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Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Primary Purpose

Heart Disease

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
1mg/kg sitaxsentan sodium
2mg/kg sitaxsentan sodium
Vehicle
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Heart Disease

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • >60 years of age
  • Body mass index <40 kg/m2
  • Left ventricular ejection fraction less than or equal to 50% documented by a pre-operative echocardiogram
  • Patients undergoing coronary artery bypass (CABG), aortic and/or mitral valve replacement or combined CABG and valve procedures requiring CPB.
  • If diabetic, be under proper control, (fasting glucose <350 mg/dL or recent hemoglobin A1c [HgbA1c] <9%).
  • If hypertensive, be on a stable medical regimen with no significant changes over the past 30 days.
  • Female of child bearing potential with a negative pregnancy test, or post-menopausal for at least 2 years
  • The patient is an appropriate study candidate as determined by the Investigator on the basis of medical history and physical examination

Exclusion Criteria:

  • Emergent revascularization
  • Previous stroke or thrombo-embolic event in the 3 months prior to study entry
  • A previous myocardial infarction within the last 7 days
  • Documented coagulopathy
  • Hepatic dysfunction as defined by aspartate transaminase (AST) or alanine transaminase (ALT) > 1.5 times the upper limit of normal
  • Patient is pregnant or breastfeeding

Sites / Locations

  • Ralph H. Johnson VA Medical Center, Charleston, SC

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Experimental

Arm Label

Vehicle

ET-ARA 1mg/kg

ET-ARA 2mg/kg

Arm Description

Vehicle Group

ET-ARA 1 mg/kg

ET-ARA 2 mg/kg

Outcomes

Primary Outcome Measures

Pulmonary Vascular Resistance
Pulmonary Vascular Resistance (d.s.cm-5)

Secondary Outcome Measures

Plasma Endothelin-1
Plasma Endothelin-1 (fmol/mL)

Full Information

First Posted
August 27, 2008
Last Updated
November 7, 2017
Sponsor
VA Office of Research and Development
Collaborators
Medical University of South Carolina
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1. Study Identification

Unique Protocol Identification Number
NCT00744211
Brief Title
Proteolytic Enzyme Induction Within the Human Myocardial Interstitium
Official Title
Proteolytic Enzyme Induction Within the Human Myocardial Interstitium
Study Type
Interventional

2. Study Status

Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
July 2008 (undefined)
Primary Completion Date
June 2011 (Actual)
Study Completion Date
April 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development
Collaborators
Medical University of South Carolina

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A robust release of endothelin-1-1 (ET) with subsequent ETA subtype receptor (ET-AR) activation occurs in patients following cardiac surgery requiring cardiopulmonary bypass (CPB). Increased ET-AR activation has been identified in patients with poor left ventricular (LV) function (reduced ejection fraction; EF). Accordingly, this study tested the hypothesis that a selective ET-AR antagonist (ET-ARA) administered peri-operatively would favorably affect post-CPB hemodynamic profiles in patients with a pre-existing poor LVEF.
Detailed Description
Patients with a reduced LVEF were prospectively randomized, in a blinded fashion, at the time of elective coronary revascularization and/or valve replacement requiring CPB, to infusion of the highly-selective and potent ET-ARA, sitaxsentan at 1 or 2 mg/kg (IV bolus) or vehicle (saline). Infusion of the ET-ARA/vehicle was performed immediately prior to separation from CPB and again at 12 hrs post-CPB. ET and hemodynamic measurements were performed at baseline, at separation from CPB (Time 0) and at 0.5, 6, 12, 24 hrs post-CPB.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Disease

