Heart Defects, CongenitalPhase 2NCT00543309
Effects of Perioperative Nesiritide or Milrinone Infusion on Recovery From Fontan Surgery
A Phase 2 study testing nesiritide and milrinone in people with Heart Defects, Congenital, run by John M Costello at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Heart Defects, Congenital
- What is being tested?
- nesiritide and milrinone
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 106 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2007to Jul 2013
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients undergoing an elective, primary Fontan operation at Children's Hospital Boston.
Who cannot join
- Revision surgery for failing Fontan circulation.
- Preoperative serum creatinine > 1.5 mg/dL or chronic dialysis.
- The attending surgeon, cardiac anesthesiologist, or cardiac intensivist has a compelling indication to initiate either nesiritide or milrinone outside of the confines of the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital Boston
Boston, Massachusetts, 02115
About this study
Official title: Impact of Empiric Nesiritide or Milrinone Infusion on Early Postoperative Recovery Following Fontan Surgery: a Randomized, Double-blind, Placebo-controlled Clinical Trial
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.
Read the detailed description
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.
- Conditions
- Heart Defects, Congenital
- Being tested
- nesiritide, milrinone, placebo
- Keywords
- Fontan Operation, Cardiopulmonary Bypass, Heart Defects, Congenital, Milrinone, Natriuretic peptide, brain
- Medical subject headings
- Heart Defects, Congenital
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
nesiritideDrug
Also called Natrecor
Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted
milrinoneDrug
Also called Primacor
Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted
placeboDrug
Placebo bolus on CPB, then placebo infusion
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: nesiritide |
| 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. Receives: Drug: milrinone |
| 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. Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Days Alive and Out of the Hospital Within 30 Days of Surgery.
Measured: 30 days
Secondary outcomes (14)
Cardiovascular: Cardiac Index
Cardiac index measured using Fick principle with measured oxygen consumption.
Measured: Postoperative hour #1
Cardiovascular: Cardiac Index
Cardiac index measured using Fick principle with measured oxygen consumption.
Measured: Postoperative hour #8
Cardiovascular: Arrhythmia
arrhythmia lasting >30 seconds or requiring treatment
Measured: 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.
Measured: Initial 24 hours in CICU
Cardiovascular: Peak Lactate Level
Measured: Initial 24 hours in CICU
Renal Function: Urine Output
Volume of urine in mL/kg per day
Measured: first 24 hours CICU admit
Renal Function: Maximum Change in Serum Creatinine
Measured: 14 days after surgery
Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation
Hours of mechanical ventilation until initial extubation following the Fontan operation.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 180 days
Plasma Norepinephrine Levels.
Plasma norepinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.
Measured: Preoperative baseline to 24 hours after CICU admission
Epinephrine Levels
Plasma epinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.
Measured: 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.
Measured: Preoperative baseline to 24 hours after CICU admission
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Oct 2007 (estimated)
- Study startOct 2007
- Primary completionJan 2013
- Study completionJul 2013
Why it stopped: DSMB recommended termination based on interim outcomes analysis
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart Defects, CongenitalStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 106 participants (actual)
Sponsor and investigators
- Lead sponsor
- John M Costello
- Sponsor type
- University, hospital or other
- Collaborators
- American Heart Association
- Responsible party
- Sponsor-investigator, John M Costello, Boston Children's Hospital
- Investigators
- John M Costello, MD MPH, Principal investigator, Boston Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00543309
- Sponsor's protocol ID
- 0735070N
- Status last verified
- May 2018
- First submitted
- 10 Oct 2007
- Last updated
- 25 Jun 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided: email the PI for data requests.
Publications
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.
PubMed 24906491
Study at a glance
From the registry record, last updated by the sponsor on 25 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Empiric Nesiritide or Milrinone Infusion on Early Postoperative Recovery Following Fontan Surgery: a Randomized, Double-blind, Placebo-controlled Clinical Trial
- ClinicalTrials.gov ID
- NCT00543309
- Acronym / sponsor ID
- 0735070N
- Conditions
- Heart Defects, Congenital
- Keywords
- Fontan Operation, Cardiopulmonary Bypass, Heart Defects, Congenital, Milrinone, Natriuretic peptide, brain
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: DSMB recommended termination based on interim outcomes analysis
- Enrolment
- 106 participants (actual)
- Lead sponsor
- John M CostelloUniversity, hospital or other
- Collaborators
- American Heart Association
- Study start
- Oct 2007
- Primary completion
- Jan 2013 (actual)
- Study completion
- Jul 2013 (actual)
- First posted
- 12 Oct 2007 (estimated)
- Results
- Posted 25 Jun 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| I- nesiritide | Experimental | Drug: nesiritidePatients 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 | Drug: milrinonePatients 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 | Drug: placeboPatients 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- Patients undergoing an elective, primary Fontan operation at Children's Hospital Boston.
Key exclusion criteria (3 listed)
- Revision surgery for failing Fontan circulation.
- Preoperative serum creatinine > 1.5 mg/dL or chronic dialysis.
- The attending surgeon, cardiac anesthesiologist, or cardiac intensivist has a compelling indication to initiate either nesiritide or milrinone outside of the confines of the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| nesiritideAlso: NatrecorNesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted | Drug | I- nesiritide |
| milrinoneAlso: PrimacorMilrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted | Drug | II- Milrinone |
| placeboPlacebo bolus on CPB, then placebo infusion | Drug | III- placebo |
Primary outcome
Days Alive and Out of the Hospital Within 30 Days of Surgery.
Time frame: 30 days
14 secondary outcomes
Cardiovascular: Cardiac Index
Time frame: Postoperative hour #1
Cardiovascular: Cardiac Index
Time frame: Postoperative hour #8
Cardiovascular: Arrhythmia
Time frame: Postoperative day (POD) #0 through 5
Cardiovascular: Peak Inotrope Score
Time frame: Initial 24 hours in CICU
Cardiovascular: Peak Lactate Level
Time frame: Initial 24 hours in CICU
Renal Function: Urine Output
Time frame: first 24 hours CICU admit
Renal Function: Maximum Change in Serum Creatinine
Time frame: 14 days after surgery
Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation
Time frame: From Fontan operation until initial extubation, assessed during initial CICU stay, up to 30 days.
Resource Utilization: Days of Initial CICU Stay
Time frame: From Fontan operation until initial discharge from the CICU, assessed during the postoperative hospitalization, up to 90 days.
Resource Utilization: Chest Tube Days
Time frame: 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
Time frame: 180 days
Plasma Norepinephrine Levels.
Time frame: Preoperative baseline to 24 hours after CICU admission
Epinephrine Levels
Time frame: Preoperative baseline to 24 hours after CICU admission
N-terminal Pro-brain Natriuretic Peptide Levels
Time frame: Preoperative baseline to 24 hours after CICU admission
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jun 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 24906491Costello 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.
- Individual participant dataSharing planned: Undecided. email the PI for data requests.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John M Costello, MD MPH principal investigator
Boston Children's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing nesiritide and milrinone in people with Heart Defects, Congenital, run by John M Costello at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Jun 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Days Alive and Out of the Hospital Within 30 Days of Surgery. (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00543309, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jun 2018.