Celiac Disease
Conditions
Keywords
Gluten Challenge
Brief summary
The primary purpose of this study is to characterize changes in gluten-specific T cells and pathology in the small intestine with specific focus on biomarkers likely to change with therapeutic celiac disease (CeD) treatment.
Detailed description
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.
Interventions
DIETARY_SUPPLEMENTGluten
Gluten powder.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in the Unites Stated from 24 April 2018 to 02 May 2019.
Pre-assignment details
Participants diagnosed with celiac disease (CeD) were enrolled in a 1:1 ratio in one of the two treatment groups: 3 gram gluten per day or 10 gram gluten per day.
Participants by arm
| Arm | Count |
|---|---|
| Group A: Gluten 3 Gram Gluten 3 gram, powder, orally, once daily up to 14 days. | 9 |
| Group B: Gluten 10 Gram Gluten 10 gram, powder, orally, once daily up to 14 days. | 7 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Other | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Group B: Gluten 10 Gram | Group A: Gluten 3 Gram |
|---|---|---|---|
| Age, Continuous | 45.0 years STANDARD_DEVIATION 17.84 | 46.0 years STANDARD_DEVIATION 18.86 | 44.2 years STANDARD_DEVIATION 18.12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 7 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 167.15 centimeter (cm) STANDARD_DEVIATION 9.02 | 169.76 centimeter (cm) STANDARD_DEVIATION 8.074 | 165.12 centimeter (cm) STANDARD_DEVIATION 9.648 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 7 Participants | 9 Participants |
| Region of Enrollment United States | 16 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Female | 13 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 1 Participants |
| Weight | 77.91 kilogram (kg) STANDARD_DEVIATION 13.918 | 81.36 kilogram (kg) STANDARD_DEVIATION 8.121 | 75.23 kilogram (kg) STANDARD_DEVIATION 17.183 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 7 |
| other Total, other adverse events | 3 / 9 | 1 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 7 |
Outcome results
Primary
Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts
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.
Time frame: Baseline and Day 15
Population: The biomarker analysis set consisted of all participants who had two endoscopic examinations with biopsies, one before and one after gluten challenge.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: Gluten 3 Gram | Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts | Baseline | 26.74 IEL per 100 epithelial cells | Standard Deviation 15.861 |
| Group A: Gluten 3 Gram | Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts | Change at Day 15 | 9.56 IEL per 100 epithelial cells | Standard Deviation 15.206 |
| Group B: Gluten 10 Gram | Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts | Baseline | 26.68 IEL per 100 epithelial cells | Standard Deviation 8.248 |
| Group B: Gluten 10 Gram | Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts | Change at Day 15 | 26.80 IEL per 100 epithelial cells | Standard Deviation 14.908 |
Comparison: Gluten 3 gram: Baseline versus Day 15. The Poisson distribution assumption was checked using Kolmogorov-Smirnov test. Poisson generalized linear mixed models (GLMM) was fitted to data, where IEL measurements were grouped by participant (the random effect) and the change in IEL counts was the fixed effect. If the data was found to not be Poisson at alpha=0.05, a 1-sided Wilcoxon signed-rank test was used instead to compare IELB and IEL15.p-value: 0.01Poisson distribution
Comparison: Gluten 10 gram: Baseline versus Day 15. The Poisson distribution assumption was checked using Kolmogorov-Smirnov test. Poisson GLMM was fitted to data, where IEL measurements were grouped by participant (the random effect) and the change in IEL counts was the fixed effect. If the data was found to not be Poisson at alpha=0.05, a 1-sided Wilcoxon signed-rank test was used instead to compare IELB and IEL15.p-value: 0.006Poisson distribution
Primary
Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio
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.
