Clinical trial NCT05093517: Effect of Novel Glucagon Receptor Antagonist REMD-477 on Glucose and Adipocyte Metabolism in T2DM
Official title: Effect of Novel Glucagon Receptor Antagonist REMD-477 on Glucose and Adipocyte Metabolism in Type 2 Diabetes Mellitus (T2DM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Type 2 Diabetes
Glucose Tolerance Impaired
Insulin Sensitivity
Keywords: Fasting plasma glucagon
Glucagon receptor antagonist
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
First posted: 2021-10-26
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized 2-arm placebo controlled trial
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Glycated Hemoglobin (HbA1c)
timeFrame: Baseline to 13 weeks
measure: Fasting Plasma glucose (FPG)
timeFrame: Baseline to 13 weeks
measure: Plasma glucose (PG)
timeFrame: Baseline to 13 weeks
measure: Hepatic insulin sensitivity
timeFrame: Baseline to 13 weeks
measure: Whole body glucose disposal
timeFrame: Baseline to 13 weeks
measure: Plasma Free Fatty Acids (FFA)
timeFrame: Baseline to 13 weeks
measure: Muscle Insulin sensitivity
timeFrame: Baseline to 13 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Texas Diabetes Institute
state: Texas
Study officials:
affiliation: University of Texas Health San Antonio
name: Ralph DeFronzo, MD
role: PRINCIPAL_INVESTIGATOR
References: