Back to resultsStudy of the Safety, Pharmacodynamics, Efficacy, and PK of TIMP-GLIA in Subjects With Celiac Disease
Primary Purpose
Celiac Disease
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
TIMP-GLIA
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Celiac Disease
Eligibility Criteria
Key Inclusion Criteria:
- Male or nonpregnant female, ages 18 to 70 years inclusive, at Screening Visit.
- Biopsy-confirmed CD (intestinal histology showing villous atrophy).
- Positive for human leukocyte antigen (HLA)-DQ2 or HLA-DQ2/DQ8 - results will be obtained at Screening if unknown or results are not available.
- Self-reported to be on a GFD for at least 6 months prior to Screening and agree to continue GFD throughout study, with the exception of the oral gluten challenge.
Normal or negative celiac serology, at screening, defined as:
- Measurable total serum immunoglobulin A (IgA) AND
- Negative or weak positive tissue transglutaminase (tTG) IgA titer OR
If IgA deficient, defined by a serum IgA level of < 3 mg/dL, negative or weak positive DGP- IgG titer.
6. Vh:Cd ≥ 1.5 on screening biopsy.
Key Exclusion Criteria:
- Positive for only HLA-DQ8.
- History of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or anaphylaxis to wheat (i.e., "wheat allergy"), barley or rye.
- Uncontrolled CD and/or active signs/symptoms of CD, in the opinion of the investigator.
- Untreated or active gastrointestinal disease such as peptic ulcer disease, esophagitis (Los Angeles Classification ≥ Grade C), irritable bowel syndrome, inflammatory bowel disease, or microscopic colitis.
- Immunocompromised individuals, including those receiving immunosuppressive doses of corticosteroids (more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more within 6 months prior Dose 1, any dose of corticosteroids within 30 days of Day 1, or high dose inhaled corticosteroids [> 960 µg/day of beclomethasone dipropionate or equivalent]) or other immunosuppressive agents.
- Presence or history of celiac-associated thyroid disease or Type 1 diabetes, regardless of current treatment.
Sites / Locations
- Jacksonville Center for Clinical Research
- Advanced Clinical Research
- Indianapolis Gastroenterology Research Foundation
- Beth Isreal Deaconess Medical Center
- Mayo Clinic
- Prism Clinical Research
- Rapid Medical Research
- Advanced Clinical Research
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
TIMP-GLIA
Placebo
Arm Description
8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.
Normal saline administered intravenously on days 1 and 8.
Outcomes
Primary Outcome Measures
Change From Baseline in Interferon-Gamma Spot Forming Units (IFN-gamma SFUs) in a Gliadin-specific Enzyme-linked Immunospot (ELISpot) at Day 20
The spots formed by interferon-gamma-secreting T-cells were counted with an automated ELISPOT analyzer. The average spot-forming units (SFU) per antigen was calculated. A response was considered positive when the average SFU in wells with a given peptide was at least twice that of the average SFU in the no-peptide control wells. Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15). Peripheral blood mononuclear cell is PBMC.
Secondary Outcome Measures
Change From Baseline in Gliadin-specific T Cell Proliferation by Enzyme-linked Immunosorbent Assay (ELISA) at Day 20
Gliadin-specific T cell proliferation was determined by ELISA test. Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15).
Change From Baseline in Gliadin-specific T Cell Cytokine Secretion by ELISA at Day 20
Gliadin-specific T Cell cytokine secretion was determined by ELISA test. Gliadin-specific cytokine included interferon gamma (IFN-γ), interleukin (IL) 1-beta (1-β), IL-10, IL-12, IL-13, IL-2, IL-4, IL-6, IL-8, tumor necrosis factor alpha (TNF-α). Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15). A negative change from baseline value was reported when the observed sample response was less than the observed background response.
Change From Baseline in Gut-Homing CD4, CD8 and Gamma Delta T-cells by Mass Cytometry (CyTOF) at Day 20
Change from baseline value for Gut-Homing cells like CD4, CD8 and Gamma Delta T-cells were reported. Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15). Phenotype (unique cell population) for CD8 cell is EM CD8 > aE+b7hi > aE+b7hiCD38+, for CD4 is EM Th > a4+b7hi > a4+b7hiCD38+ and for Gamma Delta T-cells is TCRgd T cells > aE+b7hi > aE+b7hiCD38+ in this outcome measure.
Change From Baseline in Ratio of Villus Height to Crypt Depth (Vh:Cd) at Day 29
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 29 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 CD. Crypts are grooves between the villi that are often elongated in participants with CD. A decreased Vh:Cd ratio indicates worsening disease. Baseline was defined as the last sample collected prior to the first dose of study medication (Screening Period) on Day 1.
