Study of the Safety, Tolerability and Pharmacokinetics of TIMP-GLIA in Subjects With Celiac Disease

A Phase 1, First-in-Human, 2-Part, Multicenter Dose Escalation and Repeat Dose Study of the Safety, Tolerability and Pharmacokinetics of TIMP-GLIA in Subjects With Celiac Disease

This study is to characterize the safety and tolerability of an investigational drug called TIMP-GLIA when either one or two intravenous doses are given to subjects with celiac disease. The way the body reacts to TIMP-GLIA is being checked by laboratory tests of the blood and urine, and study subject health will also be monitored by vital signs such as blood pressure, electrocardiogram (ECG), and physical examination.

Study Overview

• Status: Completed
• Conditions: Celiac Disease
• Intervention / Treatment: Drug: TIMP-GLIA

Detailed Description

This study is a 2-part, multicenter study. In Part A, eligible subjects will be enrolled into escalating dose cohorts (n = 2/cohort for 2 dose levels followed by n = 3/cohort for 4 dose levels). TIMP-GLIA will be administered as a single intravenous (IV) infusion on Day 1. A staggered dosing strategy will be used in Part A. Subjects will undergo medical observation in the clinic for at least 48 hours after dosing and participate in outpatient follow-up visits. Adverse events (AEs), vital signs, and electrocardiograms (ECGs) and laboratory data (serum chemistry, coagulation, hematology and urinalysis, cytokines) will be assessed by a Safety Committee before the next cohort will be dosed at a higher dose level.

After completion of Part A and confirmation by the Safety Committee to proceed, eligible subjects (n=3) will receive two IV infusions of TIMP-GLIA, 7 days apart, on Day 1 and on Day 8. Each subject in Part B will be observed in clinic for 48 hours after each dose and undergo similar testing and follow-up visits as in Part A.

The safety and pharmacokinetic profile of TIMP-GLIA will be characterized.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Mass General Hospital Translational and Clinical Research Centers
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Gastroenterology Research Unit
    • Saint Paul, Minnesota, United States, 55114
      • Prism Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The subject provides written informed consent and is willing and able to comply with study requirements.
• At screening the subject has a minimum body mass index (BMI) of 16 kg/m2 and a minimum body weight of 33 kg up to a maximum body weight of 129 kg, inclusive. If subject is considered to be underweight or overweight/obese, the subject is otherwise healthy in the opinion of the investigator.
• The subject has celiac disease characterized at Screening Visit by:
• a history of biopsy-confirmed celiac disease; and
• no known gluten exposure for at least 10 days; and
• willingness to maintain a gluten-free diet for the duration of the study; and
• a negative or weak positive transglutaminase (tTG)-specific IgA titer if the subject has a normal total immunoglobulin A (IgA) titer or has a partial IgA deficiency OR
• a negative or weak positive deamidated gliadin peptide (DGP)-specific immunoglobulin G (IgG) titer if the subject has IgA deficiency.
• The male subject or female subject of childbearing potential will practice medically approved contraception during the study.

Exclusion Criteria:

