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

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ClinicalTrials.gov Identifier: NCT03409796
Recruitment Status : Completed
First Posted : January 24, 2018
Results First Posted : August 18, 2020
Last Update Posted : August 18, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Other
Condition Celiac Disease
Intervention Dietary Supplement: Gluten
Enrollment 16
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.
Arm/Group Title Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Hide Arm/Group Description Gluten 3 gram, powder, orally, once daily up to 14 days. Gluten 10 gram, powder, orally, once daily up to 14 days.
Period Title: Overall Study
Started 9 7
Completed 7 6
Not Completed 2 1
Reason Not Completed
Adverse Event             2             0
Other             0             1
Arm/Group Title Group A: Gluten 3 Gram Group B: Gluten 10 Gram Total
Hide Arm/Group Description Gluten 3 gram, powder, orally, once daily up to 14 days. Gluten 10 gram, powder, orally, once daily up to 14 days. Total of all reporting groups
Overall Number of Baseline Participants 9 7 16
Hide Baseline Analysis Population Description
The safety set consisted of all participants who were enrolled and received at least 1 dose of gluten.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 7 participants 16 participants
44.2  (18.12) 46.0  (18.86) 45.0  (17.84)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 7 participants 16 participants
Female
8
  88.9%
5
  71.4%
13
  81.3%
Male
1
  11.1%
2
  28.6%
3
  18.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 7 participants 16 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
9
 100.0%
7
 100.0%
16
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 7 participants 16 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
9
 100.0%
7
 100.0%
16
 100.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 9 participants 7 participants 16 participants
9
 100.0%
7
 100.0%
16
 100.0%
Height  
Mean (Standard Deviation)
Unit of measure:  Centimeter (cm)
Number Analyzed 9 participants 7 participants 16 participants
165.12  (9.648) 169.76  (8.074) 167.15  (9.020)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kilogram (kg)
Number Analyzed 9 participants 7 participants 16 participants
75.23  (17.183) 81.36  (8.121) 77.91  (13.918)
1.Primary Outcome
Title Change From Baseline in Small Intestine Histology Based on Villous Height to Crypt Depth (Vh:Cd) Ratio
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The biomarker analysis set consisted of all participants had two endoscopic examinations with biopsies, one before and one after gluten challenge.
Arm/Group Title Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Hide Arm/Group Description:
Gluten 3 gram, powder, orally, once daily up to 14 days.
Gluten 10 gram, powder, orally, once daily up to 14 days.
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline 2.10  (0.697) 2.30  (0.893)
Change at Day 15 -0.06  (0.516) -1.53  (0.941)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A: Gluten 3 Gram
Comments 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.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.385
Comments [Not Specified]
Method t-test, 1 sided
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B: Gluten 10 Gram
Comments 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.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method t-test, 1 sided
Comments [Not Specified]
2.Primary Outcome
Title Change From Baseline in Small Intestine Histology Based on Intraepithelial Lymphocytes (IEL) Counts
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The biomarker analysis set consisted of all participants who had two endoscopic examinations with biopsies, one before and one after gluten challenge.
Arm/Group Title Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Hide Arm/Group Description:
Gluten 3 gram, powder, orally, once daily up to 14 days.
Gluten 10 gram, powder, orally, once daily up to 14 days.
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: IEL per 100 epithelial cells
Baseline 26.74  (15.861) 26.68  (8.248)
Change at Day 15 9.56  (15.206) 26.80  (14.908)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A: Gluten 3 Gram
Comments 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.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments [Not Specified]
Method Poisson distribution
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group B: Gluten 10 Gram
Comments 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.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Poisson distribution
Comments [Not Specified]
3.Secondary Outcome
Title Correlation Coefficient Changes Between Gluten-specific Blood T Cells and Standard CeD Histological Assessments
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The biomarker analysis set consisted of all participants who had two endoscopic examinations with biopsies, one before and one after gluten challenge.
Arm/Group Title Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Hide Arm/Group Description:
Gluten 3 gram, powder, orally, once daily up to 14 days.
Gluten 10 gram, powder, orally, once daily up to 14 days.
Overall Number of Participants Analyzed 7 7
Measure Type: Number
Unit of Measure: correlation coefficient
Tr: Baseline Vh:Cd ratio -0.0355 0.1480
Tr: Baseline IEL counts -0.0050 -0.0905
T6: Day 15 Vh: Cd ratio 0.0368 -0.0170
T6: Day 15 IEL counts 0.2179 0.0595
T15: Day 15 Vh: Cd ratio -0.0913 0.0214
T15: Day 15 IEL counts 0.2967 0.0192
4.Secondary Outcome
Title 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
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The biomarker analysis set consisted of all participants who had two endoscopic examinations with biopsies, one before and one after gluten challenge.
Arm/Group Title Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Hide Arm/Group Description:
Gluten 3 gram, powder, orally, once daily up to 14 days.
Gluten 10 gram, powder, orally, once daily up to 14 days.
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: per million CD4+ T cells
Baseline (ELISpot) 1.00  (1.956) 1.45  (1.756)
Change at Day 6 (ELISpot) 3.83  (6.902) 25.12  (29.025)
Baseline (Tetramer) 34.62  (29.215) 17.33  (14.894)
Change at Day 6 (Tetramer) 26.76  (54.084) 522.47  (788.177)
Time Frame Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of gluten up to Day 43
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Hide Arm/Group Description Gluten 3 gram, powder, orally, once daily up to 14 days. Gluten 10 gram, powder, orally, once daily up to 14 days.
All-Cause Mortality
Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)   0/7 (0.00%) 
Hide Serious Adverse Events
Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)   0/7 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Group A: Gluten 3 Gram Group B: Gluten 10 Gram
Affected / at Risk (%) Affected / at Risk (%)
Total   3/9 (33.33%)   1/7 (14.29%) 
Gastrointestinal disorders     
Vomiting  1  1/9 (11.11%)  1/7 (14.29%) 
Abdominal pain upper  1  1/9 (11.11%)  0/7 (0.00%) 
Diarrhoea  1  0/9 (0.00%)  1/7 (14.29%) 
Metabolism and nutrition disorders     
Gluten sensitivity  1  1/9 (11.11%)  0/7 (0.00%) 
1
Term from vocabulary, MedDRA (22.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03409796    
Other Study ID Numbers: TIMP-GLIA-5001
U1111-1202-6708 ( Other Identifier: WHO )
First Submitted: December 31, 2017
First Posted: January 24, 2018
Results First Submitted: April 30, 2020
Results First Posted: August 18, 2020
Last Update Posted: August 18, 2020