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

NCT ID: NCT02682901

Last Updated: 2021-12-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-05
• Study Completion Date: 2018-11-15

Brief Summary

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

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).

Conditions

Diabetic Autonomic Neuropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Cycloset (Bromocriptine-QR)

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).

Group Type: ACTIVE_COMPARATOR

Cycloset

Intervention Type: DRUG

Cycloset 1.6 -3.2 mg/day

Placebo

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).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Non-active placebo for cycloset

Interventions

Cycloset

Cycloset 1.6 -3.2 mg/day

Intervention Type: DRUG

Placebo

Non-active placebo for cycloset

Intervention Type: DRUG

Other Intervention Names

Bromocriptine Mesylate Quick Release

Eligibility Criteria

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.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eastern Virginia Medical School

OTHER

Sponsor Role: lead

Responsible Party

Elias S Siraj

Professor of Medicine Chief, Division of Endocrine and Metabolic Disorders Director, Strelitz Diabetes Center Associate Dean for Clinical Research

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Eastern Virgnia Medical School, Strelitz Diabetes Center

Norfolk, Virginia, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

15-06-FB-0119

Identifier Type: -

Identifier Source: org_study_id