Time frame: Baseline and Day 15
Population: The biomarker analysis set consisted of all participants had two endoscopic examinations with biopsies, one before and one after gluten challenge.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: Gluten 3 Gram | Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio | Baseline | 2.10 ratio | Standard Deviation 0.697 |
| Group A: Gluten 3 Gram | Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio | Change at Day 15 | -0.06 ratio | Standard Deviation 0.516 |
| Group B: Gluten 10 Gram | Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio | Baseline | 2.30 ratio | Standard Deviation 0.893 |
| Group B: Gluten 10 Gram | Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio | Change at Day 15 | -1.53 ratio | Standard Deviation 0.941 |
Comparison: Gluten 10 gram: Baseline versus Day 15. Change in Vh:Cd follows a normal distribution. A 1-sided paired t-test was used to compare Baseline and follow-up Vh:Cd measures. The normality assumption was checked using the Shapiro-Wilk test. If the data was not normal at alpha=0.05, a 1-sided Wilcoxon signed-rank test was used instead to compare Vh:CdB and Vh:Cd15.p-value: 0.003t-test, 1 sided
Comparison: Gluten 3 gram: Baseline versus Day 15. Change in Vh:Cd follows a normal distribution. A 1-sided paired t-test was used to compare Baseline and follow-up Vh:Cd measures. The normality assumption was checked using the Shapiro-Wilk test. If the data was not normal at alpha=0.05, a 1-sided Wilcoxon signed-rank test was used instead to compare Vh:CdBaseline (B) and Vh:Cd15.p-value: 0.385t-test, 1 sided
Secondary
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
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.
Time frame: Baseline and Day 6
Population: The biomarker analysis set consisted of all participants who had two endoscopic examinations with biopsies, one before and one after gluten challenge.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: Gluten 3 Gram | 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 (ELISpot) | 1.00 per million CD4+ T cells | Standard Deviation 1.956 |
| Group A: Gluten 3 Gram | 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 | Change at Day 6 (ELISpot) | 3.83 per million CD4+ T cells | Standard Deviation 6.902 |
| Group A: Gluten 3 Gram | 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 (Tetramer) | 34.62 per million CD4+ T cells | Standard Deviation 29.215 |
| Group A: Gluten 3 Gram | 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 | Change at Day 6 (Tetramer) | 26.76 per million CD4+ T cells | Standard Deviation 54.084 |
| Group B: Gluten 10 Gram | 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 | Change at Day 6 (Tetramer) | 522.47 per million CD4+ T cells | Standard Deviation 788.177 |
| Group B: Gluten 10 Gram | 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 (ELISpot) | 1.45 per million CD4+ T cells | Standard Deviation 1.756 |
| Group B: Gluten 10 Gram | 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 (Tetramer) | 17.33 per million CD4+ T cells | Standard Deviation 14.894 |
| Group B: Gluten 10 Gram | 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 | Change at Day 6 (ELISpot) | 25.12 per million CD4+ T cells | Standard Deviation 29.025 |
Secondary
Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments
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.
Time frame: At Baseline, Days 6 and 15
Population: The biomarker analysis set consisted of all participants who had two endoscopic examinations with biopsies, one before and one after gluten challenge.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: Gluten 3 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T6: Day 15 Vh: Cd ratio | 0.0368 correlation coefficient |
| Group A: Gluten 3 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T15: Day 15 IEL counts | 0.2967 correlation coefficient |
| Group A: Gluten 3 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T6: Day 15 IEL counts | 0.2179 correlation coefficient |
| Group A: Gluten 3 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | Tr: Baseline IEL counts | -0.0050 correlation coefficient |
| Group A: Gluten 3 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T15: Day 15 Vh: Cd ratio | -0.0913 correlation coefficient |
| Group A: Gluten 3 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | Tr: Baseline Vh:Cd ratio | -0.0355 correlation coefficient |
| Group B: Gluten 10 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T15: Day 15 IEL counts | 0.0192 correlation coefficient |
| Group B: Gluten 10 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | Tr: Baseline Vh:Cd ratio | 0.1480 correlation coefficient |
| Group B: Gluten 10 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | Tr: Baseline IEL counts | -0.0905 correlation coefficient |
| Group B: Gluten 10 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T6: Day 15 Vh: Cd ratio | -0.0170 correlation coefficient |
| Group B: Gluten 10 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T6: Day 15 IEL counts | 0.0595 correlation coefficient |
| Group B: Gluten 10 Gram | Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments | T15: Day 15 Vh: Cd ratio | 0.0214 correlation coefficient |