Assessment of Immune Activation and Tolerance in Celiac Disease During Gluten Challenge

Gluten challenge studies are used to test the effectiveness of therapies designed to prevent immune response to gluten in participants with CeD. The study will enroll approximately 20 participants. Participants will be randomly assigned (by chance, like flipping a coin) in a 1:1 ratio to one of the two treatment groups:

* Group A: Gluten 3 gm
* Group B: Gluten 10 gm

All participants will be asked to take an oral dose of gluten at the same time on Days 1 to 14 throughout the study. This multi-center trial will be conducted in the United States. The overall time to participate in this study is 10 weeks. Participants will visit to the clinic on Day -45 and will be contacted for follow-up assessment on Days 15 to 42.

• Gluten (Dietary supplement): Gluten powder.

Primary outcomes

• Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio [Baseline and Day 15]: Attenuation of the effects of gluten exposure was assessed by measuring the change from baseline in villous height (Vh) to crypt depth (Cd) ratio after 15 days of gluten challenge. Villi were the small finger like projections that line the small intestine and promote nutrient absorption and are often shortened in participants with CeD. Crypts were grooves between the villi that are often elongated in participants with CeD. A decreased Vh:Cd ratio indicates more extreme CeD disease symptoms. Baseline values was defined as the last observed value before the first dose of gluten.
• Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts [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 was defined as the last observed value before the first dose of gluten.

Secondary outcomes

• Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments [At Baseline, Days 6 and 15]: Standard measures used for diagnosing CeD: Vh:CD ratio and IEL counts. T cell measurements taken before first dose of gluten were correlated with Baseline Vh:Cd ratio and IEL counts, and T cell measurements taken after first dose of gluten were correlated with Day 15 Vh:Cd ratio and IEL counts using Spearman correlation. Villi were small finger like projections that line small intestine, promote nutrient absorption and are often shortened in CeD participants. Crypts were grooves between villi that were often elongated in CeD participants. IELs were WBCs interspersed between epithelial cells of intestine where they function to preserve integrity of mucosal barrier by protecting epithelium against pathogen/immune-induced pathology. Decreased Vh:Cd ratio and increased IELs count indicated more extreme CeD symptoms. Baseline value: last observed value before first dose of gluten. Tr: T cell value taken before first dose of gluten. T6: T cell value at Day 6. T15: T cell value at Day 15.
• Change From Baseline in Gluten-specific T Cells in Blood Based on Enzyme-linked Immune Absorbent Spot (ELISPot) Assay and T Cell Receptor (TCR) Human Leukocyte Antigen Serotype (HLA-DQ2)-Tetramers [Baseline and Day 6]: ELISpot assay and gluten specific TCR measures drug response by quantifying changes in the number or function of gluten-specific T cells. Baseline value was defined as the last observed value before the first dose of gluten.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. Be a non-smoker who has not used tobacco- or nicotine-containing products (example, nicotine patch) for at least 6 months before Day 1 gluten administration.
2. Have well-controlled biopsy-proven CeD, compliant with a gluten-free diet (GFD) for greater than or equal to (>=) 6 months preceding screening, with resolution of CeD symptoms, normalization of CeD serology, and in the judgment of the investigator, have inactive or minimally-active disease.
3. Be HLA-DQ2.5 and/or HLA-DQ8 positive, assessed at screening. If participants have already been genotyped, results from previous testing may be used in lieu of genotyping at screening.
4. Be willing to delay a planned procedure involving the use of powerful electromagnetic fields (example, magnetic resonance imaging), until the PillCam SB 3 capsule is excreted.
5. Not undergo VCE or optical coherence tomography (OCT) if has an implanted electromedical device or a swallowing disorder.
6. Not undergo OCT if has a contraindication to the device or procedure as per reference information.

Exclusion Criteria:

1. Had major surgery and/or donated or lost 1 unit of blood (approximately 500 milliliter \[mL\]) within 8 weeks before the first dose of gluten.
2. Are unable to refrain from or anticipate the use of any unapproved medication, including prescription drugs, nonprescription drugs, and herbal remedies, beginning approximately 7 days before administration of the initial dose of gluten and continuing throughout the trial until the follow-up visit.
3. Consume excessive amounts of coffee, tea, cola, energy drinks, or other caffeinated beverages per day. An excessive amount is defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine).
4. Have positive IgA anti-tissue transglutaminase (tTG), IgA anti-deamidated gliadin peptide (DGP), and IgG DGP serologies at Screening.
5. Have inflammatory gastrointestinal disorders or autoimmune diseases other than CeD or autoimmune thyroid disease.
6. Have known or suspected gastrointestinal obstructions, strictures, or fistulas based on the clinical picture or pre-procedure testing and profile of the PillCam SB 3 capsule.
7. Endoscopy and intestinal biopsy are contraindicated.

Participant flow

Outcome results

• Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio (Primary), Mean, ratio: Group A: Gluten 3 Gram 2.10 +/- 0.697; Group B: Gluten 10 Gram 2.30 +/- 0.893 (p 0.385)
• Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts (Primary), Mean, IEL per 100 epithelial cells: Group A: Gluten 3 Gram 26.74 +/- 15.861; Group B: Gluten 10 Gram 26.68 +/- 8.248 (p 0.010)
• Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments (Secondary), Number, correlation coefficient: Group A: Gluten 3 Gram -0.0355; Group B: Gluten 10 Gram 0.1480
• Change From Baseline in Gluten-specific T Cells in Blood Based on Enzyme-linked Immune Absorbent Spot (ELISPot) Assay and T Cell Receptor (TCR) Human Leukocyte Antigen Serotype (HLA-DQ2)-Tetramers (Secondary), Mean, per million CD4+ T cells: Group A: Gluten 3 Gram 1.00 +/- 1.956; Group B: Gluten 10 Gram 1.45 +/- 1.756

Adverse events

Time frame: Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of gluten up to Day 43

Other adverse events by term

• Results publication: Johansen A, Sandve GKF, Maxwell JR, Smithson G, Sollid LM, Stamnaes J. Biopsy Proteome Score Performs Well as an Effect Measure in a Gluten Challenge Trial of Celiac Disease. Clin Gastroenterol Hepatol. 2025 Apr;23(5):758-765.e8. doi: 10.1016/j.cgh.2024.08.005. Epub 2024 Aug 30. PMID 39209203
• Results publication: Leonard MM, Silvester JA, Leffler D, Fasano A, Kelly CP, Lewis SK, Goldsmith JD, Greenblatt E, Kwok WW, McAuliffe WJ, Galinsky K, Siegelman J, Chow IT, Wagner JA, Sapone A, Smithson G. Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial. Gastroenterology. 2021 Feb;160(3):720-733.e8. doi: 10.1053/j.gastro.2020.10.040. Epub 2020 Oct 29. PMID 33130104

• Study Protocol (PDF, 2017-10-06)
• Statistical Analysis Plan (PDF, 2018-05-03)

• Medical Director Clinical Science, Study director, Takeda