Study of Subcutaneously Administered ENT-03 for the Treatment of Obesity and Diabetes

Study Overview
=================
Brief Summary
-----------------
Single center, single-dose, randomized, placebo-controlled, dose-escalating study to evaluate, safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating doses of ENT-03S in obese but otherwise healthy subjects and in subjects with obesity and Type 2 diabetes.

Official Title
-----------------
A First in Human, Single Center, Single Dose, Randomized, Placebo-controlled, Dose, Escalating Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Subcutaneously Administered ENT-03S for the Treatment of Obesity and Diabetes

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

Intervention / Treatment
-----------------
* Drug: ENT-03
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects aged 18-70 years, both genders. Healthy as determined by a physician, based on history, medical examination, vital signs, and laboratory tests. Males that agree to use condoms for the duration of participation in the study. Females of non-child-bearing potential (i.e., tubal ligation, hysterectomy, or postmenopausal). Female patients of child-bearing potential with negative serum pregnancy tests and who agree to use double-barrier contraception during the study. Subjects must be able to read, speak, and understand English and/or Spanish and provide written informed consent, and be willing and able to comply with study procedures. Subjects must have a BMI 30-35 kg/m2 inclusive assessed immediately prior to screening. Fasting insulin level ≥11 mIU/L. HbA1c < 8.5% (diabetic subjects only). Subjects with Type 2 diabetes on no anti-diabetic medication or on stable doses of metformin for 4 weeks or more (diabetic cohorts only). No history of active or chronic disease other than that allowed by study: hypertension, hyperlipidemia, hyperglycemia, GERD, heartburn, or Type 2 diabetes (cohorts 6 and 7 only). Exclusion Criteria: History of excessive alcohol use (defined as >21 drinks per week for males and >14 drinks per week for females), recreational drug use within the past three months, or failure on urinary drug screen. Pregnant or breastfeeding within six months of screening assessment. Substantial changes in eating habits or exercise routine within the preceding three months. Evidence of eating disorders. >5% weight change in the past three months. Bariatric surgery within the past five years. Significant renal impairment (eGFR <60 mg/mL/1.73m2). Patients on anti-diabetic medications other than metformin. Patients with gastroparesis. Liver function tests (i.e., ALT, AST, alkaline phosphatase) greater than twice the upper limit of normal upon repeated measurements. Diseases interfering with metabolism and/or ingestive behavior (e.g., myxedema, Cushing's disease, schizophrenia, major psychoses). History of major depressive disorder within the previous two years, a lifetime history of suicide attempt, suicidal behavior within the previous month, or history of other severe psychiatric disorders. Score of >15 on the Columbia Suicide Severity Rating Scale (C-SSRS). Use of medications affecting body weight within the past three months: Drugs approved for the treatment of obesity Cyproheptadine or medroxyprogesterone Atypical anti-psychotic drugs Tricyclic antidepressants Lithium, MAO's, glucocorticoids SSRI's or SNRI's Antiepileptic drugs Any clinically significant abnormality following the Investigator's review of the physical examination and clinical laboratory tests. A baseline prolongation of QT/QTc interval after repeated measurements of >450 ms; a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome (LQTS). Participation in an investigational drug trial within the month prior to dosing in the present study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>Receive a single dose of ENT-03 sub-cutaneously | Drug: ENT-03<br>* single dose of active drug<br>|
| Placebo Comparator: Placebo<br>Receive a single dose of placebo sub-cutaneously | Drug: Placebo<br>* single dose of placebo comparator<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of ENT-03 | Adverse Events | 7 days | 
| Safety and Tolerability of ENT-03 | ECG: QTc analysis | 7 days | 
| Safety and Tolerability of ENT-03 | Vital signs: body temperature | 7 days | 
| Safety and Tolerability of ENT-03 | Vital signs: respiration rate | 7 days | 
| Safety and Tolerability of ENT-03 | Vital signs: heart rate | 7 days | 
| Safety and Tolerability of ENT-03 | Vital signs: systolic blood pressure measurements | 7 days | 
| Safety and Tolerability of ENT-03 | Vital signs: diastolic blood pressure measurements | 7 days | 
| Safety and Tolerability of ENT-03 | Vital signs: body weight in kilograms | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pharmacokinetic endpoints: maximum plasma concentration | maximum measured plasma concentration | pre-dose, 24 hours, 48 house, 72 hours | 
| pharmacokinetic endpoints: time of maximum plasma concentration | time of maximum measured plasma concentration | pre-dose, 24 hours, 48 house, 72 hours | 
| pharmacokinetic endpoints: ENT-03 half-life | terminal elimination of ENT-03 half-life in plasma | pre-dose, 24 hours, 48 house, 72 hours | 
| pharmacokinetic endpoints: plasma concentration | area under the concentration versus time curve over 24 hours | pre-dose, 24 hours, 48 house, 72 hours | 
| pharmacokinetic endpoint: ENT-03 clearance | Clearance of ENT-03 | pre-dose, 24 hours, 48 house, 72 hours | 
| pharmacokinetic endpoint: elimination phase | slope of terminal elimination phase | pre-dose, 24 hours, 48 house, 72 hours | 
| pharmacodynamic endpoint: glucose | change from screening visit in fasting plasma glucose | 7 days | 
| pharmacodynamic endpoint: insulin | change from screening visit in fasting serum insulin | 7 days | 
| pharmacodynamic endpoint: fasting lipids | change from screening visit in fasting lipids | 7 days | 
| pharmacodynamic endpoint: fasting leptin | change from screening visit in fasting leptin | 7 days | 
| pharmacodynamic endpoint: body weight | change from screening visit in body weight (kg) | 7 days | 
| effect on glucose | results of fasting and post-prandial blood glucose in subjects with obesity and T2D | Days -7, 2, 3, 4, and 7 | 
| effect on insulin and insulin sensitivity | results of fasting and post-prandial blood insulin and insulin sensitivity as measured by homeostatic assessment of insulin resistance (HOMAIR), in subjects with obesity and T2D | Days -7, 2, 3, 4, and 7 |