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

• ClinicalTrials.gov Identifier: NCT03486990
• Recruitment Status: Completed
• First Posted: April 3, 2018
• Last Update Posted: June 19, 2019
• Sponsor: COUR Pharmaceutical Development Company, Inc.
• Information provided by (Responsible Party): COUR Pharmaceutical Development Company, Inc.

Study Description

Brief Summary:

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 participant health will also be monitored by vital signs such as blood pressure, electrocardiogram (ECG), and physical examination.

Condition or disease	Intervention/treatment	Phase
Celiac Disease	Drug: TIMP-GLIA	Phase 1

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 5 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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Single ascending dose followed by repeat dose
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 9, 2018
• Actual Primary Completion Date: May 24, 2019
• Actual Study Completion Date: May 24, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; 0.1 mg/kg, single IV infusion TIMP-GLIA	Drug: TIMP-GLIA; intravenous infusion
Experimental: Cohort 2; 0.5 mg/kg, single IV infusion TIMP-GLIA	Drug: TIMP-GLIA; intravenous infusion
Experimental: Cohort 3; 1 mg/kg, single IV infusion TIMP-GLIA	Drug: TIMP-GLIA; intravenous infusion
Experimental: Cohort 4; 2 mg/kg, single IV infusion TIMP-GLIA	Drug: TIMP-GLIA; intravenous infusion
Experimental: Cohort 5; 4 mg/kg, single IV infusion TIMP-GLIA	Drug: TIMP-GLIA; intravenous infusion
Experimental: Cohort 6; 8 mg/kg, single IV infusion TIMP-GLIA	Drug: TIMP-GLIA; intravenous infusion
Experimental: Cohort 7; 10 mg/kg, single IV infusion TIMP-GLIA	Drug: TIMP-GLIA; intravenous infusion
Experimental: Cohort 8; Repeat dose, two IV infusions TIMP-GLIA, dose level to be determined	Drug: TIMP-GLIA; intravenous infusion

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 as a Measure of Safety and Tolerability of TIMP-GLIA [ Time Frame: Through study day 180 ]
   An adverse event is any untoward medical occurrence in a participant who received study drug without regard to possibility of a causal relationship to the study drug.

Secondary Outcome Measures :

1. Pharmacokinetics of TIMP-GLIA in plasma: Cmax [ Time Frame: Through to 144 hours post dose ]
   Maximum observed concentration (Cmax) after dosing
2. Pharmacokinetics of TIMP-GLIA in plasma: Tmax [ Time Frame: Through 144 hours post dose ]
   The time after dosing when Cmax is observed (Tmax)
3. Pharmacokinetics of TIMP-GLIA in plasma: Clast [ Time Frame: Through 144 hours post dose ]
   Last measurable concentration (Clast) after dosing
4. Pharmacokinetics of TIMP-GLIA in plasma: Tlast [ Time Frame: Through 144 hours post dose ]
   The time after dosing when the last measurable concentration is observed (Tlast)
5. Pharmacokinetics of TIMP-GLIA in plasma: AUClast [ Time Frame: Through 144 hours post dose ]
   Area under the TIMP-GLIA concentration-time curve from time zero to last measurable concentration (AUClast)
6. Pharmacokinetics of TIMP-GLIA in plasma: AUCinf [ Time Frame: Through 144 hours post dose ]
   Area under the TIMP-GLIA concentration-time curve from time zero extrapolated to infinity (AUCinf)
7. Pharmacokinetics of TIMP-GLIA in plasma: t1/2 [ Time Frame: Through 144 hours post dose ]
   Apparent Terminal Elimination Half-life (t1/2)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Florida

Jacksonville Center For Clinical Research

Jacksonville, Florida, United States, 32216

United States, Massachusetts

Mass General Hospital Translational and Clinical Research Centers

Boston, Massachusetts, United States, 02114

United States, Minnesota

Mayo Gastroenterology Research Unit

Rochester, Minnesota, United States, 55905

Prism Clinical Research

Saint Paul, Minnesota, United States, 55114

Sponsors and Collaborators

COUR Pharmaceutical Development Company, Inc.

Investigators

• Study Chair: Ciaran P Kelly, MD; Beth Israel Deaconess Medical Center, Dept Gastroenterology

More Information

• Responsible Party: COUR Pharmaceutical Development Company, Inc.
• ClinicalTrials.gov Identifier: NCT03486990 History of Changes
• Other Study ID Numbers: TGLIA-5.001
• First Posted: April 3, 2018
• Last Update Posted: June 19, 2019
• Last Verified: June 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by COUR Pharmaceutical Development Company, Inc.:

safety; tolerability; pharmacokinetics; celiac; gliadin; gluten

Additional relevant MeSH terms:

Celiac Disease; Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Tissue Inhibitor of Metalloproteinases; Tissue Inhibitor of Metalloproteinase-1; Matrix Metalloproteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action