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

Takeda34 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Celiac Disease

Interventions

TIMP-GLIADRUG

8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.

PlaceboDRUG

Administered intravenously on days 1 and 8.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Male or nonpregnant female, ages 18 to 70 years inclusive, at Screening Visit. 2. Biopsy-confirmed CD (intestinal histology showing villous atrophy). 3. Positive for human leukocyte antigen (HLA)-DQ2 or HLA-DQ2/DQ8 - results will be obtained at Screening if unknown or results are not available. 4. 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: 1. Measurable total serum immunoglobulin A (IgA) AND 2. Negative or weak positive tissue transglutaminase (tTG) IgA titer OR 3. 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: 1. Positive for only HLA-DQ8. 2. History of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or anaphylaxis to wheat (i.e., "wheat allergy"), barley or rye. 3. Uncontrolled CD and/or active signs/symptoms of CD, in the opinion of the investigator. 4. 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. 5. 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. 6. Presence or history of celiac-associated thyroid disease or Type 1 diabetes, regardless of current treatment.

Locations (8)

Jacksonville Center for Clinical Research

Jacksonville, Florida, United States

Advanced Clinical Research

Meridian, Idaho, United States

Indianapolis Gastroenterology Research Foundation

Indianapolis, Indiana, United States

Beth Isreal Deaconess Medical Center

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

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.

Time frame: Baseline (Day 15/Day 1), Day 20

Secondary Outcomes

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).

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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