Not provided
Not provided
Not provided
Not provided
Not provided
DSMB recommended termination based on interim outcomes analysis
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| American Heart Association | OTHER |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The staged surgical pathway to treat children with single ventricle heart defects culminates with the Fontan operation. In this procedure, systemic venous return is rerouted directly to the pulmonary arteries, which serves to separate the systemic and pulmonary circulations. Although mortality following the Fontan operation is now uncommon, early postoperative morbidity including prolonged postoperative chest tube drainage and hospitalization remains significant. The efficacy of empiric inotropic, vasodilator and neurohumoral-inhibitory therapies in the perioperative period is unknown and practice varies widely between centers.
The investigators will propose a single-center, randomized, double-blind, phase II clinical trial in children undergoing Fontan surgery. The investigators plan to compare the effects of perioperative nesiritide, milrinone and placebo infusions on the early postoperative clinical course and neurohumoral profile. The investigators hypothesize that, when compared to the milrinone and placebo groups, the nesiritide group will have more days alive and out of the hospital within the first 30 days after surgery.
The staged surgical pathway to treat children with single ventricle heart defects culminates with the Fontan operation. In this procedure, systemic venous return is rerouted directly to the pulmonary arteries, which serves to separate the systemic and pulmonary circulations. Following this operation, deoxygenated blood flows passively from the body through the lungs without a pumping chamber. Although mortality following the Fontan operation is now uncommon, early postoperative morbidity including prolonged postoperative chest tube drainage and hospitalization remains significant. The efficacy of empiric inotropic, vasodilator and neurohumoral-inhibitory therapies in the perioperative period is unknown and practice varies widely between centers.
We propose a single-center, randomized, double-blind, phase II clinical trial in children undergoing Fontan surgery. We plan to compare the effects of perioperative nesiritide, milrinone and placebo infusions on the early postoperative clinical course and neurohumoral profile. The primary aim of the study is to determine whether nesiritide, milrinone or placebo infusion is associated with fewer days alive and out of the hospital within 30 days of surgery. We hypothesize that, when compared to the milrinone and placebo groups, the nesiritide group will have more days alive and out of the hospital within the first 30 days after surgery. Secondary aims are to determine the effects of these infusions on postoperative resource consumption, hemodynamics, arrhythmias, renal function, neurohumoral activation and adverse events. Thirty-nine patients per group (117 total patients) will be enrolled over three years.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| I- nesiritide | Experimental | Patients assigned to the nesiritide group will receive an intravenous loading dose of 2 mcg/kg followed by an infusion of 0.015 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. |
|
| II- Milrinone | Active Comparator | Patients assigned to the milrinone group will receive a bolus of 50 mcg/kg followed by an infusion of 0.5 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. |
|
| III- placebo | Placebo Comparator | Patients assigned to the placebo group will receive a 0.33 mL/kg bolus of 5% dextrose in water (D5W), followed by an infusion of D5W, administered for at least 12 hours after CICU admission and up to five days, unless prespecified lack of efficacy criteria are met. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| nesiritide | Drug | Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted |
|
| Measure | Description | Time Frame |
|---|---|---|
| Days Alive and Out of the Hospital Within 30 Days of Surgery. | 30 days |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiovascular: Cardiac Index | Cardiac index measured using Fick principle with measured oxygen consumption. | Postoperative hour #1 |
| Cardiovascular: Cardiac Index | Cardiac index measured using Fick principle with measured oxygen consumption. |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| John M Costello, MD MPH | Boston Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital Boston | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24906491 | Result | Costello JM, Dunbar-Masterson C, Allan CK, Gauvreau K, Newburger JW, McGowan FX Jr, Wessel DL, Mayer JE Jr, Salvin JW, Dionne RE, Laussen PC. Impact of empiric nesiritide or milrinone infusion on early postoperative recovery after Fontan surgery: a randomized, double-blind, placebo-controlled trial. Circ Heart Fail. 2014 Jul;7(4):596-604. doi: 10.1161/CIRCHEARTFAILURE.113.001312. Epub 2014 Jun 6. |
Not provided
Not provided
email the PI for data requests.
Not provided
Not provided
Not provided
Not provided
Not provided
Recruitment period: October 2007 - January 2013.
