Combination Adjunctive Therapy to Address Multiple Metabolic Imbalances in Type 1 Diabetes

Study Overview
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Brief Summary
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This is a single site, double-blind, placebo-controlled, crossover trial to quantify the effects of combination adjunctive therapy on glycemic control, ketogenesis during insulinopenia, insulin resistance, and diabetes burden and quality of life.

Detailed Description
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This is a single site, double-blind, placebo-controlled, crossover trial to quantify the effects of combination adjunctive therapy on glycemic control, ketogenesis during insulinopenia, insulin resistance, and diabetes burden and quality of life. Up to 22 adult participants with type 1 diabetes (T1D) will be enrolled with at least 16 participants completing the study in full. After screening, baseline data (A1c, CGM, ambulatory insulin dosing, ambulatory ketones [fasting and after infusion set change], and psychosocial questionnaires) will be collected and participants will complete an insulin withdrawal test (IWT) and a hyperinsulinemic-euglycemic clamp (HEC) with indirect calorimetry (IDC). Participants will then receive 12-week insulin-adjunctive treatments with both: (1) SGLTi (sotagliflozin 200 mg daily) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg weekly), in a random-order, cross-over design with a 14-week washout period between treatment periods. Throughout the treatment periods subjects will be seen weekly in clinic for medication dosing (GRA or placebo) and download/review of CGM, insulin, and ketone data. At the end of each treatment period, the baseline studies will be repeated. Subjects will return for a safety follow up visit 6 weeks after the final GRA or placebo dose.

Official Title
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Combination Adjunctive Therapy to Address Multiple Metabolic Imbalances in Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Sotagliflozin
* Drug: Volagidemab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between the ages of 18 and 70 years old, inclusive, at the time of screening; Females of non-childbearing potential must be ≥ 1 year post-menopausal or documented as being surgically sterile. Females of childbearing 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; Treatment with a stable insulin regimen for at least 8 weeks before screening with continuous subcutaneous insulin infusion (CSII) via an insulin pump or hybrid closed loop system; Currently using a Continuous Glucose Monitoring (CGM) system; A1c > 7% and ≤ 10% 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 or liver disease; Clinically significant diagnosis of anemia (Hemoglobin < 9 g/dl at screening); Body Mass Index (BMI) < 18.5 kg/m2 and/or weight <50kg; Body Mass Index (BMI) > 35 kg/m2 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; (examples include GLP-1 RA, SGLT-2i, Pramlintide, Metformin); 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: 70 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Each participant will receive 12-week insulin-adjunctive treatment with both: (1) SGLTi (sotagliflozin 200 mg PO each day) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: sotagliflozin 200 mg<br>Each participant will receive 12-week insulin-adjunctive treatment with both: (1) SGLTi (sotagliflozin 200 mg PO each day) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods. Sotagliflozin is a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 (SGLT1/2) inhibitor. | Drug: Sotagliflozin<br>* Sotagliflozin is a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 (SGLT1/2) inhibitor.<br>|
| Active Comparator: volagidemab 35 mg<br>Each participant will receive 12-week insulin-adjunctive treatment with both: (1) SGLTi (sotagliflozin 200 mg PO each day) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods. Volagidemab is a human monoclonal antibody glucagon receptor antagonist (GRA). | Drug: Volagidemab<br>* Volagidemab is a human monoclonal antibody glucagon receptor antagonist (GRA).<br>|
| Placebo Comparator: Placebo<br>Each participant will receive 12-week insulin-adjunctive treatment with both: (1) SGLTi (sotagliflozin 200 mg PO each day) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods. | Drug: Volagidemab<br>* Volagidemab is a human monoclonal antibody glucagon receptor antagonist (GRA).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Quantify the effects of combination adjunctive therapy on glycemic control. Though it has limitations, the HbA1c remains the gold standard measurement of glycemic control in diabetes. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in percent time in range (70-180 mg/dl) by CGM | Continuous glucose monitoring (CGM) provides much more granular data relating to glucose trends and time spent in target glucose range, above range (hyperglycemia), and below range (hypoglycemia). | 12 weeks | 
| Change in subject self reported ambulatory insulin dosing | Change in ambulatory insulin dosing as shown through subject insulin diary. | 12 weeks |