Metabolic Pathways of GRA in Patients With Type 1 Diabetes

The Effects of a Glucagon Receptor Antagonist (GRA) on Non-Glucose Metabolic Pathways in Patients With Type 1 Diabetes (Pilot Study)

A pilot study for individuals with Type 1 Diabetes who are willing to add a GRA (Glucagon Receptor Antagonist) to their current Diabetes treatment regimen. There will be 10 study visits over the course of approximately 8 weeks, with 4 weeks of once weekly, subcutaneous GRA (REMD-477) injection. Testing includes 2 MRI scans, 2 glucose challenges, and 2 insulin withdrawal challenges along with physical assessments and vitals.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: REMD-477

Detailed Description

This single-center, open label, multi-dose study is 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 10 subjects with T1D, who are otherwise healthy, will be treated with REMD-477 for 4 weeks at a dose of 70mg (administered subcutaneously each week) with assessments done pre- and post-therapy. There is no comparator, nor is there any placebo in the study. In addition, there is no randomization, all subjects will receive the same 4 weeks of 70mg, once weekly dose of REMD-477.

There will be 10 study visits as outlined below:

1. Screening - Complete medical history and physical exam, review of current medications, height/weight, vital signs, and fasting laboratory (blood and urine) tests.
2. Visit 1 - Participants that meet screening criteria will be provided deuterated (heavy) water to consume overnight. Participants will ingest heavy water (2H2O) overnight in three equal doses (total 3ml/kg/body water). Participants will also undergo an MRI to evaluate hepatic (liver) fat content as well as total body composition.
3. Visit 2 - Following Visit 1, participants will return to the clinic the next morning in the fasting state (8 hours) and after completing the heavy water consumption. Blood samples will be drawn for baseline amino acid levels as well as samples of serum, plasma, PBMCs, and extracted RNA stored for future metabolomics and genetic testing. Indirect calorimetry (IDC) will be performed to provide baseline resting energy expenditure (REE). Upon completion of IDC, participants will be given a 0.15 u/kg dose of rapid acting insulin and 15 minutes afterwards will ingest a 75g glucose and 25g fructose drink. Participants will then have samples collected over 6 hours to quantify isotope enrichment in plasma water as well as triglyceride isolated from VLDL. Repeat IDC will be performed 2 hours after consumption of the drink.
4. Visit 3 - Insulin withdrawal challenge and injection #1 of REMD-477. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 6 hours.
5. Visit 4 - Injection #2 of REMD-477.
6. Visit 5 - Injection #3 of REMD-477.
7. Visit 6 - Injection #4 of REMD-477.
8. Visit 7 - Provide heavy water and complete MRI scan #2.
9. Visit 8 - Repeat all Visit 2 procedures.
10. Visit 9 - Repeat all Visit 3 procedures.
11. Visit 10 - Safety follow-up visit that includes physical exam, vitals, blood and urine sample collection.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2; Phase 1

Contacts and Locations

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
• Genders Eligible for Study: All

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 (< 1u/kg per day) for at least 8 weeks before screening with continuous subcutaneous insulin infusion (CSII) via an insulin pump;
6. HbA1c ≤ 10 % at screening;
7. A minimum weight of 50kg;
8. 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. Subjects for whom an MRI is contraindicated;
9. Unable or unwilling to follow the study protocol or who are non-compliant with screening appointments or study visits;
10. 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: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-Label REMD-477	Drug: REMD-477; 4-Week, open-label, once weekly subcutaneous injection with 70mg REMD-477.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Beta-hydoxybutyrate (BHB) Level	The change from baseline in peak BHB production as measured by the insulin withdrawal challenge.	4-Weeks
Rate of De Novo Lipogenesis (DNL)	Change from baseline in disrupted glucagon signaling as measured by the glucose challenge and deuterated water ingestion.	4-Weeks
Rate of Hepatic Steatosis	Changes from baseline in hepatic steatosis as measured by the glucose challenge and deuterated water ingestion.	4-Weeks
Rate of Resting Energy Expenditure (REE)	Change from baseline REE as measured by the glucose challenge and deuterated water ingestion.	4-Weeks

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): July 31, 2021
• Study Completion (Actual): May 31, 2022

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: April 15, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Actual): July 15, 2022
• Last Update Submitted That Met QC Criteria: July 13, 2022
• Last Verified: July 1, 2022

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-02

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
• product manufactured in and exported from the U.S.: No