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

Phase 2

Completed

• Conditions: Celiac Disease
• Interventions: Drug: TIMP-GLIA; Drug: Placebo

• Registration Number: NCT03738475
• Lead Sponsor: Takeda

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.

Study Timeline

• Study First Submitted: 2018-11-09
• Study First Submitted QC: 2018-11-09
• Study Start: 2018-11-11
• Study First Posted: 2018-11-13
• Primary Completion: 2019-06-24
• Study Completion: 2019-07-22
• Results First Submitted: 2020-06-22
• Status Verified: 2020-07
• Results First Submitted QC: 2020-07-27
• Last Update Submitted: 2020-07-27
• Results First Posted: 2020-08-12
• Last Update Posted: 2020-08-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TIMP-GLIA	TIMP-GLIA	8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.
Placebo	Placebo	Normal saline administered intravenously on days 1 and 8.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Interferon-Gamma Spot Forming Units (IFN-gamma SFUs) in a Gliadin-specific Enzyme-linked Immunospot (ELISpot) at Day 20	Baseline (Day 15/Day 1), 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

Name	Time	Method
Change From Baseline in Gliadin-specific T Cell Proliferation by Enzyme-linked Immunosorbent Assay (ELISA) at Day 20	Baseline (Day 15/Day 1), 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	Baseline (Day 15/Day 1), 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	Baseline (Day 15/Day 1), 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	Baseline (Screening), 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	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	Baseline (Screening), 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	Days 15, 20, 29 and 35	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	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 (Screening), 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 (Day 1), 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 (Day 1) , 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 (Day 1), 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 (Day 1), 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.

Trial Locations

Locations (7)

Advanced Clinical Research; 🇺🇸 West Jordan, Utah, United States

Prism Clinical Research; 🇺🇸 Saint Paul, Minnesota, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Rapid Medical Research; 🇺🇸 Beachwood, Ohio, United States

Jacksonville Center for Clinical Research; 🇺🇸 Jacksonville, Florida, United States

Beth Isreal Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Indianapolis Gastroenterology Research Foundation; 🇺🇸 Indianapolis, Indiana, United States