Study of the Safety, Pharmacodynamics, Efficacy, and PK of TIMP-GLIA in Subjects With Celiac Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Celiac Disease

Intervention / Treatment
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* Drug: TIMP-GLIA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized double-blind placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TIMP-GLIA<br>8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8. | Drug: TIMP-GLIA<br>* 8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.<br>* Other names: TAK-101;|
| Placebo Comparator: Placebo<br>Normal saline administered intravenously on days 1 and 8. | Drug: Placebo<br>* Administered intravenously on days 1 and 8.<br>* Other names: 0.9% sodium chloride (normal saline);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Day 15/Day 1), Day 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline (Day 15/Day 1), Day 20 | 
| 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. | Baseline (Day 15/Day 1), Day 20 | 
| 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. | Baseline (Day 15/Day 1), Day 20 | 
| 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. | Baseline (Screening), Day 29 | 
| 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. | Day 29 | 
| 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. | Baseline (Screening), Day 29 | 
| 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. | Days 15, 20, 29 and 35 | 
| Plasma Concentrations of TIMP-GLIA |  | Day 8: 0 hours (pre-infusion), end of infusion, and at 2 hours post-infusion | 
| Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) |  | From the first dose of study drug up to Day 35 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs |  | From the first dose of study drug up to Day 35 | 
| Number of Participants With Clinically Significant Change From Baseline in Hematology or Serum Chemistry Laboratory Values |  | From the first dose of study drug up to Day 35 | 
| 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. | Baseline (Screening), Days 8, 15, 20, 29, and 35 | 
| 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. | Baseline (Day 1), Days 2, 8, 9, and 15 | 
| 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. | Baseline (Day 1) , Days 2, 8, 9, and 15 | 
| 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. | Baseline (Day 1), Days 15, 20, 29, and 35 | 
| 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. | Baseline (Day 1), Days 2, 8, 9, and 15 |