• The subject has a history of clinically confirmed immunoglobulin E-mediated reaction and/or anaphylaxis to wheat (i.e., "wheat allergy"), barley or rye.
• The subject has a known history of hypersensitivity or allergies to TIMP-GLIA components OR any other known severe hypersensitivity or allergic reaction (resulted in hospitalization [initial or prolonged], congenital anomaly, or disability, or that required medical intervention to prevent permanent impairment or damage) to any other allergens (medications, food or environmental).
• The subject has uncontrolled celiac disease and/or complications of celiac disease, or otherwise has experienced celiac symptomology within 10 days of screening, in the opinion of the investigator.
• The subject has a history of, or has an active, significant, clinically relevant, comorbidity (including Type 1 and Type 2 diabetes mellitus and other autoimmune disorders, splenectomy) that, in the opinion of the investigator, would make the subject unsuitable for participation in the study and/or could adversely affect interpretation of the study results.
• The subject has had significant changes to or anticipates changes to prescription or non-prescription medication used to manage an underlying comorbidity within 30 days prior to first dosing (Day 1).
• The subject is currently taking or received systemic biologics 6 months prior to first dosing (Day 1).
• The subject has a compromised immune system, e.g.
• known human immunodeficiency virus (HIV) infection or positive for HIV antibodies at Screening or
• immunosuppressive medical treatment taken during the 2 months prior to first dosing (Day 1) or
• immunosuppressive doses of corticosteroids (more than 20 mg of prednisone given daily for 2 weeks or more within 2 months prior to first dosing (Day 1), or any dose of corticosteroids within 30 days of first dosing (Day 1), or high dose inhaled corticosteroids [>960 µg/day of beclomethasone dipropionate or equivalent]) within 30 days of first dosing Day 1.
• The subject has currently 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.
• The subject has an active malignancy, or history of malignancy or chemotherapy, within the past 5 years other than history of localized or surgical removal of focal basal cell skin cancer, cervical cancer in situ treated successfully in the past by local treatment (including but not limited to cryotherapy or laser therapy) or by hysterectomy.
• The subject has known liver disease or serology positive for hepatitis C infection; positive hepatitis B surface antigen (HBsAg) at Screening Visit.
• The subject has a positive test result for drugs of abuse, cannabinoids, or alcohol at Screening Visit or at Check-in.
• The subject has a history of any drug or alcohol abuse in the past 5 years or alcohol consumption habits that, in the opinion of the investigator, would interfere with the subject's ability to comply with the study requirements.
• The subject has clinically significant laboratory test results (e.g., liver tests) or electrocardiogram (EGC) abnormalities (e.g., cardiac conduction abnormalities) at Screening
• The subject received a live or inactive vaccine within 28 days prior or a subunit vaccine within 14 days prior to first dosing/Day 1 or the subject has a planned vaccination during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A, Cohort 1: 0.1 mg/kg; TIMP-GLIA 0.1 mg/kg, infusion, intravenously, once on Day 1.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part A, Cohort 2: 0.5 mg/kg; TIMP-GLIA 0.5 mg/kg, infusion, intravenously, once on Day 1.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part A, Cohort 3: 1.0 mg/kg; TIMP-GLIA 1.0 mg/kg, infusion, intravenously, once on Day 1.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part A, Cohort 4: 2.0 mg/kg; TIMP-GLIA 2.0 mg/kg, infusion, intravenously, once on Day 1.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part A, Cohort 5: 4.0 mg/kg; TIMP-GLIA 4.0 mg/kg, infusion, intravenously, once on Day 1.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part A, Cohort 6: 8.0 mg/kg; TIMP-GLIA 8.0 mg/kg, infusion, intravenously, once on Day 1.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part B, Cohort 1: 2.0 mg/kg; TIMP-GLIA 2.0 mg/kg, infusion, intravenously, once on Days 1 and 8.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part B, Cohort 2: 4.0 mg/kg; TIMP-GLIA 4.0 mg/kg, infusion, intravenously, once on Days 1 and 8.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101
Experimental: Part B, Cohort 3: 8.0 mg/kg; TIMP-GLIA 8.0 mg/kg, infusion, intravenously, once on Days 1 and 8.	Drug: TIMP-GLIA; intravenous infusion.; Other Names: TAK-101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		From Day 1 up to Day 180
Number of Participants With Grade 3 or Higher TEAEs and Drug-related Adverse Events	AE Grades will be evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), version 4.0. Grade 1 scaled as Mild; Grade 2 scaled as Moderate; Grade 3 scaled as severe or medically significant but not immediately life-threatening; Grade 4 scaled as life-threatening consequences; and Grade 5 scaled as death related to AE. Drug-related adverse events are those that the investigator assessed as possibly or probably related to the study treatment.	From Day 1 up to Day 180
Number of Participants With Clinically Significant Physical Examination Findings		From Day 1 up to Day 60
Number of Participants With Clinically Significant Electrocardiograms (ECG) Findings		From Day 1 up to Day 60
Number of Participants With Clinically Significant Change From Baseline in Arterial Oxygen Saturation Levels		From Day 1 up to Day 60
Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values		From Day 1 up to Day 60
Part B: Change From Baseline (Day 1 Pre-dose) in C1q Binding at Day 3	Baseline is defined as Day 1 pre-dose.	Baseline (Day 1 pre-dose) and Day 3
Part B: Change From Baseline (Day 1 Pre-dose) in C1q Binding at Day 7	Baseline is defined as Day 1 pre-dose.	Baseline (Day 1 pre-dose) and Day 7
Part B: Change From Baseline (Day 1 Pre-dose) in C1q Binding at Day 8	Baseline is defined as Day 1 pre-dose.	Baseline (Day 1 pre-dose) and Day 8
Part B: Change From Baseline (Day 1 Pre-dose) in C1q Binding at Day 10	Baseline is defined as Day 1 pre-dose.	Baseline (Day 1 pre-dose) and Day 10
Part B: Change From Baseline (Day 1 Pre-dose) in C1q Binding at Day 14	Baseline is defined as Day 1 pre-dose.	Baseline (Day 1 pre-dose) and Day 14
Part B: Change From Baseline (Day 1 Pre-dose) in C1q Binding at Day 38	Baseline is defined as Day 1 pre-dose.	Baseline (Day 1 pre-dose) and Day 38
Part B: Change From Baseline (Day 1 Pre-dose) in C1q Binding at Day 60	Baseline is defined as Day 1 pre-dose.	Baseline (Day 1 pre-dose) and Day 60
Part B: Change From Baseline (Day 1 Pre-dose) in C3a and SC5B-9 Levels at 15 Minutes Post-dose on Day 1	Baseline was defined as Day 1 Pre-dose.	Baseline (Day 1 pre-dose) and 15 minutes (min) post-dose on Day 1
Part B: Change From Baseline (Day 1 Pre-dose) in C3a and SC5B-9 Levels at 30 Minutes Post-dose on Day 1	Baseline was defined as Day 1 Pre-dose.	Baseline (Day 1 pre-dose) and 30 min post-dose on Day 1
Part B: Change From Baseline (Day 1 Pre-dose) in C3a and SC5B-9 Levels at Day 2	Baseline was defined as Day 1 Pre-dose.	Baseline (Day 1 pre-dose) and Day 2
Number of Participants With Clinically Significant Change From Baseline in Hematology, Serum Chemistry, Coagulation, and Urinalysis		From Day 1 up to Day 60
Part A (Greater Than or Equal to [>=] 4.0 mg/kg) and Part B: Number of Participants With Clinically Significant Change From Baseline in Gliadin-Specific T-cell Proliferation and Cytokine Release Markers		Part A (>=4.0 mg/kg): Day 1 pre-dose up to 144 hours post-dose on Day 7; Part B: Day 8 pre-dose up to 144 hours post-dose on Day 14
Number of Participants With Clinically Significant Laboratory Abnormalities		From Day 1 up to Day 60

