effects of gra in patients with type 1

Conditions: Type 1 Diabetes

Summary: 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.

Eligibility criteria:
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.