Combination GRA and SGLT-2i Treatment in Type 1 Diabetes

This is a single-center, randomized, double-blind, cross-over, multi-dose study designed to elicit pilot data for a larger project. To accomplish the specific aims proposed, a single clinical trial will be conducted in which a maximum of 12 subjects with T1D, who are otherwise healthy, will be treated with an oral SGLT-2i (Sodium-Glucose Cotransporter-2 Inhibitor), 10mg dapagliflozin taken daily in combination with a GRA (Glucagon Receptor Antagonist), 70mg REMD-477 subcutaneous injection once a week or placebo (subcutaneous injection to match the volume of REMD-477) once a week. There will be two treatments: Treatment "A" consists of an SGLT-2i + GRA for 4 weeks and Treatment "B" consists of an SGLT-2i + placebo for 4 weeks. Participants will be randomly assigned to either start with Treatment A or Treatment B for the first 4 weeks of treatment. After completing the first treatment group, participants will be washed off all study drug for 6 weeks. After the washout period, participants will complete 4 weeks of dosing with the opposite treatment they received during the first 4 weeks.

There will be 15 study visits as outlined below:

• Screening - Complete medical history, physical exam, review current medications, height/weight, vital signs, ECG and fasting laboratory (blood and urine) tests.
• Baseline 1 - Complete vitals, weight, physical exam, fasting blood collection, download CGM data, collect insulin usage, complete measurements of blood vessels using EndoPat and ultrasound, complete diabetes questionnaires, and complete fat and muscle biopsies.
• Baseline 2 - Complete vitals, weight, fasting blood collection, insulin withdraw procedure and start first dose of study medications.
• Visit 4 - Complete vitals, weight, dose 2 of REMD-477/Placebo, review CGM data and insulin dosing.
• Visit 5 - Complete vitals, weight, dose 3 of REMD-477/Placebo, review CGM data and insulin dosing.
• Visit 6 - Complete vitals, weight, dose 4 of REMD-477/Placebo, review CGM data and insulin dosing.
• Repeat Measures 1 - Complete vitals, weight, physical exam, fasting blood collection, download CGM data, collect insulin usage, complete measurements of blood vessels using EndoPat and ultrasound, complete diabetes questionnaires, and complete fat and muscle biopsies.
• Repeat Measures 2 - Complete vitals, weight, fasting blood collection, insulin withdraw procedure and begin wash-out of study medications.
• Crossover Visit - Update medical history, complete physical exam, review of current medications, weight, vital signs, fasting laboratory (blood and urine) tests, collect insulin usage, download CGM data and start opposite doses of medication.
• Visit 10 - Complete vitals, weight, dose 2 of REMD-477/Placebo, review CGM data and insulin dosing.
• Visit 11 - Complete vitals, weight, dose 3 of REMD-477/Placebo, review CGM data and insulin dosing.
• Visit 12 - Complete vitals, weight, dose 4 of REMD-477/Placebo, review CGM data and insulin dosing.
• Final Measures 1 - Complete vitals, weight, physical exam, fasting blood collection, download CGM data, collect insulin usage, complete measurements of blood vessels using EndoPat and ultrasound, complete diabetes questionnaires, and complete fat and muscle biopsies.
• Final Measures 2 - Complete vitals, weight, fasting blood collection, insulin withdraw procedure and review CGM data/insulin dosing for return to pre-baseline diabetes treatment.
• Safety Follow-up - Complete vitals, physical exam, weight, and review CGM data/insulin dosing to verify diabetes treatment is stable.

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 (< 1u/kg per day) 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 ≤ 9 % 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 of T2DM, maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis
• Pancreas, pancreatic islet cells or renal transplant recipient
• T1DM treatment with any other antihyperglycemic drug (e.g. metformin, alpha- glucosidase inhibitors, SGLT-2 inhibitors, pramlintide, inhaled insulin, pre-mixed insulins, etc.) within 30 days of run-in (visit 2)
• Occurrence of severe hypoglycemia involving coma and/or seizure that required hospitalization or hypoglycemia-related treatment by an emergency physician or paramedic within 3 months prior to Visit 1 or Visit 2
• Occurrence of DKA within 3 months prior to Visit 1 or Visit 2
• Occurrence of symptomatic hypotension within 3 months prior to Visit 1 (Screen) or Visit 2
• Occurrence of multiple genital mycotic infections within 6 months prior to Visit 1 (Screen) or Visit 2
• Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or transient ischemic attack (TIA) within 3 months prior to Visit 1 or Visit 2
• Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal (ULN) at Visit 1
• Current signs and symptoms of anemia accompanied by a hemoglobin laboratory value at or below 10.0 g/dL at screening.
• Active eating disorders such as bulimia or anorexia nervosa
• 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;
• Treatment with systemic corticosteroids within 30 days of run-in (visit 2), or planned initiation of such therapy at Visit 1 or Visit 2. Inhaled or topical use of corticosteroids (e.g. for asthma/chronic obstructive pulmonary disease) is acceptable.
• Medical history of bladder cancer or treatment for any cancer in the last five years prior to Visit 1. Resected basal cell carcinoma considered cured is exempted.
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial
• Intake of an investigational drug in another trial within 30 days prior to Visit 1
• Patient not able to understand and comply with study requirements, based on Investigator's judgment
• Any other clinical condition that, based on Investigator's judgment, would jeopardize patient safety during trial participation or would affect the study outcome (e.g. immunocompromised patients who might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections etc.)