T Cell Receptor (TCR) Sequencing and Transcriptional Profiling in Adult Celiac Disease Patients Undergoing Gluten Challenge
Study Details
Study Description
Brief Summary
The primary objectives are:
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Characterize the T cell receptor (TCR) repertoire in duodenal biopsy samples of participants pre- and post-challenge.
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Compare for each patient the TCR repertoire of duodenal biopsy samples with the peripheral blood TCR repertoire of each study participant
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Characterize the transcriptome of duodenal biopsy samples and blood from study participants pre- and post-challenge
The secondary objectives are:
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Ex vivo identification and validation of DQ-restricted gliadin specific TCRs.
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Characterize the gluten-challenge induced changes in small intestine histology using standard for Celiac Disease (CeD) histological assessments
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Gluten Challenge
|
Dietary Supplement: Gluten Powder
Administered orally daily for 14 days
|
Outcome Measures
Primary Outcome Measures
- Change from Baseline in small intestine TCR repertoire [Up to 30 days post challenge]
Change in the T-cell receptor repertoire (measured by T cell receptor sequencing) in the small intestine after gluten challenge
- Change from Baseline in peripheral blood TCR repertoire [Up to 30 days post challenge]
Change in the T-cell receptor repertoire (measured by T cell receptor sequencing) in peripheral blood after gluten challenge
- Changes from baseline in small intestine and peripheral blood transcriptome [Up to 30 days post challenge]
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
Secondary Outcome Measures
- Change from Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Count per 100 epithelial cells [Baseline and Day 15]
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.
- Change from Baseline in Small Intestine Histology Based on Villous Height (Microns), Crypt Depth (Microns) and Villous Height to Crypt Depth Ratio (Vh:Cd) [Baseline and Day 15]
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.
- Identification and ex vivo functional validation of gluten-specific T cells [Up to 30 days post challenge]
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
Eligibility Criteria
Criteria
Key Inclusion Criteria:
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Have a body mass index (BMI) ≥17 and ≤40 kg/m2 and a body weight >45 kg at the Screening Visit
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Be a nonsmoker who has not used tobacco- or nicotine-containing products (e.g., nicotine patch) for at least 6 months before Day 1 gluten administration
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Be judged to be in good health as defined in the protocol
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Have well-controlled biopsy-proven CeD, compliant with a GFD for ≥6 months preceding Screening as defined in the protocol
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Be HLA-DQ2.5 and/or HLA-DQ8 positive as defined in the protocol
Key Exclusion Criteria:
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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)
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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
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Have participated in another investigational trial within 4 weeks before Screening
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Have a history of cancer (malignancy) other than nonmelanoma skin cancer
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Have a history of significant multiple and/or severe allergies (e.g., latex allergy)
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Presence of HIV (HIV Ab), hepatitis B (HBsAg, HBAb) or Hepatitis C (HCV Ab) seropositivity at screening
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Ongoing immunosuppression or receive any treatment that might alter T cell repertoire or phenotype
Note: Other protocol-defined inclusion/ exclusion criteria apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Celiac Research Centre Mass General Hospital | Boston | Massachusetts | United States | 02114 |
Sponsors and Collaborators
- Regeneron Pharmaceuticals
Investigators
- Study Director: Clinical Trial Administrator, Regeneron Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 0000-CD-CES-1880