Bromocriptine-QR Therapy on Sympathetic Tone and Vascular Biology in Type 2 Diabetes Subjects

This is an interventional, twenty-four week, randomized, double blind, placebo-controlled
trial with bromocriptine QR in subjects with newly diagnosed and established type 2 diabetes
mellitus (T2DM) to evaluate its effects on the cardiovascular and peripheral autonomic
nervous system, as well as on inflammatory markers, the leptin/adiponectin system, hormonal
levels of RAS and HPA axis, indices of insulin resistance, and measures of oxidative and
nitrosative stress. Forty newly diagnosed diabetes subjects and 40 subjects with established
diabetes will be enrolled in the study and each randomized to treatment with bromocriptine-QR
or placebo.

Secondary endpoints will demonstrate the effects of dopaminergic activation with
Bromocriptine-QR on the regulation of Hypothalamic-Pituitary-Axis (HPA) axis hormones, on the
plasma levels of markers of inflammation and oxidative/nitrosative stress in newly diagnosed
vs. established type 2 diabetes subjects. The study will evaluate treatment effects on
inflammatory markers, the Leptin/Adiponectin system, and hormonal levels of
rennin-angiotensin system (RAS), aldosterone and cortisol. Specifically, the following
markers of inflammation and oxidative/nitrosative stress: 1) C reactive protein (CRP), 2)
interleukin-6, 12, and 10, 3) tumor necrosis factor (TNFalpha), 4) plasminogen activator
inhibitor (PAI1), superoxide dismutase (SOD), Thiobarbituric acid reactive substances (TBARS)
and Asymmetric dimethylarginine (ADMA) will be evaluated. A co-secondary objective of the
study will be to assess the impact of Bromocriptine-QR vs Placebo on measures of insulin
resistance and glycemic control (e.g., oral glucose tolerance test (OGTT) glucose and
insulin, Matsuda index, Homeostasis Model Assessment-insulin resistance (HOMA-IR), Hemoglobin
A1c (HbA1c).

Inclusion Criteria:

- Type 2 diabetes subjects between the ages of 30 and 80 years of age, inclusive, at
Screening

- Hemoglobin A1c (HbA1c) ≤10.0% at screening

- Male or female (female of child bearing age must use definitive contraceptive therapy)

- Type 2 Diabetes Mellitus subjects on a stable anti-diabetes regimen of diet and/or
metformin alone therapy or on metformin plus an insulin secretion enhancer
(sulfonylureas, dipeptidyl peptidase 4 (DPP4) Inhibitors, Glucagon-like peptide
(GLP-1) analogs) therapy for a 60 day period prior to randomization. Subjects with
diabetes duration of ≥ 4 years must be using an insulin secretion enhancer (e.g.
sulphonylureas (SU), DPP4, GLP-1 analog). Subjects must have a documented C-peptide
level (either fasting or random) of >2 ng/ml from the screening visit.

Exclusion Criteria:

- Presence of type 1 diabetes mellitus (defined as C-peptide <1 ng /ml)

- Type 2 diabetes mellitus subjects on insulin.

- Use of prescription sympathomimetics, ergot alkaloid derivatives, or anti-migraine
medications, dopamine2 (D2)-like receptor antagonists (e.g. metoclopramide,
domperidone) or systemic corticosteroids

- Uncontrolled hypertension (systolic BP >160 or diastolic BP > 100 at screening) or a
history of orthostatic hypotension

- History of significant gastroparesis

- Presence of diabetic retinopathy that is more severe than "background" level

- Presence of diabetic nephropathy, or renal impairment defined by blood urea nitrogen
(BUN) >40mg/dl and serum creatinine > 1.4 mg/dl if female taking metformin, >1.5
mg/dl. if male taking metformin, and >1.6 mg/dl if not taking metformin

- Presence of clinically significant peripheral or autonomic neuropathy that is clearly
of non-diabetic origin

- History of major macrovascular events such as myocardial infarction or cerebrovascular
event such as stroke within the past 6 months. Other exclusions include coronary
artery bypass graft or coronary angioplasty in the previous 3 months, unstable angina
pectoris (chest pain at rest, worsening chest pain, or admission to the emergency room
or hospital for chest pain) within the previous 3 months, or seizure disorders.

- Active infection (e.g., human immunodeficiency virus (HIV), hepatitis), or a history
of severe infection during the 30 days prior to screening

- Major surgical operation during the 30 days prior to screening

- Cancer, other than non-melanoma skin or non-metastatic prostate cancer, within the
past 5 years

- Uncontrolled or untreated hypothyroidism as evidenced by thyroid stimulating hormone
(TSH) concentrations >4.8 µU/ml

- Other serious medical conditions which, in the opinion of the investigator, would
compromise the subject's participation in the study, including any concurrent illness,
other than diabetes mellitus, not controlled by a stable therapeutic regimen, or
conditions or abnormalities (e.g., blindness) that might interfere with interpretation
of safety or efficacy data, or history of non-compliance

- Clinically significant abnormalities on screening laboratory evaluation, unless
approved by the Sponsor

- Abnormalities of liver function defined as any liver enzymes (aspartate
aminotransferase (AST), alanine aminotransferase (ALT), serum glutamic-pyruvic
transaminase (SGPT), Serum glutamic oxaloacetic transaminase (SGOT) greater than 3
times the upper limit of normal

- History of New York Heart Association (NYHA) Class III-IV congestive heart failure.

- Concurrent participation in another clinical trial with use of an experimental drug or
device within 30 days of study entry.

- History of alcohol or substance abuse or dementia

- Pregnant or lactating women. Women of childbearing potential must have a negative
pregnancy test at screening. Women who become pregnant will be discontinued from the
study.

- Known hypersensitivity to any of the formulation components

- Working rotating, varying or night shifts

- Use of unapproved herbal supplements that may be associated with a risk of
cardiovascular events (such as ephedra, yohimbe etc)

- Patients who have started therapy with an erectile dysfunction drug within 2 weeks
prior to screening; patients may not begin treatment with an erectile dysfunction drug
during the study period; patients currently taking erectile dysfunction drugs should
do so only under medical supervision.

- Donation of blood in the previous 30 days. Blood donation is also not allowed during
the study or for 30 days after completion of the study.