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Short Interval Resveratrol Trial in Cardiovascular Surgery (SIRT-CVS)

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ClinicalTrials.gov Identifier: NCT03762096
Recruitment Status : Recruiting
First Posted : December 3, 2018
Last Update Posted : December 3, 2018
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
Michael Robich, Maine Medical Center

Tracking Information
First Submitted Date  ICMJE November 30, 2018
First Posted Date  ICMJE December 3, 2018
Last Update Posted Date December 3, 2018
Actual Study Start Date  ICMJE March 6, 2018
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2018)
  • Change in endothelial function [ Time Frame: 6 weeks ]
    Serum levels of nitric oxide (ELISA assay)
  • Change in endothelial function [ Time Frame: 14 days ]
    Nitric oxide synthase levels in heart tissue (Western blot assay)
Original Primary Outcome Measures  ICMJE
 (submitted: November 30, 2018)
  • Change in endothelial function [ Time Frame: 6 weeks ]
    Serum level of nitric oxide
  • Change in endothelial function [ Time Frame: 14 days ]
    Nitric oxide level in heart tissue
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2018)
  • Effects of resveratrol on caveolar function [ Time Frame: 14 days ]
    Lipidomic changes in cell membranes (Mass spectrometry)
  • Effects of resveratrol on molecular signaling [ Time Frame: 14 days ]
    Serum and tissue levels of pathways associated with glucose metabolism (Western blot assay)
Original Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2018)
  • Effects of resveratrol on caveolar function [ Time Frame: 14 days ]
    Lipidomics
  • Effects of resveratrol on molecular signaling [ Time Frame: 14 days ]
    Serum and tissue levels of pathways associated with glucose metabolism
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Short Interval Resveratrol Trial in Cardiovascular Surgery
Official Title  ICMJE Short Interval Resveratrol Trial in Cardiovascular Surgery
Brief Summary

Major Problem

People with diabetes have an increased risk of heart disease, heart failure, and death from a cardiovascular cause. Diabetes prevents efficient metabolism of fuel, causes inflammation and vascular disease that blocks normal blood flow, and inhibits the function of the heart after injury. These changes make diabetics more susceptible to heart attacks and heart failure.

Resveratrol is found in grapes and red wine and has been shown to have beneficial effects in diabetic patients. In previous studies the investigators have shown that resveratrol can improve heart metabolism and function in pigs with diabetes and chronic lack of blood flow to the heart.

Questions

The investigators believe resveratrol will help reverse the negative effects of diabetes on the heart. The questions are: 1.How does the molecular machinery in the hearts of patients with diabetes differ from patients without diabetes? 2.Will resveratrol have an effect on heart metabolism, intracellular signaling, inflammation and blood vessel function? 3.Will resveratrol improve the number and function of cardiac stem cells, cells involved in heart repair? The investigators have been safely collecting tissue from the hearts of patients undergoing heart surgery. Preliminary studies show the investigators can isolate and study cells. The investigators have collected and assessed the function of endothelial cells, a measure of vascular health and can measure the level of endothelial injury and have studied the make-up of caveolae, structures on the cell membrane that are important for cell signaling and are negatively impacted by diabetes. This study is a unique collaboration among cardiologists, cardiac surgeons, and basic scientists.

Detailed Description

Patients with diabetes and metabolic diseases such as obesity, hypertension and dyslipidemia have a myocardial environment that results in endothelial dysfunction, altered metabolism and little potential for regeneration by intrinsic or extrinsically delivered therapies. Based upon work in animal and cell culture models of human disease, caveolae, lipid rafts found on the cell membrane of endothelial cells and myocytes, are important in cell signaling and metabolism. A growing body of literature suggests that disruption of membrane lipid microdomains in diabetes can lead to altered signaling that contributes to cardiovascular pathology. One possible method to improve the "endothelial health" of the heart could involve normalizing metabolic processes and decreasing signals that lead to inflammation and pathways that lead to fibrosis in the myocardium. This presents an opportunity to improve outcomes in our diabetic patients and improve the success of future therapies aimed at improving endothelial function.

