Effects of GRA in Patients With Type 1

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: REMD-477; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Todd May; Phone Number: 8582462169; Email: tmay@ucsd.edu

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • UC San Diego Altman Clinical & Translational Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: REMD Biotherapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: February 22, 2021
• First Submitted That Met QC Criteria: March 2, 2021
• First Posted (Actual): March 3, 2021

Study Record Updates

• Last Update Posted (Estimated): January 23, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Volagidemab
• Other Study ID Numbers: UC-MEDJP-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No