Effects of GRA in Patients With Type 1
Effects of GRA in Patients With Type 1
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).
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:

 1. 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.

 2. 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.

 3. Baseline Visit 2 - Participants will complete a 2-Step Hyperinsulinemic/Euglycemic clamp
 with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies.

 4. 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.

 5. Visit 4 - Injection #2 of REMD-477 or placebo and blood collection for safety labs.

 6. Visit 5 - Injection #3 of REMD-477 or placebo.

 7. Visit 6 - Injection #4 of REMD-477 or placebo and blood collection for safety labs.

 8. Visit 7 - Injection #5 of REMD-477 or placebo.

 9. Visit 8 - Injection #6 of REMD-477 or placebo and blood collection for safety labs.

 10. Visit 9 - Injection #7 of REMD-477 or placebo.

 11. Visit 10 - Injection #8 of REMD-477 or placebo and blood collection for safety labs.

 12. Visit 11 - Injection #9 of REMD-477 or placebo.

 13. Visit 12 - Injection #10 of REMD-477 or placebo and blood collection for safety labs.

 14. Visit 13 - Injection #11 of REMD-477 or placebo.

 15. Visit 14 - Injection #12 of REMD-477 or placebo and blood collection for safety labs.

 16. Visit 15 - Repeat cardiovascular tests including flow mediated dilation and EndoPat,
 complete vital signs, weight and laboratory tests for safety and CVD markers.

 17. Visit 16 - Repeat 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect
 Calorimetry, muscle and adipose tissue biopsies.

 18. 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.

 19. Visit 18 - Safety follow-up visit that includes physical exam, vitals, blood and urine
 sample collection.
Inclusion Criteria:

 1. Men and women between the ages of 18 and 65 years old, inclusive, at the time of
 screening;

 2. 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;

 3. 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;

 4. Diagnosed with Type 1 diabetes based on clinical history or as defined by the current
 American Diabetes Association (ADA) criteria for > 5 years;

 5. Treatment with a stable insulin regimen for at least 8 weeks before screening with
 continuous subcutaneous insulin infusion (CSII) via an insulin pump;

 6. Currently using a Continuous Glucose Monitoring (CGM) system;

 7. HbA1c ≤ 8.5 % at screening;

 8. A minimum weight of 50kg;

 9. eGFR ≥ 60 mL/min/1.73m²

 10. Able to provide written informed consent approved by an Institutional Review Board
 (IRB).

 Exclusion Criteria:

 1. 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;

 2. History of pancreatitis, medullary thyroid carcinoma and/or liver disease;

 3. Clinically significant diagnosis of anemia;

 4. Body Mass Index (BMI) < 18.5 kg/m2 and/or weight less than 50kg;

 5. 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;

 6. Current or recent (within 1 month of screening) use of diabetes medications other than
 insulin;

 7. Women who are pregnant or lactating/breastfeeding;

 8. Unable or unwilling to follow the study protocol or who are non-compliant with
 screening appointments or study visits;

 9. 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.