Resveratrol, a polyphenol found in abundance in red wine, activates sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, which influences a diverse array of metabolic pathways. Studies in cultured cells, small animal models, and humans demonstrate that SIRT1 is involved in endothelial function, mitochondrial biogenesis, insulin production, inflammation, and glucose and lipid homeostasis. These processes are often dysfunctional in patients with diabetes and other metabolic diseases.

The central hypothesis of this proposal is that molecular pathology of diabetes on cardiac endothelium can be corrected with orally supplemented resveratrol.

The investigators propose to test this hypothesis in by first assessing endothelial function, lipidomic signatures, and cell signaling in patients with and without diabetes mellitus undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). The second Aim of this proposal is a pilot placebo-controlled, double-blind clinical trial that will assess the effects of supplemental resveratrol in diabetic patients undergoing CABG with CPB. The goal will be to better understand the influence of resveratrol on key molecular signals that determine endothelial function, calveolar makeup and function, as well as cytoprotective signaling and responses in the heart.

The Specific Aims of this proposal are to:

Aim 1: Define the molecular pathology of diabetes on cardiac cells and tissues in non-diabetic and diabetic patients undergoing surgical revascularization. We will assess the effects of DM on endothelial function and damage, lipidomics, caveolar expression, disrupted receptor expression and neuregulin signaling.

Aim 2: Determine the effect of resveratrol on the microvascular function of diabetic patients undergoing surgical revascularization. Through a pilot randomized placebo-controlled clinical trial, the investigators will evaluate the effect of resveratrol on endothelial damage at the time of cardiopulmonary bypass, endothelial function, and cell signaling.

This study will further our understanding of how resveratrol impacts patients in a controlled setting, and will allow for a thorough and complete investigation of how the supplement affects this patient population clinically and on a molecular level. The data will inform the development of larger studies examining the benefits of resveratrol in diabetes and metabolic syndrome. Finally, the investigators successful completion of this trial will inform the study of other therapeutics where direct myocardial effects are being considered.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Diabetes Mellitus, Type 2
  • Coronary Artery Disease
Intervention  ICMJE
  • Dietary Supplement: Trans-resveratrol
    1 gram, twice a day by mouth Transmax (Biotivia)
    Other Name: resveratrol
  • Dietary Supplement: Placebo
    Placebo
Study Arms  ICMJE
  • Experimental: Resveratrol
    Intervention: Dietary Supplement: Trans-resveratrol
  • Placebo Comparator: Placebo
    Intervention: Dietary Supplement: 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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 30, 2018)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adult patients (age >18 years)
  • Type 2 diabetes (controlled by either oral agents or insulin)
  • Coronary artery disease referred for elective CABG with CPB

Exclusion Criteria:

  • Known decompensated congestive heart failure or systolic heart failure with an ejection fraction < 45% at the time of evaluation
  • Liver Function Tests (LFT) greater than 2 times normal
  • Renal dysfunction (GFR less than 60 mL/min)
  • Abnormal coagulation profile (PT/PTT and INR)
  • Alcohol consumption more than 3 grams (equivalent to 2.5 glasses of wine) daily
  • Positive HIV, Hepatitis B or C testing
  • Severe ventricular arrhythmias
  • Significant hypotension (SBP < 90 mmHg) at the time of enrollment
  • Patients who are pregnant
  • Known malignancy other than non-melanoma skin cancers
  • Expected survival less than one year.
  • Allergy or intolerance to the ingredients of the supplement or the placebo
  • Inability to comply with the study requirements.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michael Robich, MD 2077738161 mrobich@mmc.org
Contact: Betsey Gallant 2077738161 BGallant@mmc.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03762096
Other Study ID Numbers  ICMJE 1095584
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Michael Robich, Maine Medical Center
Study Sponsor  ICMJE Maine Medical Center
Collaborators  ICMJE American Heart Association
Investigators  ICMJE Not Provided
PRS Account Maine Medical Center
Verification Date November 2018

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