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

Study Overview
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Brief Summary
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The main objective is to demonstrate the effects of early dopaminergic activation on the autonomic nervous system in subjects with newly diagnosed vs. established type 2 diabetes. The primary endpoint is the effect of Bromocriptine QR on changes in autonomic function measured by assessing sympathetic and parasympathetic function using conventional measures of autonomic function, including power spectral analysis of heart rate as well as peripheral autonomic function using sudorimetry and laser scanning of peripheral microvascular autonomic control.

Detailed Description
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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).

Official Title
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Impact of Timed Bromocriptine-QR Therapy Upon Measures of Sympathetic Tone and Vascular Biology in Type 2 Diabetes Subjects

Conditions
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Diabetic Autonomic Neuropathy

Intervention / Treatment
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* Drug: Cycloset
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cycloset (Bromocriptine-QR)<br>Subjects will be randomized in a 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects will be titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug will be titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) is achieved. Subjects will be maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study. Subjects will be seen at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). | Drug: Cycloset<br>* Cycloset 1.6 -3.2 mg/day<br>* Other names: Bromocriptine Mesylate Quick Release;|
| Placebo Comparator: Placebo<br>Subjects will be randomized in a 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects will be titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug will be titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) is achieved. Subjects will be maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects will be seen at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). | Drug: Placebo<br>* Non-active placebo for cycloset<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in E/I Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | Cardiac Autonomic Reflex Tests (CARTs) based on heart rate variations are the deep breathing test (E/I ratio), the lying to standing test (30:15 ratio) and the Valsalva maneuver (Valsalva ratio). These tests require a continuous recording of heart rate by either a simple electrocardiograph (ECG), subsequently elaborated via a specialist software. It is essential to inspect the ECG trace (on paper or monitor) in order to exclude artifacts or any type of arrhythmias from the calculations. Expiration/Inspiration (E/I) ratio: Standardized CART that measures parasympathetic control of the HR. The subject in a supine or sitting position is asked to breathe deeply at six breaths per minute (5 seconds in and 5 seconds out) for one minute. The E/I ratio is obtained by calculating the ratio between the average of the 3 longest RR intervals during expiration and the average of the 3 shortest RR intervals during inspiration. | Baseline to 24 weeks | 
| Change in Valsalva Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | Cardiac Autonomic Reflex Tests (CARTs) based on heart rate variations are the deep breathing test (E/I ratio), the lying to standing test (30:15 ratio) and the Valsalva maneuver (Valsalva ratio). These tests require a continuous recording of heart rate by simple electrocardiograph (ECG), subsequently elaborated via a specialist software. It is essential to inspect the ECG trace (on paper or monitor) in order to exclude artifacts or any type of arrhythmias from the calculations. Valsalva maneuver is a forced expiration with an open glottis against resistance. This causes changes in both BP and heart rate. During strain, tachycardia is initially determined by vagal withdrawal and afterwards by sympathetic activation. The Valsalva ratio is calculated as the ratio between the longest RR interval after the expiratory straining and the shortest RR interval during the expiratory straining | Baseline to 24 weeks | 
| Change in 30:15 Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | Lying to Standing (30:15) ratio: HR increases after standing to maintain an appropriate stroke volume, and then decreases. The maximum increase in heart rate generally occurs between the 10th and the 20th beat after standing, whereas heart rate generally returns to lower values between the 25th and the 35th beat. After lying in the supine position for at least 5 minutes, the subject is invited to stand up quickly but remain relaxed for 3 to 5 minutes. The ratio is the longest RR interval measured between the 25th and the 35th beat divided by the shortest RR interval measured between the 10th and the 20th beat after standing up. | Baseline to 24 weeks | 
| Change in SDNN From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | Time domain analysis of Heart Rate Variability includes SDNN and RMSSD measurements. It is acquired by continuous recording of heart rate by simple electrocardiograph (ECG) with the subject in supine or sitting position, resting and breathing at a controlled rate (15 breaths per minute) for 5 minutes. It is essential to inspect the ECG trace in order to exclude artifacts or any type of arrhythmias from the calculations. SDNN is the standard deviation of the beat to beat (NN) variability which is a measure of both sympathetic and parasympathetic action on HR. | Baseline to 24 weeks | 
| Change in RMSSD From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | Time domain analysis of Heart Rate Variability includes SDNN and RMSSD measurements. It is acquired by continuous recording of heart rate by simple electrocardiograph (ECG) with the subject in supine or sitting position, resting and breathing at a controlled rate (15 breaths per minute) for 5 minutes. It is essential to inspect the ECG trace in order to exclude artifacts or any type of arrhythmias from the calculations. RMSSD is the root mean square of successive R-R intervals and is a measure primarily of parasympathetic activity on HR. | Baseline to 24 weeks | 
| Change in Resting Heart Rate From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | The primary outcome is the change from baseline to endpoint (24 weeks) in measures of autonomic function using provocative tests (CARTs), measures of heart rate variability and resting heart rate | Baseline to 24 weeks | 
| Change in Feet ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | The coprimary outcome is the change, from baseline to endpoint (24 weeks), of peripheral autonomic function using sudorimetry. Sudoscan measures the sweating capacity of palms and soles and is expressed as electrochemical skin conductance (ESC) of feet and hands. ESC, expressed in micro-Siemens (µS), is the ratio between the current generated and the constant direct voltage stimulus applied to palms and soles between the electrodes. ESC is dependent on the glands' capability to transfer chloride ions and reflects small-C fiber function. | Baseline to 24 weeks | 
| Change in Hands ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo | The coprimary outcome is the change, from baseline to endpoint (24 weeks), of peripheral autonomic function using sudorimetry. Sudoscan measures the sweating capacity of palms and soles and is expressed as electrochemical skin conductance (ESC) of feet and hands. ESC, expressed in micro-Siemens (µS), is the ratio between the current generated and the constant direct voltage stimulus applied to palms and soles between the electrodes. ESC is dependent on the glands' capability to transfer chloride ions and reflects small-C fiber function. | Baseline to 24 weeks |