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Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Status
Completed
Phases
Unknown
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00744211
Enrollment
29
Registered
2008-08-29
Start date
2008-07-01
Completion date
2013-04-01
Last updated
2026-08-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Disease

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.

Interventions

DRUG1mg/kg sitaxsentan sodium

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

DRUG2mg/kg sitaxsentan sodium

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

OTHERVehicle

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

Sponsors

VA Office of Research and Development
Lead SponsorFED
Medical University of South Carolina
CollaboratorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Pulmonary Vascular ResistanceBaseline, 0, 6, 12 and 24 hours post-cardiopulmonary bypass (CPB)Pulmonary Vascular Resistance (d.s.cm-5)

Secondary

MeasureTime frameDescription
Plasma Endothelin-1Baseline, 0, 6, 12 and 24 hours post-CPBPlasma Endothelin-1 (fmol/mL)

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORFrancis Spinale, MD PhD

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

Participant flow

Recruitment details

Prospective randomization in a blinded fashion, at the time of elective coronary revascularization or valve replacement requiring cardiopulmonary bypass.

Participants by arm

ArmCount
Vehicle
Saline, intravenous bolus
10
ET-ARA 1mg/kg
1mg/kg sitaxsentan sodium
9
ET-ARA 2mg/kg
2mg/kg sitaxsentan sodium
10
Total29

Baseline characteristics

CharacteristicVehicleET-ARA 1mg/kgET-ARA 2mg/kgTotal
Age, Continuous67 years
STANDARD_DEVIATION 2
62 years
STANDARD_DEVIATION 3
68 years
STANDARD_DEVIATION 3
66 years
STANDARD_DEVIATION 2
Left Ventricular Ejection Fraction (LVEF)35 percent
STANDARD_DEVIATION 3
38 percent
STANDARD_DEVIATION 2
37 percent
STANDARD_DEVIATION 3
37 percent
STANDARD_DEVIATION 2
Plasma Endothelin3.9 fmol/mL
STANDARD_DEVIATION 0.4
3.7 fmol/mL
STANDARD_DEVIATION 0.3
4.3 fmol/mL
STANDARD_DEVIATION 0.7
4.0 fmol/mL
STANDARD_DEVIATION 0.3
Pulmonary vascular resistance153.8 dyne*second/centimeter˄5
STANDARD_DEVIATION 19.9
213.0 dyne*second/centimeter˄5
STANDARD_DEVIATION 65.3
174.6 dyne*second/centimeter˄5
STANDARD_DEVIATION 28.4
180 dyne*second/centimeter˄5
STANDARD_DEVIATION 23
Sex: Female, Male
Female
1 Participants2 Participants0 Participants3 Participants
Sex: Female, Male
Male
9 Participants7 Participants10 Participants26 Participants
Systemic vascular resistance1408 dyne*second/centimeter˄5
STANDARD_DEVIATION 119
1359 dyne*second/centimeter˄5
STANDARD_DEVIATION 210
1307 dyne*second/centimeter˄5
STANDARD_DEVIATION 112
1358 dyne*second/centimeter˄5
STANDARD_DEVIATION 83

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
other
Total, other adverse events
0 / 00 / 00 / 0
serious
Total, serious adverse events
6 / 106 / 96 / 10

