Low Cardiac Output SyndromePhase 1/2NCT01576094
Two Inodilators Postsurgery in Neonates
A Phase 1/2 study testing Milrinone and Levosimendan in people with Low Cardiac Output Syndrome, run by Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz at 1 site in Spain.
Trial summary
Congenital heart defects are the most prevalent group of congenital malformations in newborns. Surgery-related low cardiac output syndrome (LCOS) could be one of the reason for the unfavourable outcome of this population. Read more about this study
- Who is it for?
- Ages Up to 40 days
- Conditions the study is for
- Low Cardiac Output Syndrome
- What is being tested?
- Milrinone and Levosimendan
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteSpain
- Study dates
- Nov 2009to Nov 2010
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
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 Up to 40 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Newborns undergoing cardiovascular surgery who were in stable pre-operative haemodynamic condition
- Parental consent given
Who cannot join
- Parental consent refused
- Inodilators contraindicated
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase I Study of Two Inodilators in Neonates Undergoing Cardiovascular Surgery
Congenital heart defects are the most prevalent group of congenital malformations in newborns. Surgery-related low cardiac output syndrome (LCOS) could be one of the reason for the unfavourable outcome of this population. The early use of inodilators (INDs), specifically milrinone (MR), is proposed to reduce afterload and increase inotropism. Studies in the paediatric population appear to support a clinical usefulness of MR similar to that observed in adults. Levosimendan (LEVO) is a novel class IND developed for the treatment of heart failure. Experience with LEVO in paediatric patients is scarce. The purpose of this study was to systematically test the efficacy and safety of milrinone (MR) and levosimendan (LEVO) in newborns undergoing cardiovascular surgery with cardiopulmonary bypass (CPB). Given the uncertainty about LEVO pharmacokinetics in neonates, the study was designed as a pilot, phase I feasibility study.
Read the detailed description
Surgical repair is the primary therapy for congenital heart defects in the newborn. The neonatal cardiovascular system is at particular risk to develop the surgery-related low cardiac output syndrome (LCOS), thus vasoactive agents are routinely used in the postoperative management. Systematic research on the efficacy of these drugs is scarce in the newborn. As LCOS pathophysiology joints impaired myocardial contractility and the peripheral effects of ischemia/reperfusion injury on the endothelium, early use of inodilators (IND) are strongly recommended to reduce afterload and improve contractility. This study aims to test the equivalence in dose-dependent hemodynamic effects of 2 IND, Milrinone and Levosimendan, used early without loading dose in the preoperative period to prevent LCOS. By means of non-invasive technology the investigators will assess cardiac function (serial structural and functional echocardiography), the cerebral and peripheral perfusion and oxygenation (continuous near-infrared monitoring), cerebral function (continuous amplitude integrated EEG monitoring), will rule out CNS acquired lesions (serial transfontanelar echo-Doppler studies), and will follow up different biochemical markers of myocardial stress and apoptosis. Pharmacokinetic studies will be also performed.
- Conditions
- Low Cardiac Output Syndrome
- Being tested
- Milrinone, Levosimendan
- Keywords
- congenital heart disease
- Medical subject headings
- Cardiac Output, Low, Heart Defects, Congenital
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MilrinoneDrug
Also called cronotrope
Before surgery, patients received milrinone (MR) (milrinone lactate 1 mg/ml). Intravenous continuous infusion of the study drug through a separate central line started intraoperatively and was increased step-wise at predefined time points: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission providing the patient was in stable haemodynamic condition; dose 3, starting after 2 hours of stability with dose 2, and maintained up to 48 hours IND infusion started. Accordingly, patients randomised to MR received 0.5 , 0.75 and 1 microg/kg per min
LevosimendanDrug
Also called Simdax
Before surgery patients received levosimendan (levosimendan 2.5 mg/ml). Intravenous continuous infusion of the study drug through a separate central line started intraoperatively and was increased step-wise at predefined time points: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission providing the patient was in stable haemodynamic condition; dose 3, starting after 2 hours of stability with dose 2, and maintained up to 48 hours IND infusion started. Accordingly, patients randomised to LEVO received 0.1 , 0.15 and 0.2 microg/kg per min, for doses 1, 2 and 3, respectively.
