Effects of GRA in Patients With Type 1

Study Overview
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Brief Summary
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This study will examine the effects a Glucagon Receptor Antagonist (GRA), has on Insulin Sensitivity, Cardiovascular risks (CVD), and Ketone body formation in participants with Type 1 diabetes. The participants will complete blood tests, tests to measure energy expenditure, CVD risks, and insulin resistance. These tests will be performed prior to start of treatment and again after 12-weeks of treatment with the GRA (called REMD-477).

Detailed Description
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This single-center, double-blind, placebo-controlled, multi-dose study is designed to evaluate the effects of glucagon antagonism on insulin sensitivity, cardiovascular risk and ketogenesis in individuals with Type 1 Diabetes. To accomplish the specific aims proposed, a single clinical trial will be conducted in which a maximum of 30 subjects with T1D, who are otherwise healthy, will be treated with REMD-477 or matching placebo for up to 12 weeks at a dose of 70mg (administered subcutaneously each week) with assessments done pre- and post-therapy. Subjects will be randomized on a 1:1 basis to either the REMD-477 group or placebo group and all subjects will remain on their standard of care insulin therapy throughout the study. There will be 19 study visits as outlined below: Screening - Complete consenting process, complete medical history and physical exam, review of current medications, collect height/weight, vital signs, and fasting laboratory (blood and urine) tests. Baseline Visit 1 - Participants that meet screening criteria will complete cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers. Baseline Visit 2 - Participants will complete a 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies. Baseline Visit 3 - Insulin withdrawal challenge and injection #1 of REMD-477 or placebo. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours. Visit 4 - Injection #2 of REMD-477 or placebo and blood collection for safety labs. Visit 5 - Injection #3 of REMD-477 or placebo. Visit 6 - Injection #4 of REMD-477 or placebo and blood collection for safety labs. Visit 7 - Injection #5 of REMD-477 or placebo. Visit 8 - Injection #6 of REMD-477 or placebo and blood collection for safety labs. Visit 9 - Injection #7 of REMD-477 or placebo. Visit 10 - Injection #8 of REMD-477 or placebo and blood collection for safety labs. Visit 11 - Injection #9 of REMD-477 or placebo. Visit 12 - Injection #10 of REMD-477 or placebo and blood collection for safety labs. Visit 13 - Injection #11 of REMD-477 or placebo. Visit 14 - Injection #12 of REMD-477 or placebo and blood collection for safety labs. Visit 15 - Repeat cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers. Visit 16 - Repeat 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies. Visit 17 - Repeat Insulin withdrawal challenge. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours. Visit 18 - Safety follow-up visit that includes physical exam, vitals, blood and urine sample collection.

Official Title
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The Effects of Glucagon Antagonism on Insulin Sensitivity, Cardiovascular Risk, and Ketogenesis in Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: REMD-477
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between the ages of 18 and 65 years old, inclusive, at the time of screening; Females of non-child bearing potential must be ≥ 1 year post-menopausal or documented as being surgically sterile. Females of child bearing potential must agree to use two methods of contraception during the entire study and for an additional 3 months after the end of dosing with the investigational product; Male subjects must be willing to use clinically acceptable method of contraception during the entire study and for an additional 6 months after the end of the treatment period; Diagnosed with Type 1 diabetes based on clinical history or as defined by the current American Diabetes Association (ADA) criteria for > 5 years; Treatment with a stable insulin regimen for at least 8 weeks before screening with continuous subcutaneous insulin infusion (CSII) via an insulin pump; Currently using a Continuous Glucose Monitoring (CGM) system; HbA1c ≤ 8.5 % at screening; A minimum weight of 50kg; eGFR ≥ 60 mL/min/1.73m² Able to provide written informed consent approved by an Institutional Review Board (IRB). Exclusion Criteria: History or evidence of clinically-significant disorder or condition that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion; History of pancreatitis, medullary thyroid carcinoma and/or liver disease; Clinically significant diagnosis of anemia; Body Mass Index (BMI) < 18.5 kg/m2 and/or weight less than 50kg; Whole blood donation of 1 pint (500 mL) within 8 weeks prior to Screening. Donations of plasma, packed RBCs, platelets or quantities less than 500 mL are allowed at investigator discretion; Current or recent (within 1 month of screening) use of diabetes medications other than insulin; Women who are pregnant or lactating/breastfeeding; Unable or unwilling to follow the study protocol or who are non-compliant with screening appointments or study visits; Any other condition(s) that might reduce the chance of obtaining study data, or that might cause safety concerns, or that might compromise the ability to give truly informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single-center, double-blind, placebo-controlled, multi-dose study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GRA (REMD-477) Group<br>Once weekly, subcutaneous injection of 70mg REMD-477 (in 1 mL solution) for up to 12 weeks. | Drug: REMD-477<br>* 12-Week, once weekly subcutaneous injection with 70mg REMD-477<br>|
| Placebo Comparator: Placebo Group<br>Once weekly, subcutaneous injection of 1mL saline solution for up to 12 weeks. | Drug: Placebo<br>* 12-Week, once weekly subcutaneous injection with placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic Clearance Rate of Insulin | The change from baseline in calculated metabolic clearance rate of insulin as measured by the 2-step Hyperinsulinemic-Euglycemic Clamp. | 12-Weeks | 
| Rate of Resting Energy Expenditure (REE) | Change from baseline REE as measured by indirect calorimetry. | 12-Weeks | 
| Change in Beta-hydroxybutyrate (BHB) Level | The change from baseline in peak BHB production as measured by the insulin withdrawal challenge. | 12-Weeks | 
| Change in Free Fatty Acid (FFA) Level | The change from baseline in peak FFA production as measured by the insulin withdrawal challenge. | 12-Weeks | 
| Change in mRNA Expression | The change from baseline in gene mRNA expression as measured by adipose and muscle tissue samples. | 12-Weeks | 
| Change in Peripheral Macrovascular Vasodilation | The change from baseline in post-stimulus vessel diameter as measured by flow mediated dilation. | 12-Weeks | 
| Change in Peripheral Microvascular Vasodilation | The change from baseline in reactive hyperemia index as measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT). | 12-Weeks | 
| Change in Cardiovascular Disease (CVD) Risk Markers. | The change in pg/mL from baseline in CVD risk markers (SAA, CRP, VCAM-1 and ICAM-1) as measure by blood samples. | 12-Weeks | 
| Change in Cardiovascular Disease (CVD) Risk Markers. | The change in ng/mL from baseline in CVD risk markers (Thrombomodulin, ICAM-3, E-Selectin and P-Selectin) as measure by blood samples. | 12-Weeks |