Single-dose Study to Evaluate Safety, Tolerability, and Pharmacodynamics of REMD-477 in Subjects With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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This is a randomized, placebo-controlled, double-blind study to evaluate safety, tolerability and pharmacodynamics of REMD-477 in subjects who have Type 1 diabetes and are currently receiving insulin treatment. This proof of concept study will determine whether glucagon receptor blockade using a single dose REMD-477 can improve short-term glucose homeostasis in people with Type 1 diabetes.

Detailed Description
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The study will be conducted at two sites in the United States, and approximately 20 subjects with type 1 diabetes will be enrolled. Eligible subjects will be admitted to the clinical research unit, to carefully monitor blood glucose; and establish the baseline insulin requirement for maintaining targeted normoglycemia (postabsorptive: 90-120 mg/dL; and postprandial: <180 mg/dL). The patients will then be subjected to a hyperglycemic period (250-300 mg/dL) by a stepwise reduction in insulin infusion. After receiving a single SC dose of REMD-477 or matching placebo in a double-blinded fashion, all subjects will be assessed for the post-treatment 24-hour insulin requirement needed to maintain targeted normoglycemia (postabsorptive: 90-120 mg/dL; and postprandial: <180 mg/dL); and to be monitored closely for safety, tolerability and targeted glycemic control, for a 48-hr period. After the in-patient residency period, subjects will return to the clinic for weekly out-patient safety follow-up visits for 8 weeks.

Official Title
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A Randomized, Placebo-controlled, Double-blind, In-patient Study to Evaluate Safety, Tolerability, and Pharmacodynamics of REMD-477 Following a Single Dose in Subjects With Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus, Diabetes

Intervention / Treatment
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* Biological: REMD-477
* Biological: Placebo Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between the ages of 18 and 60 years old, inclusive, at the time of screening; Females of non-child bearing potential must be ≥1 year post-menopausal (confirmed by a serum follicle-stimulating hormone (FSH) levels ≥ 40 IU/mL) or documented as being surgically sterile. Females of child bearing potential must agree to use two methods of contraception; Male subjects must be willing to use clinically acceptable method of contraception during the entire study; Body mass index between 18.5 and 26.9 kg/m2, inclusive, at screening; Diagnosed with Type 1 diabetes for greater than 2 years, based on clinical history or as defined by the current American Diabetes Association (ADA) criteria; HbA1c ≥6.0 % but <9.0 % at screening; Fasting C-peptide <0.2 ng/mL; Current use of insulin pump and willing to use continuous glucose monitoring (CGM) system (e.g. DexCom) throughout the entire study; ALT and/or AST within <1.5x ULN at screening; Serum amylase and lipase within normal limits at screening; Able to provide written informed consent approved by an Institutional Review Board (IRB). Exclusion Criteria: 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; Significant organ system dysfunction (e.g., clinically significant pulmonary or cardiovascular disease, anemia [Hemoglobin <10.0 g/dL], and renal dysfunction [eGFR <90 ml/1.73M2/min]); Any severe symptomatic hypoglycemic event associated with a seizure or requiring help from other people or medical facility in the past 6 months; Current or recent (within 1 month of screening) use of diabetes medications other than insulin; Use of steroids and/or other prescribed or over-the-counter medications that are known to affect the outcome measures in this study or known to influence glucose metabolism; Smokes tobacco; Known sensitivity to mammalian-derived drug preparations, recombinant protein-based drugs or to humanized or human antibodies; History of illegal drug use or alcohol abuse within the last 6 months or a positive drug urine test result at screening; History of pancreatitis, pancreatic neuroendocrine tumors or multiple endocrine neoplasia; History of pheochromocytoma, or family history of familial pheochromocytoma; Known or suspected susceptibility to infectious disease (eg, taking immunosuppressive agents or has a documented inherited or acquired immunodeficiency); Positive for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HbsAg), or hepatitis C antibodies (HepC Ab); Participation in an investigational drug or device trial within 30 days of screening or within 5 times the half-life of the investigational agent in the other clinical study, if known, whichever period is longer; Blood donor or blood loss >500 mL within 30 days of Day 1; Women who are pregnant or lactating/breastfeeding; Regular exercise >120 min/week within 14 days of Day 1; Unable or unwilling to follow the study protocol or who are non-compliant with screening appointments or study visits; Family history of multiple endocrine neoplasia. Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REMD-477 Treatment A<br>Administered as a single SC dose in subjects with Type 1 Diabetes | Biological: REMD-477<br> <br> |
| Placebo Comparator: Matching placebo<br>Administered as a single SC dose in subjects with Type 1 Diabetes | Biological: Placebo Comparator<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment emergent adverse events per subject, including changes in vital signs, physical and neurological examinations, laboratory safety tests and ECGs |  | Baseline and 57 days | 
| Changes from baseline in 24-hour insulin requirements on Day 1 relative to the two 24 hour periods post-treatment on Days 3 and 4, between the REMD-477 and placebo treated subjects, needed to maintain targeted glycemic control. |  | Baseline (24 hour period on Day 1) and Days 3 and 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity: Incidence of REMD-477 neutralizing and non-neutralizing antibodies |  | Baseline and 57 days | 
| Changes from baseline over time of AST. | Incidence of elevated serum aspartate transaminase (AST) values > 3x the upper limit of normal (ULN). | Baseline and 57 days | 
| Changes from baseline over time of ALT. | Incidence of elevated serum alanine transaminase (ALT) values >3x the upper limit of normal (ULN). | Baseline and 57 days | 
| Changes from baseline over time of ALP. | Incidence of elevated serum alkaline phosphatase (ALP) >2x upper limit of normal (ULN) | Baseline and 57 days | 
| Changes from baseline over time of total bilirubin. | Incidence of elevated serum total bilirubin >2x upper limit of normal (ULN). | Baseline and 57 days | 
| Changes from baseline over time of amylase | Incidence of elevated serum amylase values at >2.5x ULN | Baseline and 57 days | 
| Changes from baseline over time of lipase | Incidence of elevated serum lipase values at >2.5x ULN | Baseline and 57 days |