| Study group | Role | What they receive |
|---|---|---|
| Milrinone | Active comparator | Milrinone (MR) lactate 1 mg/ml: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission; dose 3, after 2 hours of stability with dose 2, and maintained up to 48 hours. Accordingly, patients randomised to MR received 0.5 , 0.75 and 1 microg/kg per min Receives: Drug: Milrinone |
| Levosimendan | Active comparator | Not described Receives: Drug: Levosimendan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Perfusion-oxygenation
Changes in cerebral and thigh oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), total haemoglobin (THb) and tissue oxygenation index (TOI). The cerebral and peripheral intravascular oxygenation as c∆HbD was also assessed.
Measured: NIRS evaluation started immediately after surgery and was maintained during 24 h. At 48 h after surgery, a new NIRS evaluation during 4 hours. At 96 h post-surgery, during 4h.
Secondary outcomes (11)
Blood gases
Measured: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
Blood pressure
Measured: preoperative (baseline) to post-operative day 6.
temperature
central (axilla) and peripheral (foot) temperature
Measured: preoperative (baseline) to post-operative day 6.
arterial oxygen saturation
Measured: preoperative (baseline) to post-operative day 6.
cooximetry
Measured: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
lactate
Measured: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
glucose
Measured: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
haemoglobin concentration
Measured: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
Biochemical markers
Serum creatinine, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponine I (TnI) and proinflammatory and antinflammatory factors [interleukin (IL) beta 1, IL 6, IL 7, IL 8, IL 10, and tumor necrotic factor alpha
Measured: baseline, at 24h after surgery and on day 6 post-surgery
Inodilators concentration
Milrinone and Levosimendan plasma concentration
Measured: Basal, two hours after dose 2; and at 24 and 48h from the start of the IND infusion in infants receiving IND dose 3. Beyond that period (open study), daily samples were obtained for LEVO up to day 7 postsurgery, and at 10 and 14 days.
inotrope score
calculated according to Wernovsky
Measured: preoperative (baseline) and then one evaluation every 6 hours until 24 h post-surgery. At 48h post-surgery. At 96 h post-surgery.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2012 (estimated)
- Study startNov 2009
- Primary completionNov 2010
- Study completionNov 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Low Cardiac Output SyndromeStudies 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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
- Sponsor type
- University, hospital or other
- Collaborators
- Hospital Universitario La Paz, Fondo de Investigacion Sanitaria
- Responsible party
- Principal investigator, Adelina Pellicer, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
- Investigators
- Adelina Pellicer, PhD, Principal investigator, Dept. of Neonatology, La Paz University Hospital, MadridJoan Riera, MBE, Study chair, Bio-Engineer and Nanotechnology Dept., Polytechnic University of MadridPaloma López, MD, Study chair, Dept. of Neonatology, La Paz University Hospital, MadridMaría Carmen Bravo, PhD, Study chair, Dept. of Neonatology, La Paz University Hospital, MadridRosario Madero, MD, Study chair, Division of Biostatistics, La Paz University Hospital, MadridJesús Pérez-Rodríguez, PhD, Study chair, Dept. of Neonatology, La Paz University Hospital, MadridCarlos Labrandero, MD, Study chair, Dept. Paediatric Cardiology, La Paz University Hospital, MadridJosé Quero, PhD, Study chair, Dept. of Neonatology, La Paz University Hospital, Madrid
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01576094
- Sponsor's protocol ID
- MilevoNeo
- Status last verified
- Apr 2012
- First submitted
- 31 Mar 2012
- Last updated
- 12 Apr 2012
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Bravo MC, Lopez P, Cabanas F, Perez-Rodriguez J, Perez-Fernandez E, Quero J, Pellicer A. Acute effects of levosimendan on cerebral and systemic perfusion and oxygenation in newborns: an observational study. Neonatology. 2011;99(3):217-23. doi: 10.1159/000314955. Epub 2010 Sep 25.
