Effect of Novel Glucagon Receptor Antagonist REMD-477 on Glucose and Adipocyte Metabolism in T2DM

Effect of Novel Glucagon Receptor Antagonist REMD-477 on Glucose and Adipocyte Metabolism in Type 2 Diabetes Mellitus (T2DM)

With REMD's glucagon receptor antagonist, the study team propose to provide a comprehensive examination of the effect of elevated plasma glucagon concentrations in Type 2 Diabetes Mellitus (T2D) patients on:

(i) glucose tolerance; (ii) insulin sensitivity in liver, muscle, and adipocytes; (iii) beta cell function; (iv) adipocyte inflammation.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Insulin Sensitivity; Glucose Tolerance Impaired
• Intervention / Treatment: Drug: REMD-477; Drug: Placebo Subcutaneous injection

Detailed Description

Subjects with T2DM inadequately controlled on current medications will participate in a glucose tolerance test, euglycemic insulin clamp combined with 3-3H-glucose and 14-C glycerol infusion, adipose tissue biopsy, before and 12 weeks after treatment with REMD 477 or placebo.

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

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78207
      • Texas Diabetes Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Type 2 diabetic subjects, males/females;
2. age = 18-70 years
3. BMI = 25-40 kg/m2;
4. HbA1c = 7.5-10.0%;
5. Type 2 Diabetics who are drug naïve or treated with metformin, sulfonylureas, SGLT-2 inhibitors or any combination thereof.
6. Subjects must be on a stable dose of antidiabetic medications for at least 3 months prior to study.
7. Patients must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
8. Female patients must be non-lactating and must either be at least two years post-menopausal, or be using adequate contraceptive precautions (i.e. oral contraceptives, approved hormonal implant, intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period

Exclusion Criteria:

1. Subjects with a personal or family history of pancreatic neuroendocrine tumors or multiple endocrine neoplasia, due to the potential increased of pancreatic alpha cell carcinogenicity associated with glucagon receptor antagonists.
2. Subjects with a contraindication to MRI including artificial heart valves or pacemakers
3. Patients with a known sensitivity to humanized antibodies
4. Subjects treated with GLP-1 RAs or insulin are excluded.
5. Subjects treated with a non-antidiabetic medication that may impact insulin sensitivity, such as systemic steroids, or lipase inhibitors (orlistat, Alli or Xenical)
6. Hematocrit < 34 vol%
7. Serum creatinine > 1.8 mg/dl
8. AST (SGOT) > 2 times upper limit of normal
9. ALT (SGPT) > 2 times upper limit of normal
10. Any major organ system disease as identified by medical history, physical exam, and screening blood tests, EKG
11. Subjects who cannot give written, voluntary consent
12. Subjects with a major psychiatric disturbance
13. Only subjects whose body weight has been stable (±3-4 pounds) over the three months prior to study will be included.
14. Patients must not have type 1 diabetes
15. Patients must not have a fasting plasma glucose of greater than 270 mg/dl or HbA1c > 10.0%
16. Patients must not have received a thiazolidinedione, GLP-1 agonist, or insulin for more than one week during the year prior to randomization
17. Patients with a history of clinically significant heart disease (New York Heart Classification greater than class 2; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glucagon Receptor Agonist (GRA) REMD-477 group; Participants are assigned to a 12 week treatment of REMD-477	Drug: REMD-477; A biologic glucagon receptor agonist to which randomized subjects are assigned 2:1
Placebo Comparator: Placebo group; Participants are assigned to a 12 week course of placebo for REMD-477	Drug: Placebo Subcutaneous injection; Placebo for REMD-477 to which subjects will be randomized 1:2.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycated Hemoglobin (HbA1c)	Change in HbA1c measured at baseline and after intervention administration	Baseline to 13 weeks
Fasting Plasma glucose (FPG)	Change in fasting plasma glucose measured at baseline and after intervention administration	Baseline to 13 weeks
Plasma glucose (PG)	Change in plasma PG measured at baseline and after intervention administration using an oral glucose tolerance test (OGTT)	Baseline to 13 weeks
Hepatic insulin sensitivity	Change in hepatic glucose production (HGP)	Baseline to 13 weeks
Whole body glucose disposal	Change in whole body glucose disposal measured in mg/kg/min	Baseline to 13 weeks
Plasma Free Fatty Acids (FFA)	Change in plasma free fatty acids	Baseline to 13 weeks
Muscle Insulin sensitivity	Change in muscle insulin sensitivity measured by insulin-stimulated glucose uptake during low dose high dose insulin clamp.	Baseline to 13 weeks

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Investigators: Principal Investigator: Ralph DeFronzo, MD, University of Texas Health San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2021
• Primary Completion (Actual): March 16, 2022
• Study Completion (Actual): March 16, 2022

Study Registration Dates

• First Submitted: October 14, 2021
• First Submitted That Met QC Criteria: October 14, 2021
• First Posted (Actual): October 26, 2021

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 7, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Fasting plasma glucagon; Glucagon receptor antagonist
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Hyperglycemia; Diabetes Mellitus, Type 2; Glucose Intolerance; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Volagidemab
• Other Study ID Numbers: HSC20210463H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Summary results will be published in ClinicalTrials.gov as required by law and research findings will be published in a peer reviewed scientific journal.
• IPD Sharing Time Frame: Once the study has completed enrollment and data analysis is complete, data will become available.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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