Location: Cardiac operating rooms and cardiac intensive care unit (CICU) at Boston Children's Hospital
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | I- Nesiritide | Patients assigned to the nesiritide group will receive an intravenous loading dose of 2 mcg/kg followed by an infusion of 0.015 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. nesiritide: Nesiritide bolus 2 mcg/kg on cardiopulmonary bypass (CPB), then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted |
| FG001 | II- Milrinone | Patients assigned to the milrinone group will receive a bolus of 50 mcg/kg followed by an infusion of 0.5 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. milrinone: Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted |
| FG002 | III- Placebo | Patients assigned to the placebo group will receive a 0.33 mL/kg bolus of 5% dextrose in water (D5W), followed by an infusion of D5W, administered for at least 12 hours after CICU admission and up to five days, unless prespecified lack of efficacy criteria are met. placebo: Placebo bolus on CPB, then placebo infusion |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | I- Nesiritide | Patients assigned to the nesiritide group will receive an intravenous loading dose of 2 mcg/kg followed by an infusion of 0.015 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. nesiritide: Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Days Alive and Out of the Hospital Within 30 Days of Surgery. | Posted | Median | Full Range | days | 30 days |
|
Not provided
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | I- Nesiritide | Patients assigned to the nesiritide group will receive an intravenous loading dose of 2 mcg/kg followed by an infusion of 0.015 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. nesiritide: Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension | Cardiac disorders | Systematic Assessment |
Single center design limits generalizability of findings. Study drug doses were extrapolated from published experience in other patient types. Study may have been underpowered to detect differences among treatment groups for secondary outcomes.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John M. Costello, M.D., M.P.H. | Ann & Robert H. Lurie Children's Hospital of Chicago | 312 227 1551 | jmcostello@luriechildrens.org |
Not provided
| ID | Term |
|---|---|
| D006330 | Heart Defects, Congenital |
| ID | Term |
|---|---|
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
Not provided
Not provided
| ID | Term |
|---|---|
| D020097 | Natriuretic Peptide, Brain |
| D020105 | Milrinone |
| ID | Term |
|---|---|
| D045265 | Natriuretic Peptides |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| milrinone | Drug | Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted |
|
|
| placebo | Drug | Placebo bolus on CPB, then placebo infusion |
|
| Postoperative hour #8 |
| Cardiovascular: Arrhythmia | arrhythmia lasting >30 seconds or requiring treatment | Postoperative day (POD) #0 through 5 |
| Cardiovascular: Peak Inotrope Score | Peak Inotrope Score = Doses of dopamine in mcg/kg/minute + dobutamine in mcg/kg/minute + (epinephrine in mcg/kg/minute x 100). The lowest (best) possible Peak Inotrope Score = 0 dose equivalents. There is no maximum Peak Inotrope Score. | Initial 24 hours in CICU |
| Cardiovascular: Peak Lactate Level | Initial 24 hours in CICU |
| Renal Function: Urine Output | Volume of urine in mL/kg per day | first 24 hours CICU admit |
| Renal Function: Maximum Change in Serum Creatinine | 14 days after surgery |
| Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation | Hours of mechanical ventilation until initial extubation following the Fontan operation. | From Fontan operation until initial extubation, assessed during initial CICU stay, up to 30 days. |
| Resource Utilization: Days of Initial CICU Stay | Days of initial postoperative CICU care following the Fontan operation. | From Fontan operation until initial discharge from the CICU, assessed during the postoperative hospitalization, up to 90 days. |
| Resource Utilization: Chest Tube Days | Days during which one or more chest tubes were in place following the Fontan operation. | From Fontan operation until final chest tube removed, assessed during postoperative hospitalization, up to 90 days. |
| Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery | Days the patient was alive and out of hospital within the 180 days after Fontan surgery | 180 days |
| Plasma Norepinephrine Levels. | Plasma norepinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Preoperative baseline to 24 hours after CICU admission |
| Epinephrine Levels | Plasma epinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Preoperative baseline to 24 hours after CICU admission |
| N-terminal Pro-brain Natriuretic Peptide Levels | N-terminal pro-brain natriuretic peptide levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Preoperative baseline to 24 hours after CICU admission |
| BG001 | II- Milrinone | Patients assigned to the milrinone group will receive a bolus of 50 mcg/kg followed by an infusion of 0.5 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. milrinone: Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted |
| BG002 | III- Placebo | Patients assigned to the placebo group will receive a 0.33 mL/kg bolus of 5% dextrose in water (D5W), followed by an infusion of D5W, administered for at least 12 hours after CICU admission and up to five days, unless prespecified lack of efficacy criteria are met. placebo: Placebo bolus on CPB, then placebo infusion |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Weight | Median | Full Range | kilograms |
