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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Type 2 Diabetes, Glucose Tolerance Impaired, Insulin Sensitivity

Intervention / Treatment
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* Drug: REMD-477
* Drug: Placebo Subcutaneous injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetic subjects, males/females; age = 18-70 years BMI = 25-40 kg/m2; HbA1c = 7.5-10.0%; Type 2 Diabetics who are drug naïve or treated with metformin, sulfonylureas, SGLT-2 inhibitors or any combination thereof. Subjects must be on a stable dose of antidiabetic medications for at least 3 months prior to study. Patients must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent. 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: 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. Subjects with a contraindication to MRI including artificial heart valves or pacemakers Patients with a known sensitivity to humanized antibodies Subjects treated with GLP-1 RAs or insulin are excluded. Subjects treated with a non-antidiabetic medication that may impact insulin sensitivity, such as systemic steroids, or lipase inhibitors (orlistat, Alli or Xenical) Hematocrit < 34 vol% Serum creatinine > 1.8 mg/dl AST (SGOT) > 2 times upper limit of normal ALT (SGPT) > 2 times upper limit of normal Any major organ system disease as identified by medical history, physical exam, and screening blood tests, EKG Subjects who cannot give written, voluntary consent Subjects with a major psychiatric disturbance Only subjects whose body weight has been stable (±3-4 pounds) over the three months prior to study will be included. Patients must not have type 1 diabetes Patients must not have a fasting plasma glucose of greater than 270 mg/dl or HbA1c > 10.0% Patients must not have received a thiazolidinedione, GLP-1 agonist, or insulin for more than one week during the year prior to randomization 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.

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: Parallel Assignment
Interventional Model Description: A randomized 2-arm placebo controlled trial
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fasting plasma glucagon, Glucagon receptor antagonist