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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Celiac Disease

Intervention / Treatment
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* Drug: TIMP-GLIA


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Single ascending dose followed by repeat dose.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, tolerability, pharmacokinetics, celiac, gliadin, gluten