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vehicle
Arm Type
Placebo Comparator
Arm Description
Vehicle Group
Arm Title
ET-ARA 1mg/kg
Arm Type
Experimental
Arm Description
ET-ARA 1 mg/kg
Arm Title
ET-ARA 2mg/kg
Arm Type
Experimental
Arm Description
ET-ARA 2 mg/kg
Intervention Type
Drug
Intervention Name(s)
1mg/kg sitaxsentan sodium
Other Intervention Name(s)
TBC11251Na
Intervention Description
1mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.
Intervention Type
Drug
Intervention Name(s)
2mg/kg sitaxsentan sodium
Other Intervention Name(s)
TBC11251Na
Intervention Description
2mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.
Intervention Type
Other
Intervention Name(s)
Vehicle
Other Intervention Name(s)
Saline
Intervention Description
Intravenous bolus performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.
Primary Outcome Measure Information:
Title
Pulmonary Vascular Resistance
Description
Pulmonary Vascular Resistance (d.s.cm-5)
Time Frame
Baseline, 0, 6, 12 and 24 hours post-cardiopulmonary bypass (CPB)
Secondary Outcome Measure Information:
Title
Plasma Endothelin-1
Description
Plasma Endothelin-1 (fmol/mL)
Time Frame
Baseline, 0, 6, 12 and 24 hours post-CPB
Other Pre-specified Outcome Measures:
Title
Sitaxsentan Levels
Description
Sitaxsentan levels (microg/mL)
Time Frame
0, 6, 12 and 24 hours post-CPB
Title
Number of Other Adverse Events By Type
Description
Other (non-serious) Adverse Events (reported by arm/group)
Time Frame
up to 24-hours post-CPB

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: >60 years of age Body mass index <40 kg/m2 Left ventricular ejection fraction less than or equal to 50% documented by a pre-operative echocardiogram Patients undergoing coronary artery bypass (CABG), aortic and/or mitral valve replacement or combined CABG and valve procedures requiring CPB. If diabetic, be under proper control, (fasting glucose <350 mg/dL or recent hemoglobin A1c [HgbA1c] <9%). If hypertensive, be on a stable medical regimen with no significant changes over the past 30 days. Female of child bearing potential with a negative pregnancy test, or post-menopausal for at least 2 years The patient is an appropriate study candidate as determined by the Investigator on the basis of medical history and physical examination Exclusion Criteria: Emergent revascularization Previous stroke or thrombo-embolic event in the 3 months prior to study entry A previous myocardial infarction within the last 7 days Documented coagulopathy Hepatic dysfunction as defined by aspartate transaminase (AST) or alanine transaminase (ALT) > 1.5 times the upper limit of normal Patient is pregnant or breastfeeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francis Spinale, MD PhD
Organizational Affiliation
Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ralph H. Johnson VA Medical Center, Charleston, SC
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29401-5799
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
18824748
Citation
Spinale FG, Koval CN, Deschamps AM, Stroud RE, Ikonomidis JS. Dynamic changes in matrix metalloprotienase activity within the human myocardial interstitium during myocardial arrest and reperfusion. Circulation. 2008 Sep 30;118(14 Suppl):S16-23. doi: 10.1161/CIRCULATIONAHA.108.786640.
Results Reference
result
PubMed Identifier
19049753
Citation
Ford RL, Mains IM, Hilton EJ, Reeves ST, Stroud RE, Crawford FA Jr, Ikonomidis JS, Spinale FG. Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation. Ann Thorac Surg. 2008 Nov;86(5):1576-83. doi: 10.1016/j.athoracsur.2008.06.076.
Results Reference
result
PubMed Identifier
20074751
Citation
Toole JM, Ikonomidis JS, Szeto WY, Zellner JL, Mulcahy J, Deardorff RL, Spinale FG. Selective endothelin-1 receptor type A inhibition in subjects undergoing cardiac surgery with preexisting left ventricular dysfunction: Influence on early postoperative hemodynamics. J Thorac Cardiovasc Surg. 2010 Mar;139(3):646-54. doi: 10.1016/j.jtcvs.2009.11.046. Epub 2010 Jan 13.
Results Reference
result

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Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

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