Outcome results

Primary

Pulmonary Vascular Resistance

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

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

ArmMeasureGroupValue (MEAN)Dispersion
VehiclePulmonary Vascular ResistanceBaseline153.8 dyne*second/centimeter˄5Standard Deviation 19.9
VehiclePulmonary Vascular Resistance0 hours post-CPB123.5 dyne*second/centimeter˄5Standard Deviation 20.7
VehiclePulmonary Vascular Resistance6 hours post-CPB138.7 dyne*second/centimeter˄5Standard Deviation 28
VehiclePulmonary Vascular Resistance12 hours post-CPB146.8 dyne*second/centimeter˄5Standard Deviation 21.6
VehiclePulmonary Vascular Resistance24 hours post-CPB163.3 dyne*second/centimeter˄5Standard Deviation 26.6
1mg/kg ET-ARAPulmonary Vascular Resistance12 hours post-CPB132.7 dyne*second/centimeter˄5Standard Deviation 12.7
1mg/kg ET-ARAPulmonary Vascular Resistance24 hours post-CPB125.5 dyne*second/centimeter˄5Standard Deviation 22.3
1mg/kg ET-ARAPulmonary Vascular Resistance0 hours post-CPB125.3 dyne*second/centimeter˄5Standard Deviation 24.8
1mg/kg ET-ARAPulmonary Vascular ResistanceBaseline213.0 dyne*second/centimeter˄5Standard Deviation 65.3
1mg/kg ET-ARAPulmonary Vascular Resistance6 hours post-CPB144.6 dyne*second/centimeter˄5Standard Deviation 15.2
2mg/kg ET-ARAPulmonary Vascular Resistance24 hours post-CPB138.7 dyne*second/centimeter˄5Standard Deviation 20
2mg/kg ET-ARAPulmonary Vascular Resistance6 hours post-CPB132.7 dyne*second/centimeter˄5Standard Deviation 17.6
2mg/kg ET-ARAPulmonary Vascular Resistance12 hours post-CPB136.6 dyne*second/centimeter˄5Standard Deviation 17.5
2mg/kg ET-ARAPulmonary Vascular ResistanceBaseline174.6 dyne*second/centimeter˄5Standard Deviation 28.4
2mg/kg ET-ARAPulmonary Vascular Resistance0 hours post-CPB175.8 dyne*second/centimeter˄5Standard Deviation 26.6
p-value: <0.05ANOVA
Secondary

Plasma Endothelin-1

Plasma Endothelin-1 (fmol/mL)

Time frame: Baseline, 0, 6, 12 and 24 hours post-CPB

ArmMeasureGroupValue (MEAN)Dispersion
VehiclePlasma Endothelin-112 hours post-CPB8.6 fmol/mLStandard Deviation 1.1
VehiclePlasma Endothelin-16 hours post-CPB8.2 fmol/mLStandard Deviation 1.1
VehiclePlasma Endothelin-1Baseline3.9 fmol/mLStandard Deviation 0.4
VehiclePlasma Endothelin-10 hours post-CPB5.5 fmol/mLStandard Deviation 0.8
VehiclePlasma Endothelin-124 hours post-CPB8.0 fmol/mLStandard Deviation 1
1mg/kg ET-ARAPlasma Endothelin-16 hours post-CPB7.2 fmol/mLStandard Deviation 1.3
1mg/kg ET-ARAPlasma Endothelin-1Baseline3.7 fmol/mLStandard Deviation 0.3
1mg/kg ET-ARAPlasma Endothelin-10 hours post-CPB4.7 fmol/mLStandard Deviation 0.5
1mg/kg ET-ARAPlasma Endothelin-112 hours post-CPB8.8 fmol/mLStandard Deviation 1.7
1mg/kg ET-ARAPlasma Endothelin-124 hours post-CPB8.3 fmol/mLStandard Deviation 1
2mg/kg ET-ARAPlasma Endothelin-124 hours post-CPB8.6 fmol/mLStandard Deviation 1.4
2mg/kg ET-ARAPlasma Endothelin-112 hours post-CPB10.4 fmol/mLStandard Deviation 1.6
2mg/kg ET-ARAPlasma Endothelin-1Baseline4.3 fmol/mLStandard Deviation 0.7
2mg/kg ET-ARAPlasma Endothelin-16 hours post-CPB7.6 fmol/mLStandard Deviation 1.2
2mg/kg ET-ARAPlasma Endothelin-10 hours post-CPB4.1 fmol/mLStandard Deviation 0.5
p-value: 0.001ANOVA
Other Pre-specified

Number of Other Adverse Events By Type

Other (non-serious) Adverse Events (reported by arm/group)