|
| Ventricular Morphology | Count of Participants | Participants |
|
| Prior Cardiac Operations | Median | Full Range | operations |
|
| Prior Interventional Cardiac Catheterization | Count of Participants | Participants |
|
| History of Arrhythmias | Count of Participants | Participants |
|
| Noncardiac congenital anomaly | Count of Participants | Participants |
|
| Chromosomal abnormality or syndrome | Count of Participants | Participants |
|
| OG002 | III- Placebo | Patients assigned to the placebo group will receive a 0.33 mL/kg bolus of 5% dextrose in water (D5W), followed by an infusion of D5W, administered for at least 12 hours after CICU admission and up to five days, unless prespecified lack of efficacy criteria are met. placebo: Placebo bolus on CPB, then placebo infusion |
|
|
| Secondary | Cardiovascular: Cardiac Index | Cardiac index measured using Fick principle with measured oxygen consumption. | Study patients for whom cardiac index measurements were available. | Posted | Median | Full Range | L/min/m2 | Postoperative hour #1 |
|
|
|
| Secondary | Cardiovascular: Cardiac Index | Cardiac index measured using Fick principle with measured oxygen consumption. | Study patients for whom cardiac index measurements were available. | Posted | Median | Full Range | L/min/m2 | Postoperative hour #8 |
|
|
|
| Secondary | Cardiovascular: Arrhythmia | arrhythmia lasting >30 seconds or requiring treatment | Posted | Count of Participants | Participants | Postoperative day (POD) #0 through 5 |
|
|
|
| Secondary | Cardiovascular: Peak Inotrope Score | Peak Inotrope Score = Doses of dopamine in mcg/kg/minute + dobutamine in mcg/kg/minute + (epinephrine in mcg/kg/minute x 100). The lowest (best) possible Peak Inotrope Score = 0 dose equivalents. There is no maximum Peak Inotrope Score. | Posted | Median | Full Range | dose equivalents | Initial 24 hours in CICU |
|
|
|
| Secondary | Cardiovascular: Peak Lactate Level | Posted | Median | Full Range | mEq/liter | Initial 24 hours in CICU |
|
|
|
| Secondary | Renal Function: Urine Output | Volume of urine in mL/kg per day | Posted | Median | Full Range | mL/kg per day | first 24 hours CICU admit |
|
|
|
| Secondary | Renal Function: Maximum Change in Serum Creatinine | Posted | Median | Full Range | mg/dL | 14 days after surgery |
|
|
|
| Secondary | Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation | Hours of mechanical ventilation until initial extubation following the Fontan operation. | Posted | Median | Full Range | hours | From Fontan operation until initial extubation, assessed during initial CICU stay, up to 30 days. |
|
|
|
| Secondary | Resource Utilization: Days of Initial CICU Stay | Days of initial postoperative CICU care following the Fontan operation. | Posted | Median | Full Range | days | From Fontan operation until initial discharge from the CICU, assessed during the postoperative hospitalization, up to 90 days. |
|
|
|
| Secondary | Resource Utilization: Chest Tube Days | Days during which one or more chest tubes were in place following the Fontan operation. | Posted | Median | Full Range | days | From Fontan operation until final chest tube removed, assessed during postoperative hospitalization, up to 90 days. |
|
|
|
| Secondary | Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery | Days the patient was alive and out of hospital within the 180 days after Fontan surgery | Posted | Median | Full Range | days | 180 days |
|
|
|
| Secondary | Plasma Norepinephrine Levels. | Plasma norepinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Posted | Median | Full Range | ng/mL | Preoperative baseline to 24 hours after CICU admission |
|
|
|
| Secondary | Epinephrine Levels | Plasma epinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Posted | Median | Full Range | ng/mL | Preoperative baseline to 24 hours after CICU admission |
|
|
|
| Secondary | N-terminal Pro-brain Natriuretic Peptide Levels | N-terminal pro-brain natriuretic peptide levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Posted | Median | Full Range | fmol/mL | Preoperative baseline to 24 hours after CICU admission |
|
|
|
| 1 |
| 35 |
| 0 |
| 35 |
| 24 |
| 35 |
| EG001 | II- Milrinone | Patients assigned to the milrinone group will receive a bolus of 50 mcg/kg followed by an infusion of 0.5 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. milrinone: Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted | 0 | 36 | 0 | 36 | 27 | 36 |
| EG002 | III- Placebo | Patients assigned to the placebo group will receive a 0.33 mL/kg bolus of 5% dextrose in water (D5W), followed by an infusion of D5W, administered for at least 12 hours after CICU admission and up to five days, unless prespecified lack of efficacy criteria are met. placebo: Placebo bolus on CPB, then placebo infusion | 0 | 35 | 0 | 35 | 24 | 35 |
| Acute renal insufficiency | Renal and urinary disorders | Systematic Assessment | >= three-fold increase in serum creatinine c/w baseline or dialysis |
|
Not provided
Not provided
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D000676 | Amrinone |
| D000631 | Aminopyridines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
|
| 8 hours after CICU admit |
|
| 24 hours after CICU admit |
|
|
| 8 hours after CICU admit |
|
| 24 hours after CICU admit |
|
|
| 8 hours after CICU admit |
|
| 24 hours after CICU admit |
|