Percentage of Participants With Greater Than or Equal to (>=) 0.4 Decrease in Vh:Cd at Day 29
Villi were the small finger like projections that line the small intestine and promote nutrient absorption and are often shortened in participants with CD. Crypts are grooves between the villi that are often elongated in participants with CD. A decreased Vh:Cd ratio indicates worsening disease.
Change From Baseline in Number of Intestinal Intraepithelial Lymphocytes (IELs) at Day 29
IELs were white blood cells 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 intraepithelial lymphocytes was associated with celiac disease. Baseline was defined as the last sample collected prior to the first dose of study medication (Screening Period) on Day 1.
Number of Participants Based on Celiac Symptom Index-Modified (CSI-M) Questionnaire Results by Treatment
The CSI were clinically oriented, easily administered, questionnaires with 16 items. The modified CSI (6-items) was derived from a subset of questions from the CSI questionnaire, including the diarrhea, nausea, rumbling in stomach, stomach felt bloated, diarrhea and low energy level abdominal pain domains (a total of 6 questions), which were each assessed on a scale of 1 to 5- none of the time, a little of the time, some of the time, most of the time and all of the time respectively. Higher CSI scores correlate with more severe CD symptoms. It is to be used to assess symptoms before, during, and after the oral gluten challenge. Here D refers to Day.
Plasma Concentrations of TIMP-GLIA
Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Number of Participants With Clinically Significant Change From Baseline in Hematology or Serum Chemistry Laboratory Values
Change From Baseline in Deamidated Gliadin Peptide Immunoglobulin G (DGP-IgG) Antibodies at Days 8, 15, 20, 29, and 35
Baseline was defined as the last sample collected prior to the first dose of study medication (Screening Period) on Day 1.
Change From Baseline in Serum Complement Levels of C3a and SC5B-9 at Days 2, 8, 9, and 15
Baseline was defined as the pre-dose value on Day 1.
Change From Baseline in Serum Complement Levels of C5a at Days 2, 8, 9, and 15
Baseline was defined as the pre-dose value on Day 1.
Change From Baseline in Serum Complement Levels of C1q Binding at Days 15, 20, 29, and 35
Baseline was defined as the pre-dose value on Day 1.
Change From Baseline in Serum Cytokines (IFN-γ, IL 1-β, IL-2, IL-4, IL-6, IL-8 , IL-10, IL-12p70, and TNF-Alpha) at Days 2, 8, 9, and 15
Baseline was defined as Day 1 pre-dose. A negative change from baseline value was reported when the observed sample response was less than the observed background response.
Full Information
NCT ID
NCT03738475
First Posted
November 9, 2018
Last Updated
July 27, 2020
Sponsor
Takeda
Collaborators
COUR Pharmaceuticals Development Company, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT03738475
Brief Title
Study of the Safety, Pharmacodynamics, Efficacy, and PK of TIMP-GLIA in Subjects With Celiac Disease
Official Title
A Randomized, Double-blind, Placebo-controlled Study of the Safety, Pharmacodynamics, Efficacy, and Pharmacokinetics of TIMP-GLIA in Subjects With Well-controlled Celiac Disease Undergoing Oral Gluten Challenge
Study Type
Interventional
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
November 11, 2018 (Actual)
Primary Completion Date
June 24, 2019 (Actual)
Study Completion Date
July 22, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Takeda
Collaborators
COUR Pharmaceuticals Development Company, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Subjects enrolled in this study will be evaluated for immune responses and histological changes in the small bowel following 2 doses of TIMP-GLIA or placebo and a 14-day oral gluten challenge.
Detailed Description
This study is a randomized, double-blind, placebo-controlled clinical trial to assess the safety, pharmacodynamics, efficacy, and PK, of TIMP-GLIA in subjects with well-controlled celiac disease (CD) following an oral gluten challenge. Subjects aged 18 to 70 years inclusive, with documented history of biopsy-proven confirmed CD, and on a gluten-free diet (GFD) for a minimum of 6 months, will be screened. Subjects who meet all inclusion and no exclusion criteria, and provide written informed consent, will be randomized within 45 days after Screening to receive 2 intravenous (IV) infusions of TIMP-GLIA, 8 mg/kg up to a maximum of 650 mg or placebo (normal saline) in a 1:1 ratio. Treatment with drug or placebo will be followed by 14 days gluten challenge.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Celiac Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomized double-blind placebo-controlled
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
34 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TIMP-GLIA
Arm Type
Experimental
Arm Description
8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Normal saline administered intravenously on days 1 and 8.
