Dose Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of REMD-477 in Subjects With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
This is a randomized, placebo-controlled, double-blind, dose escalation study to evaluate safety, tolerability, PK and PD of single and repeated SC doses of REMD-477 in Type 2 diabetic subjects. The study will be conducted at multiple sites in the United States and will enroll approximately 102 subjects with Type 2 diabetes who are either treatment-naïve, controlled with diet and exercise or treated with oral antidiabetic medications.

Detailed Description
-----------------
The study will consist of three parts: Part A - Dose Escalation, Part B - Adaptive Dose Cohort, and Part C - REMD-477 in Combination with Metformin. Part A includes 5 cohorts that will be enrolled and dosed sequentially at escalating doses. Each cohort will consist of 12 subjects randomized in a 3:1 (active: placebo) fashion. Part B includes a single dose cohort that will enroll 12 subjects (9 on active treatment and 3 on placebo) with dose level and frequency determined by a Dose Level Review Meeting (DLRM)Committee. Part C includes 2 cohorts of T2DM patients currently treated with metformin alone, and each cohort will consist of 15 subjects (10 on active treatment and 3 on placebo).

Official Title
-----------------
A Randomized, Placebo-controlled, Double-blind, Dose Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeated Subcutaneous (SC) Doses of REMD-477 in Subjects With Type 2 Diabetes Mellitus

Conditions
-----------------
Type 2 Diabetes Mellitus, Diabetes

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women between the ages of 18 and 65 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, and females of child bearing potential must use two medically acceptable methods of contraception; Male subjects must be willing to use clinically acceptable contraception during treatment and for 2 months after the last administration of REMD-477; Normal or clinically-acceptable physical examination, laboratory test values, and 12-lead ECG (reporting heart rate and PR, QRS, QT, and QTcF) at screening; Body mass index between 23 and 40 kg/m2, inclusive, at screening; Diagnosed with Type 2 diabetes as defined by the current American Diabetes Association (ADA) criteria; Subjects in Parts A and B only: Treatment-naive, controlled with diet and exercise, or treated with oral antidiabetic medications and willing to wash-out and discontinue oral medications during the study; Fasting plasma glucose 126 - 270 mg/dL (7-15 mM), inclusive, at screening and at re-test on Day -1; Subjects in Parts A and B only: Screening HbA1c of 7.0-10 % inclusive for subjects not currently taking any oral antidiabetic medications, or 6.5-9.5% for subjects receiving acceptable oral antidiabetic medications; Subjects in Part C only: Screening HbA1c of 7.5-10 % inclusive for subjects on stable doses of metformin. Exclusion Criteria: History of drug or alcohol abuse within the last 6 months or a positive illegal drug urine test result; History or family history of pancreatic neuroendocrine tumors or multiple endocrine neoplasia; History or family history of 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>300 mL, within 30 days of Day 1; Recent use (6 weeks prior to Screening) of thiazolidinediones, >half-maximal dose sulfonylurea agent therapy, or any injectable antidiabetic agents (exenatide and other injectable GLP-1 agonists, insulin and insulin analogs, etc.); Other gastrointestinal, cardiac, renal and CNS (i.e. hypoglycemia unawareness) conditions specific to diabetes that would pose additional risk to subject's safety or interfere with the study evaluation, procedures or completion; Lipid panel profiles of non-HDL-C (total cholesterol minus HDL-C) >219 mg/dL, LDL-C >189 mg/dL, and/or fasting triglycerides >499 mg/dL; Female subject is pregnant or breastfeeding. Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REMD-477 Treatment A<br>Administered as a single and repeated SC doses in subjects with Type 2 Diabetes | Biological: REMD-477<br> <br> |
| Placebo Comparator: Matching placebo<br>Placebo administered as single and repeated SC doses in subjects with Type 2 Diabetes | Biological: REMD-477<br> <br> |
| Experimental: REMD-477 Treatment B<br>Administered as a single and repeated SC doses in subjects with Type 2 Diabetes | Biological: REMD-477<br> <br> |
| Experimental: REMD-477 Treatment C<br>Administered as a single and repeated SC doses in subjects with Type 2 Diabetes | Biological: REMD-477<br> <br> |
| Experimental: REMD-477 Treatment D<br>Administered as a single and repeated SC doses in subjects with Type 2 Diabetes | Biological: REMD-477<br> <br> |
| Experimental: REMD-477 Treatment E<br>Administered as a single and repeated SC doses in subjects with Type 2 Diabetes | Biological: REMD-477<br> <br> |

What is the study measuring?
-----------------
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 |  | 141 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile (parameters including maximum observed concentration (Cmax), area under the curve (AUC) serum-concentration, clearance, and half-life (t1/2) after single and repeated SC doses. |  | 141 Days | 
| Changes in fasting glucose and insulin levels following single and repeated SC doses of REMD-477. |  | 141 Days | 
| Changes in glucose and insulin AUC following a Mixed Meal Tolerance Test. |  | Day 29, Day 57 and Day 85 | 
| Incidence of REMD-477 neutralizing and non-neutralizing antibodies |  | 141 Days | 
| Incidence of elevated alanine transaminase (ALT) or aspartate transaminase (AST) values >3x the upper limit of normal with concomitant >2x increases in alkaline phosphatase (ALP) and/or >2x total bilirubin. |  | 141 Days | 
| Incidence and severity of elevated amylase and lipase values at >2.5x ULN after study treatment |  | 141 Days | 
| Geometric mean ratio to baseline over time of AST, ALT, ALP and total bilirubin. |  | 141 |