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

NCT02682901 | Completed Phase 4 Results

• 1 other identifier: 15-06-FB-0119
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

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.

Conditions

Diabetic Autonomic Neuropathy

Outcome Measures

Primary Outcomes (8)

• 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

Study Arms (2)

Cycloset (Bromocriptine-QR)

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Cycloset DRUG

Cycloset 1.6 -3.2 mg/day

Also known as: Bromocriptine Mesylate Quick Release

Cycloset (Bromocriptine-QR)

Placebo DRUG

Non-active placebo for cycloset

Placebo

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Eastern Virginia Medical School: lead

Study Sites (1)

Eastern Virgnia Medical School, Strelitz Diabetes Center

Norfolk, Virginia, 23510f, United States

Location

MeSH Terms

Conditions

Diabetic Neuropathies

Interventions

Bromocriptine

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Ergotamines; Ergot Alkaloids; Alkaloids; Heterocyclic Compounds; Ergolines; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Henri Parson
• Organization: Eastern Virginia Medical School

parsonhk@evms.edu

7574467976

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine Chief, Division of Endocrine and Metabolic Disorders Director, Strelitz Diabetes Center Associate Dean for Clinical Research

Study Record Dates

• First Submitted: February 4, 2016
• First Posted: February 17, 2016
• Study Start: October 5, 2015
• Primary Completion: November 15, 2018
• Study Completion: November 15, 2018
• Last Updated: December 10, 2021
• Results First Posted: December 10, 2021

Record last verified: 2021-11

Locations

US (1)