Secondary Outcome Measures

Outcome Measure	Time Frame
Cmax: Maximum Observed Plasma Concentration For TIMP-GLIA	Parts A and B, Day 1: pre-dose and at multiple time points (up to 144 hours) post-dose; Part B, Day 8: pre-dose and at multiple time points (up to 144 hours) post-dose
Clast: Last Measurable Observed Plasma Concentration For TIMP-GLIA	Parts A and B, Day 1: pre-dose and at multiple time points (up to 144 hours) post-dose; Part B, Day 8: pre-dose and at multiple time points (up to 144 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TIMP-GLIA	Parts A and B, Day 1: pre-dose and at multiple time points (up to 144 hours) post-dose; Part B, Day 8: pre-dose and at multiple time points (up to 144 hours) post-dose
AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TIMP-GLIA	Parts A and B, Day 1: pre-dose and at multiple time points (up to 144 hours) post-dose; Part B, Day 8: pre-dose and at multiple time points (up to 144 hours) post-dose
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TIMP-GLIA	Parts A and B, Day 1: pre-dose and at multiple time points (up to 144 hours) post-dose; Part B, Day 8: pre-dose and at multiple time points (up to 144 hours) post-dose
Tlast: Time to Reach the Last Measurable Plasma Concentration for TIMP-GLIA	Parts A and B, Day 1: pre-dose and at multiple time points (up to 144 hours) post-dose; Part B, Day 8: pre-dose and at multiple time points (up to 144 hours) post-dose
T1/2: Terminal Phase Elimination Half-life (T1/2) for TIMP-GLIA	Parts A and B, Day 1: pre-dose and at multiple time points (up to 144 hours) post-dose; Part B, Day 8: pre-dose and at multiple time points (up to 144 hours) post-dose

Collaborators and Investigators

• Sponsor: Takeda
• Collaborators: COUR Pharmaceutical Development Company, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2018
• Primary Completion (Actual): May 24, 2019
• Study Completion (Actual): July 22, 2019

Study Registration Dates

• First Submitted: March 21, 2018
• First Submitted That Met QC Criteria: April 2, 2018
• First Posted (Actual): April 3, 2018

Study Record Updates

• Last Update Posted (Actual): June 5, 2020
• Last Update Submitted That Met QC Criteria: May 20, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: tolerability; safety; pharmacokinetics; gluten; celiac; gliadin
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Gastrointestinal Diseases; Intestinal Diseases; Malabsorption Syndromes; Celiac Disease
• Other Study ID Numbers: TGLIA-5.001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No