Time frame: up to 24-hours post-CPB

ArmMeasureGroupValue (NUMBER)
VehicleNumber of Other Adverse Events By TypeCardiovascular12 events
VehicleNumber of Other Adverse Events By TypeNeurological2 events
VehicleNumber of Other Adverse Events By TypePsychological/Behavioral3 events
VehicleNumber of Other Adverse Events By TypeFever0 events
VehicleNumber of Other Adverse Events By TypeUrinary2 events
VehicleNumber of Other Adverse Events By TypeEndocrine/Metabolic1 events
VehicleNumber of Other Adverse Events By TypeHEENT1 events
VehicleNumber of Other Adverse Events By TypeGastrointestinal9 events
VehicleNumber of Other Adverse Events By TypePulmonary3 events
VehicleNumber of Other Adverse Events By TypeDermatological0 events
VehicleNumber of Other Adverse Events By TypeHepatic0 events
VehicleNumber of Other Adverse Events By TypeImmunological/Allergic0 events
VehicleNumber of Other Adverse Events By TypeHematological/Lymphatic1 events
VehicleNumber of Other Adverse Events By TypeMusculoskeletal1 events
VehicleNumber of Other Adverse Events By TypeInfection3 events
VehicleNumber of Other Adverse Events By TypeGenitourinary/Gynecological0 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeImmunological/Allergic1 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeGenitourinary/Gynecological0 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeEndocrine/Metabolic1 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeCardiovascular20 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeInfection0 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeFever3 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeDermatological3 events
1mg/kg ET-ARANumber of Other Adverse Events By TypePulmonary4 events
1mg/kg ET-ARANumber of Other Adverse Events By TypePsychological/Behavioral4 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeNeurological0 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeHematological/Lymphatic4 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeUrinary0 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeGastrointestinal8 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeHEENT0 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeHepatic3 events
1mg/kg ET-ARANumber of Other Adverse Events By TypeMusculoskeletal7 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeDermatological2 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeHematological/Lymphatic10 events
2mg/kg ET-ARANumber of Other Adverse Events By TypePsychological/Behavioral7 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeHEENT0 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeCardiovascular17 events
2mg/kg ET-ARANumber of Other Adverse Events By TypePulmonary8 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeNeurological0 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeUrinary3 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeGastrointestinal8 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeHepatic1 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeMusculoskeletal5 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeGenitourinary/Gynecological0 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeEndocrine/Metabolic5 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeInfection2 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeFever4 events
2mg/kg ET-ARANumber of Other Adverse Events By TypeImmunological/Allergic0 events
p-value: 0.015Chi-squared
Other Pre-specified

Sitaxsentan Levels

Sitaxsentan levels (microg/mL)

Time frame: 0, 6, 12 and 24 hours post-CPB

ArmMeasureGroupValue (MEAN)Dispersion
VehicleSitaxsentan Levels0 hours post-CPB7.35 microg/mLStandard Deviation 0.83
VehicleSitaxsentan Levels6 hours post-CPB0.06 microg/mLStandard Deviation 0.01
VehicleSitaxsentan Levels12 hours post-CPB1.88 microg/mLStandard Deviation 1.26
VehicleSitaxsentan Levels24 hours post-CPB0.06 microg/mLStandard Deviation 0.01
1mg/kg ET-ARASitaxsentan Levels24 hours post-CPB0.09 microg/mLStandard Deviation 0.01
1mg/kg ET-ARASitaxsentan Levels0 hours post-CPB11.78 microg/mLStandard Deviation 1.17
1mg/kg ET-ARASitaxsentan Levels12 hours post-CPB8.63 microg/mLStandard Deviation 3.24
1mg/kg ET-ARASitaxsentan Levels6 hours post-CPB2.24 microg/mLStandard Deviation 2.13
p-value: <0.05ANOVA

Source: ClinicalTrials.gov · Data processed: Aug 14, 2026