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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03738475
Recruitment Status : Completed
First Posted : November 13, 2018
Results First Posted : August 12, 2020
Last Update Posted : August 12, 2020
Sponsor:
Collaborator:
COUR Pharmaceuticals Development Company, Inc.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Celiac Disease Drug: TIMP-GLIA Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized double-blind placebo-controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : November 11, 2018
Actual Primary Completion Date : June 24, 2019
Actual Study Completion Date : July 22, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Celiac Disease

Arm Intervention/treatment
Experimental: TIMP-GLIA
8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.
Drug: TIMP-GLIA
8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.
Other Name: TAK-101

Placebo Comparator: Placebo
Normal saline administered intravenously on days 1 and 8.
Drug: Placebo
Administered intravenously on days 1 and 8.
Other Name: 0.9% sodium chloride (normal saline)




Primary Outcome Measures :
  1. Change From Baseline in Interferon-Gamma Spot Forming Units (IFN-gamma SFUs) in a Gliadin-specific Enzyme-linked Immunospot (ELISpot) at Day 20 [ Time Frame: 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 :
  1. Change From Baseline in Gliadin-specific T Cell Proliferation by Enzyme-linked Immunosorbent Assay (ELISA) at Day 20 [ Time Frame: 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).

  2. Change From Baseline in Gliadin-specific T Cell Cytokine Secretion by ELISA at Day 20 [ Time Frame: 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.

  3. Change From Baseline in Gut-Homing CD4, CD8 and Gamma Delta T-cells by Mass Cytometry (CyTOF) at Day 20 [ Time Frame: 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.

  4. Change From Baseline in Ratio of Villus Height to Crypt Depth (Vh:Cd) at Day 29 [ Time Frame: 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.

  5. Percentage of Participants With Greater Than or Equal to (>=) 0.4 Decrease in Vh:Cd at Day 29 [ Time Frame: 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.

  6. Change From Baseline in Number of Intestinal Intraepithelial Lymphocytes (IELs) at Day 29 [ Time Frame: 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.

  7. Number of Participants Based on Celiac Symptom Index-Modified (CSI-M) Questionnaire Results by Treatment [ Time Frame: 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.

  8. Plasma Concentrations of TIMP-GLIA [ Time Frame: Day 8: 0 hours (pre-infusion), end of infusion, and at 2 hours post-infusion ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. Change From Baseline in Deamidated Gliadin Peptide Immunoglobulin G (DGP-IgG) Antibodies at Days 8, 15, 20, 29, and 35 [ Time Frame: 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.

  13. Change From Baseline in Serum Complement Levels of C3a and SC5B-9 at Days 2, 8, 9, and 15 [ Time Frame: Baseline (Day 1), Days 2, 8, 9, and 15 ]
    Baseline was defined as the pre-dose value on Day 1.

  14. Change From Baseline in Serum Complement Levels of C5a at Days 2, 8, 9, and 15 [ Time Frame: Baseline (Day 1) , Days 2, 8, 9, and 15 ]
    Baseline was defined as the pre-dose value on Day 1.

  15. Change From Baseline in Serum Complement Levels of C1q Binding at Days 15, 20, 29, and 35 [ Time Frame: Baseline (Day 1), Days 15, 20, 29, and 35 ]
    Baseline was defined as the pre-dose value on Day 1.

  16. 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03738475


Locations
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United States, Florida
Jacksonville Center for Clinical Research
Jacksonville, Florida, United States, 32216
United States, Idaho
Advanced Clinical Research
Meridian, Idaho, United States, 83642
United States, Indiana
Indianapolis Gastroenterology Research Foundation
Indianapolis, Indiana, United States, 46237
United States, Massachusetts
Beth Isreal Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Prism Clinical Research
Saint Paul, Minnesota, United States, 55114
United States, Ohio
Rapid Medical Research
Beachwood, Ohio, United States, 44122
United States, Utah
Advanced Clinical Research
West Jordan, Utah, United States, 84088
Sponsors and Collaborators
Takeda
COUR Pharmaceuticals Development Company, Inc.
Investigators
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Study Director: Medical Director Clinical Science Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Statistical Analysis Plan  [PDF] May 14, 2019
Study Protocol  [PDF] December 10, 2018

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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03738475    
Other Study ID Numbers: TGLIA-5.002
First Posted: November 13, 2018    Key Record Dates
Results First Posted: August 12, 2020
Last Update Posted: August 12, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Celiac Disease
Malabsorption Syndromes
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Metabolic Diseases