Intervention Type
Drug
Intervention Name(s)
TIMP-GLIA
Other Intervention Name(s)
TAK-101
Intervention Description
8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
0.9% sodium chloride (normal saline)
Intervention Description
Administered intravenously on days 1 and 8.
Primary Outcome Measure Information:
Title
Change From Baseline in Interferon-Gamma Spot Forming Units (IFN-gamma SFUs) in a Gliadin-specific Enzyme-linked Immunospot (ELISpot) at Day 20
Description
The spots formed by interferon-gamma-secreting T-cells were counted with an automated ELISPOT analyzer. The average spot-forming units (SFU) per antigen was calculated. A response was considered positive when the average SFU in wells with a given peptide was at least twice that of the average SFU in the no-peptide control wells. Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15). Peripheral blood mononuclear cell is PBMC.
Time Frame
Baseline (Day 15/Day 1), Day 20
Secondary Outcome Measure Information:
Title
Change From Baseline in Gliadin-specific T Cell Proliferation by Enzyme-linked Immunosorbent Assay (ELISA) at Day 20
Description
Gliadin-specific T cell proliferation was determined by ELISA test. Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15).
Time Frame
Baseline (Day 15/Day 1), Day 20
Title
Change From Baseline in Gliadin-specific T Cell Cytokine Secretion by ELISA at Day 20
Description
Gliadin-specific T Cell cytokine secretion was determined by ELISA test. Gliadin-specific cytokine included interferon gamma (IFN-γ), interleukin (IL) 1-beta (1-β), IL-10, IL-12, IL-13, IL-2, IL-4, IL-6, IL-8, tumor necrosis factor alpha (TNF-α). Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15). A negative change from baseline value was reported when the observed sample response was less than the observed background response.
Time Frame
Baseline (Day 15/Day 1), Day 20
Title
Change From Baseline in Gut-Homing CD4, CD8 and Gamma Delta T-cells by Mass Cytometry (CyTOF) at Day 20
Description
Change from baseline value for Gut-Homing cells like CD4, CD8 and Gamma Delta T-cells were reported. Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15). Phenotype (unique cell population) for CD8 cell is EM CD8 > aE+b7hi > aE+b7hiCD38+, for CD4 is EM Th > a4+b7hi > a4+b7hiCD38+ and for Gamma Delta T-cells is TCRgd T cells > aE+b7hi > aE+b7hiCD38+ in this outcome measure.
Time Frame
Baseline (Day 15/Day 1), Day 20
Title
Change From Baseline in Ratio of Villus Height to Crypt Depth (Vh:Cd) at Day 29
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 29 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 CD. Crypts are grooves between the villi that are often elongated in participants with CD. A decreased Vh:Cd ratio indicates worsening disease. Baseline was defined as the last sample collected prior to the first dose of study medication (Screening Period) on Day 1.
Time Frame
Baseline (Screening), Day 29
Title
Percentage of Participants With Greater Than or Equal to (>=) 0.4 Decrease in Vh:Cd at Day 29
Description
Villi were the small finger like projections that line the small intestine and promote nutrient absorption and are often shortened in participants with CD. Crypts are grooves between the villi that are often elongated in participants with CD. A decreased Vh:Cd ratio indicates worsening disease.
Time Frame
Day 29
Title
Change From Baseline in Number of Intestinal Intraepithelial Lymphocytes (IELs) at Day 29
Description
IELs were white blood cells 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 intraepithelial lymphocytes was associated with celiac disease. Baseline was defined as the last sample collected prior to the first dose of study medication (Screening Period) on Day 1.
Time Frame
Baseline (Screening), Day 29
Title
Number of Participants Based on Celiac Symptom Index-Modified (CSI-M) Questionnaire Results by Treatment
Description
The CSI were clinically oriented, easily administered, questionnaires with 16 items. The modified CSI (6-items) was derived from a subset of questions from the CSI questionnaire, including the diarrhea, nausea, rumbling in stomach, stomach felt bloated, diarrhea and low energy level abdominal pain domains (a total of 6 questions), which were each assessed on a scale of 1 to 5- none of the time, a little of the time, some of the time, most of the time and all of the time respectively. Higher CSI scores correlate with more severe CD symptoms. It is to be used to assess symptoms before, during, and after the oral gluten challenge. Here D refers to Day.
Time Frame
Days 15, 20, 29 and 35
Title
Plasma Concentrations of TIMP-GLIA
Time Frame
Day 8: 0 hours (pre-infusion), end of infusion, and at 2 hours post-infusion
Title
Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
Time Frame
From the first dose of study drug up to Day 35
Title
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Time Frame
From the first dose of study drug up to Day 35
Title
Number of Participants With Clinically Significant Change From Baseline in Hematology or Serum Chemistry Laboratory Values
Time Frame
From the first dose of study drug up to Day 35
Title
Change From Baseline in Deamidated Gliadin Peptide Immunoglobulin G (DGP-IgG) Antibodies at Days 8, 15, 20, 29, and 35
Description
Baseline was defined as the last sample collected prior to the first dose of study medication (Screening Period) on Day 1.
