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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02682901
Recruitment Status : Completed
First Posted : February 17, 2016
Results First Posted : December 10, 2021
Last Update Posted : December 10, 2021
Sponsor:
Information provided by (Responsible Party):
Elias S Siraj, Eastern Virginia Medical School

Tracking Information
First Submitted Date  ICMJE February 4, 2016
First Posted Date  ICMJE February 17, 2016
Results First Submitted Date  ICMJE February 2, 2021
Results First Posted Date  ICMJE December 10, 2021
Last Update Posted Date December 10, 2021
Actual Study Start Date  ICMJE October 5, 2015
Actual Primary Completion Date November 15, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 12, 2021)
  • Change in E/I Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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.
  • Change in Valsalva Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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
  • Change in 30:15 Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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.
  • Change in SDNN From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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.
  • Change in RMSSD From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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.
  • Change in Resting Heart Rate From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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
  • Change in Feet ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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.
  • Change in Hands ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo [ Time Frame: Baseline to 24 weeks ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 10, 2016)
Primary Outcome Measures: Comparison of Pre and Post Measures of Autonomic Function after Intervention [ Time Frame: 6 months ]
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.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: February 10, 2016)
  • Secondary Outcome Measures: Comparison of Pre and Post Measures of Inflammatory Markers after Intervention [ Time Frame: 6 months ]
    Secondary endpoints evaluate Bromocriptine QR's effects on inflammatory markers, the Leptin/Adiponectin system, and hormonal levels of rennin-angiotensin system (RAS), aldosterone and cortisol.
  • Secondary Outcome Measures: Comparison of Pre and Post Measures of Leptin/Adiponectin after Intervention [ Time Frame: 6 months ]
    Secondary endpoints evaluate Bromocriptine QR's effects on Leptin/Adiponectin system and hormonal levels of rennin-angiotensin system (RAS), aldosterone and cortisol.
  • Secondary Outcome Measures: Comparison of Pre and Post Measures of Rennin-angiotensin system (RAS) after Intervention [ Time Frame: 6 months ]
    Secondary endpoints evaluate Bromocriptine QR's effects on hormonal levels of rennin-angiotensin system (RAS).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bromocriptine-QR Therapy on Sympathetic Tone and Vascular Biology in Type 2 Diabetes Subjects
Official Title  ICMJE Impact of Timed Bromocriptine-QR Therapy Upon Measures of Sympathetic Tone and Vascular Biology in Type 2 Diabetes Subjects
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Autonomic Neuropathy
Intervention  ICMJE
  • Drug: Cycloset
    Cycloset 1.6 -3.2 mg/day
    Other Name: Bromocriptine Mesylate Quick Release
  • Drug: Placebo
    Non-active placebo for cycloset
Study Arms  ICMJE
  • Active Comparator: 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).
    Intervention: Drug: Cycloset
  • Placebo Comparator: 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).
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 25, 2018)
84
Original Estimated Enrollment  ICMJE
 (submitted: February 10, 2016)
80
Actual Study Completion Date  ICMJE November 15, 2018
Actual Primary Completion Date November 15, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02682901
Other Study ID Numbers  ICMJE 15-06-FB-0119
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Elias S Siraj, Eastern Virginia Medical School
Original Responsible Party Aaron I. Vinik, MD, PhD, Eastern Virginia Medical School, Professor of Medicine/Pathology/Neurobiology Director of Research & Neuroendocrine Unit
Current Study Sponsor  ICMJE Eastern Virginia Medical School
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Eastern Virginia Medical School
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP