Study of Two Doses of Oral HDV-Insulin and Placebo With Background Metformin Treatment in Patients With Type 2 Diabetes Mellitus

The primary objective of this trial is to compare the reduction in mean glycated hemoglobin levels (HbA1c) between 2 doses of oral HDV-I and placebo in type 2 diabetic patients on background metformin therapy at the end of 18 weeks of treatment.

The secondary objectives are:

* To evaluate the effects of oral HDV-I versus placebo on the 7-point glucose test, fasting plasma glucose (FPG), insulin, homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-β), frequency of hypoglycemic events, body weight, and lipid levels; and
* To evaluate the safety and tolerability of oral HDV-I.

This is a multicenter, randomized, double-blind, placebo-controlled study with a washout/stabilization period of up to 12 weeks in duration and an 18-week double-blind treatment period. There will be a total of 8 visits.

Eligibility Criteria:
Inclusion Criteria:

* Age 18 to 70 years, inclusive;
* Diagnosis of type 2 diabetes mellitus;
* Fasting plasma glucose \<=250 mg/dL;
* BMI \<=45 kg/m2;
* HbA1c levels as follows at Screening:
* On a stable dose of metformin monotherapy with an HbA1c \>=7.5% and \<=9.5%;
* On metformin and 1 other OAD (excluding TZD, exenatide, or insulin) with an HbA1c \>=6.8% and \<=9.0%;
* Naïve to antidiabetic therapy or have not been on a stable dose of metformin monotherapy for \<12 weeks with an HbA1c \>=8.0% and \<=10.5%;
* Understanding of the study procedures and agreement to participate in the study, giving written informed consent;
* Women may be enrolled if all of the following criteria (in addition to the above criteria) are met:
* They are not pregnant (women of childbearing potential must have a negative serum pregnancy test at Visit 1);
* They are not breast-feeding;
* They do not plan to become pregnant during the study; and
* They have had a hysterectomy or tubal ligation 6 months prior to the study, have been post-menopausal for 1 year, or will practice a method of birth control throughout the study.

Exclusion Criteria:

* History of type 1 diabetes and/or history of ketoacidosis;
* History of chronic (\>2 months) use of insulin therapy or recent initiation of insulin use intended for chronic administration;
* Use of TZD (pioglitazone or rosiglitazone) or exenatide within 3 months prior to Screening;
* Use of prescription or over the counter weight loss agents within 1 month prior to Screening;
* Use of any lipid-altering, antihypertensive, and other chronic use medication not stable for 1 month prior to Screening;
* Use of any medication that may alter blood glucose analyses;
* Any serious disorder including cardiac, pulmonary, hepatic, uncontrolled endocrine/metabolic, hematologic/oncologic (within the last 5 years), neurologic, and psychiatric diseases that would interfere with the conduct of the study or interpretation of the data;
* Require regular use of medication that interferes with the oral absorption and/or metabolism of insulin or metformin;
* History of pancreatitis;
* History of acquired immune deficiency syndrome or human immunodeficiency virus;
* History of drug or alcohol abuse within the past 2 years;
* Hospitalization for any cause within 14 days prior to the study;
* History of an allergic or toxic response to oral HDV-I;
* Uncontrolled hypertension: systolic blood pressure \>160 mmHg and diastolic blood pressure \>95 mmHg;
* Triglycerides \>400 mg/dL;
* Aspartate aminotransferase or alanine aminotransferase \>2.5 times the upper limit of normal (ULN);
* Creatine phosphokinase \>3 times the ULN;
* Patients on a weight loss program with ongoing weight loss, or starting an intensive exercise program within 4 weeks of starting the study;
* Use of any investigational drug within 30 days preceding the first dose of study medication; or
* Employment by the research center.