Clinical trial NCT03738475: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Celiac Disease
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: COUR Pharmaceutical Development Company, Inc.
First posted: 2018-11-13
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized double-blind placebo-controlled
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Change From Baseline in Interferon-Gamma Spot Forming Units (IFN-gamma SFUs) in a Gliadin-specific Enzyme-linked Immunospot (ELISpot) at Day 20
timeFrame: Baseline (Day 15/Day 1), Day 20
Secondary outcomes:
measure: Change From Baseline in Gliadin-specific T Cell Proliferation by Enzyme-linked Immunosorbent Assay (ELISA) at Day 20
timeFrame: Baseline (Day 15/Day 1), Day 20
measure: Change From Baseline in Gliadin-specific T Cell Cytokine Secretion by ELISA at Day 20
timeFrame: Baseline (Day 15/Day 1), Day 20
measure: Change From Baseline in Gut-Homing CD4, CD8 and Gamma Delta T-cells by Mass Cytometry (CyTOF) at Day 20
timeFrame: Baseline (Day 15/Day 1), Day 20
measure: Change From Baseline in Ratio of Villus Height to Crypt Depth (Vh:Cd) at Day 29
timeFrame: Baseline (Screening), Day 29
measure: Percentage of Participants With Greater Than or Equal to (>=) 0.4 Decrease in Vh:Cd at Day 29
timeFrame: Day 29
measure: Change From Baseline in Number of Intestinal Intraepithelial Lymphocytes (IELs) at Day 29
timeFrame: Baseline (Screening), Day 29
measure: Number of Participants Based on Celiac Symptom Index-Modified (CSI-M) Questionnaire Results by Treatment
timeFrame: Days 15, 20, 29 and 35
measure: Plasma Concentrations of TIMP-GLIA
timeFrame: Day 8: 0 hours (pre-infusion), end of infusion, and at 2 hours post-infusion
measure: Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
timeFrame: From the first dose of study drug up to Day 35
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: From the first dose of study drug up to Day 35
measure: Number of Participants With Clinically Significant Change From Baseline in Hematology or Serum Chemistry Laboratory Values
timeFrame: From the first dose of study drug up to Day 35
measure: Change From Baseline in Deamidated Gliadin Peptide Immunoglobulin G (DGP-IgG) Antibodies at Days 8, 15, 20, 29, and 35
timeFrame: Baseline (Screening), Days 8, 15, 20, 29, and 35
measure: Change From Baseline in Serum Complement Levels of C3a and SC5B-9 at Days 2, 8, 9, and 15
timeFrame: Baseline (Day 1), Days 2, 8, 9, and 15
measure: Change From Baseline in Serum Complement Levels of C5a at Days 2, 8, 9, and 15
timeFrame: Baseline (Day 1) , Days 2, 8, 9, and 15
measure: Change From Baseline in Serum Complement Levels of C1q Binding at Days 15, 20, 29, and 35
timeFrame: Baseline (Day 1), Days 15, 20, 29, and 35
measure: 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
timeFrame: Baseline (Day 1), Days 2, 8, 9, and 15
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Meridian
country: United States
facility: Advanced Clinical Research
state: Idaho
city: Indianapolis
country: United States
facility: Indianapolis Gastroenterology Research Foundation
state: Indiana
city: Boston
country: United States
facility: Beth Isreal Deaconess Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Paul
country: United States
facility: Prism Clinical Research
state: Minnesota
city: Beachwood
country: United States
facility: Rapid Medical Research
state: Ohio
city: West Jordan
country: United States
facility: Advanced Clinical Research
state: Utah
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
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.