Time Frame
Baseline (Screening), Days 8, 15, 20, 29, and 35
Title
Change From Baseline in Serum Complement Levels of C3a and SC5B-9 at Days 2, 8, 9, and 15
Description
Baseline was defined as the pre-dose value on Day 1.
Time Frame
Baseline (Day 1), Days 2, 8, 9, and 15
Title
Change From Baseline in Serum Complement Levels of C5a at Days 2, 8, 9, and 15
Description
Baseline was defined as the pre-dose value on Day 1.
Time Frame
Baseline (Day 1) , Days 2, 8, 9, and 15
Title
Change From Baseline in Serum Complement Levels of C1q Binding at Days 15, 20, 29, and 35
Description
Baseline was defined as the pre-dose value on Day 1.
Time Frame
Baseline (Day 1), Days 15, 20, 29, and 35
Title
Change From Baseline in Serum Cytokines (IFN-γ, IL 1-β, IL-2, IL-4, IL-6, IL-8 , IL-10, IL-12p70, and TNF-Alpha) at Days 2, 8, 9, and 15
Description
Baseline was defined as Day 1 pre-dose. A negative change from baseline value was reported when the observed sample response was less than the observed background response.
Time Frame
Baseline (Day 1), Days 2, 8, 9, and 15
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Male or nonpregnant female, ages 18 to 70 years inclusive, at Screening Visit.
Biopsy-confirmed CD (intestinal histology showing villous atrophy).
Positive for human leukocyte antigen (HLA)-DQ2 or HLA-DQ2/DQ8 - results will be obtained at Screening if unknown or results are not available.
Self-reported to be on a GFD for at least 6 months prior to Screening and agree to continue GFD throughout study, with the exception of the oral gluten challenge.
Normal or negative celiac serology, at screening, defined as:
Measurable total serum immunoglobulin A (IgA) AND
Negative or weak positive tissue transglutaminase (tTG) IgA titer OR
If IgA deficient, defined by a serum IgA level of < 3 mg/dL, negative or weak positive DGP- IgG titer.
6. Vh:Cd ≥ 1.5 on screening biopsy.
Key Exclusion Criteria:
Positive for only HLA-DQ8.
History of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or anaphylaxis to wheat (i.e., "wheat allergy"), barley or rye.
Uncontrolled CD and/or active signs/symptoms of CD, in the opinion of the investigator.
Untreated or active gastrointestinal disease such as peptic ulcer disease, esophagitis (Los Angeles Classification ≥ Grade C), irritable bowel syndrome, inflammatory bowel disease, or microscopic colitis.
Immunocompromised individuals, including those receiving immunosuppressive doses of corticosteroids (more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more within 6 months prior Dose 1, any dose of corticosteroids within 30 days of Day 1, or high dose inhaled corticosteroids [> 960 µg/day of beclomethasone dipropionate or equivalent]) or other immunosuppressive agents.
Presence or history of celiac-associated thyroid disease or Type 1 diabetes, regardless of current treatment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director Clinical Science
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
Facility Name
Jacksonville Center for Clinical Research
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32216
Country
United States
Facility Name
Advanced Clinical Research
City
Meridian
State/Province
Idaho
ZIP/Postal Code
83642
Country
United States
Facility Name
Indianapolis Gastroenterology Research Foundation
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46237
Country
United States
Facility Name
Beth Isreal Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Prism Clinical Research
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55114
Country
United States
Facility Name
Rapid Medical Research
City
Beachwood
State/Province
Ohio
ZIP/Postal Code
44122
Country
United States
Facility Name
Advanced Clinical Research
City
West Jordan
State/Province
Utah
ZIP/Postal Code
84088
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Citations:
PubMed Identifier
33722583
Citation
Kelly CP, Murray JA, Leffler DA, Getts DR, Bledsoe AC, Smithson G, First MR, Morris A, Boyne M, Elhofy A, Wu TT, Podojil JR, Miller SD; TAK-101 Study Group. TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study. Gastroenterology. 2021 Jul;161(1):66-80.e8. doi: 10.1053/j.gastro.2021.03.014. Epub 2021 Mar 17.
Results Reference
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Study of the Safety, Pharmacodynamics, Efficacy, and PK of TIMP-GLIA in Subjects With Celiac Disease
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