Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

NCT00744211 | Completed Results DMC

• 1 other identifier: SURG-001-07F
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

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.

Conditions

Heart Disease

Outcome Measures

Primary Outcomes (1)

• Pulmonary Vascular Resistance

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

  Baseline, 0, 6, 12 and 24 hours post-cardiopulmonary bypass (CPB)

Secondary Outcomes (1)

• Plasma Endothelin-1

  Baseline, 0, 6, 12 and 24 hours post-CPB

Other Outcomes (2)

• Sitaxsentan Levels

  0, 6, 12 and 24 hours post-CPB

• Number of Other Adverse Events By Type

  up to 24-hours post-CPB

Study Arms (3)

Vehicle

PLACEBO COMPARATOR

Vehicle Group

Other: Vehicle

ET-ARA 1mg/kg

EXPERIMENTAL

ET-ARA 1 mg/kg

Drug: 1mg/kg sitaxsentan sodium

ET-ARA 2mg/kg

EXPERIMENTAL

ET-ARA 2 mg/kg

Drug: 2mg/kg sitaxsentan sodium

Interventions

1mg/kg sitaxsentan sodium DRUG

1mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

Also known as: TBC11251Na

ET-ARA 1mg/kg

2mg/kg sitaxsentan sodium DRUG

2mg/kg sitaxsentan sodium (intravenous bolus) performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

Also known as: TBC11251Na

ET-ARA 2mg/kg

Vehicle OTHER

Intravenous bolus performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass.

Also known as: Saline

Vehicle

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \>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

You may not qualify if:

• 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

Sponsors & Collaborators

• VA Office of Research and Development: lead
• Medical University of South Carolina: collaborator

Study Sites (1)

Ralph H. Johnson VA Medical Center, Charleston, SC

Charleston, South Carolina, 29401-5799, United States

Location

Related Publications (3)

• 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.

  PMID: 18824748 RESULT

• 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.

  PMID: 19049753 RESULT

• 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.

  PMID: 20074751 RESULT

MeSH Terms

Conditions

Heart Diseases

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

Small sample size, which in turn can result in a disproportionate number of patients with greater pre-operative risk profiles randomized to one treatment group.

Results Point of Contact

• Title: Francis G. Spinale
• Organization: University of South Carolina SOM

cvctrc@uscmed.sc.edu

803-777-3964

Study Officials

• Francis Spinale, MD PhD

  Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2008
• First Posted: August 29, 2008
• Study Start: July 1, 2008
• Primary Completion: June 1, 2011
• Study Completion: April 1, 2013
• Last Updated: November 9, 2017
• Results First Posted: November 9, 2017

Record last verified: 2017-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)