives are: Characterize the T cell receptor (TCR) repertoire in duodenal biopsy samples of participants pre- and post-challenge. Compare for each patient the TCR repertoire of duodenal biopsy samples with the peripheral blood TCR repertoire of each study participant Characterize the transcriptome of duodenal biopsy samples and blood from study participants pre- and post-challenge The secondary objectives are: Ex vivo identification and validation of DQ-restricted gliadin specific TCRs. Characterize the gluten-challenge induced changes in small intestine histology using standard for Celiac Disease (CeD) histological assessments

Official Title
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TCR Sequencing and Transcriptional Profiling in Celiac Disease Patients Undergoing Gluten Challenge

Conditions
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Celiac Disease

Intervention / Treatment
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* Dietary Supplement: Gluten Powder


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Have a body mass index (BMI) ≥17 and ≤40 kg/m2 and a body weight >45 kg at the Screening Visit Be judged to be in good health as defined in the protocol Have well-controlled biopsy-proven CeD, compliant with a GFD for ≥6 months preceding Screening as defined in the protocol Be HLA-DQ2 and/or HLA-DQ8 positive as defined in the protocol Key Exclusion Criteria: Have a history of gluten triggered acute symptoms (≤24 hours after gluten exposure), and/or severe symptoms (abdominal pain interfering with daily activities, diarrhea with >5 stools/day), and/or prolonged symptoms (duration >7 days) Have a history of clinically significant endocrine, cardiovascular, hematological, hepatic, immunological (other than CeD or autoimmune thyroid disease), renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or disease Have participated in another investigational trial within 4 weeks before Screening Have a history of cancer (malignancy) other than nonmelanoma skin cancer Have a history of significant multiple and/or severe allergies (e.g., latex allergy) Presence of HIV (HIV Ab), hepatitis B (HBsAg, HBAb) or Hepatitis C (HCV Ab) seropositivity at screening Ongoing immunosuppression or receive any treatment that might alter T cell repertoire or phenotype Note: Other protocol-defined inclusion/ exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Gluten Challenge<br> | Dietary Supplement: Gluten Powder<br>* Administered orally daily for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in small intestine TCR repertoire | Change in the T-cell receptor repertoire (measured by T cell receptor sequencing) in the small intestine after gluten challenge | Up to 30 days post challenge | 
| Change from Baseline in peripheral blood TCR repertoire | Change in the T-cell receptor repertoire (measured by T cell receptor sequencing) in peripheral blood after gluten challenge | Up to 30 days post challenge | 
| Changes from baseline in small intestine and peripheral blood transcriptome | Change in the gene expression profile (transcriptomic analysis by ribonucleic acid [RNA] sequencing and cellular indexing of transcriptomes and epitopes by sequencing [CITEseq]) of the small intestine and peripheral blood after gluten challenge | Up to 30 days post challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Count per 100 epithelial cells | IELs are white blood cells (WBCs) interspersed between epithelial cells of the small and large intestine where they function to preserve the integrity of the mucosal barrier by protecting the epithelium against pathogen or immune-induced pathology. Increased IELs count indicated more extreme CeD disease symptoms. Baseline values are defined as the last observed value before the first dose of gluten. | Baseline and Day 15 | 
| Change from Baseline in Small Intestine Histology Based on Villous Height (Microns), Crypt Depth (Microns) and Villous Height to Crypt Depth Ratio (Vh:Cd) | Villi are the small finger like projections that line the small intestine and promote nutrient absorption and are often shortened in active CeD. Crypts are grooves between the villi that are often elongated in CeD. A decreased Vh:Cd ratio indicates more extreme CeD disease symptoms. Baseline values (Microns) will be defined as the last observed value before the first dose of gluten. | Baseline and Day 15 | 
| Identification and ex vivo functional validation of gluten-specific T cells | Clonality of peripheral blood mononuclear cell (PBMC)-derived gluten-specific T cells (measured by T cell receptor sequencing) after ex vivo expansion with gluten peptides | Up to 30 days post challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CeD, HLA-DQ2 positive, HLA-DQ8 positive