PubMed 20881438
Study at a glance
From the registry record, last updated by the sponsor on 12 Apr 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Two Inodilators in Neonates Undergoing Cardiovascular Surgery
- ClinicalTrials.gov ID
- NCT01576094
- Acronym / sponsor ID
- MilevoNeo
- Conditions
- Low Cardiac Output Syndrome
- Keywords
- congenital heart disease
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Fundacion para la Investigacion Biomedica del Hospital Universitario la PazUniversity, hospital or other
- Collaborators
- Hospital Universitario La Paz, Fondo de Investigacion Sanitaria
- Study start
- Nov 2009
- Primary completion
- Nov 2010 (actual)
- Study completion
- Nov 2010 (actual)
- First posted
- 12 Apr 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Congenital heart defects are the most prevalent group of congenital malformations in newborns. Surgery-related low cardiac output syndrome (LCOS) could be one of the reason for the unfavourable outcome of this population. The early use of inodilators (INDs), specifically milrinone (MR), is proposed to reduce afterload and increase inotropism. Studies in the paediatric population appear to support a clinical usefulness of MR similar to that observed in adults. Levosimendan (LEVO) is a novel class IND developed for the treatment of heart failure. Experience with LEVO in paediatric patients is scarce. The purpose of this study was to systematically test the efficacy and safety of milrinone (MR) and levosimendan (LEVO) in newborns undergoing cardiovascular surgery with cardiopulmonary bypass (CPB). Given the uncertainty about LEVO pharmacokinetics in neonates, the study was designed as a pilot, phase I feasibility study.
Detailed description
Surgical repair is the primary therapy for congenital heart defects in the newborn. The neonatal cardiovascular system is at particular risk to develop the surgery-related low cardiac output syndrome (LCOS), thus vasoactive agents are routinely used in the postoperative management. Systematic research on the efficacy of these drugs is scarce in the newborn. As LCOS pathophysiology joints impaired myocardial contractility and the peripheral effects of ischemia/reperfusion injury on the endothelium, early use of inodilators (IND) are strongly recommended to reduce afterload and improve contractility. This study aims to test the equivalence in dose-dependent hemodynamic effects of 2 IND, Milrinone and Levosimendan, used early without loading dose in the preoperative period to prevent LCOS. By means of non-invasive technology the investigators will assess cardiac function (serial structural and functional echocardiography), the cerebral and peripheral perfusion and oxygenation (continuous near-infrared monitoring), cerebral function (continuous amplitude integrated EEG monitoring), will rule out CNS acquired lesions (serial transfontanelar echo-Doppler studies), and will follow up different biochemical markers of myocardial stress and apoptosis. Pharmacokinetic studies will be also performed.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Milrinone | Active comparator | Drug: MilrinoneMilrinone (MR) lactate 1 mg/ml: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission; dose 3, after 2 hours of stability with dose 2, and maintained up to 48 hours. Accordingly, patients randomised to MR received 0.5 , 0.75 and 1 microg/kg per min |
| Levosimendan | Active comparator | Drug: Levosimendan |
Who may qualify
- Ages
- Up to 40 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- Newborns undergoing cardiovascular surgery who were in stable pre-operative haemodynamic condition
- Parental consent given
Key exclusion criteria (2 listed)
- Parental consent refused
- Inodilators contraindicated
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 |
|---|---|---|
| MilrinoneAlso: cronotropeBefore surgery, patients received milrinone (MR) (milrinone lactate 1 mg/ml). Intravenous continuous infusion of the study drug through a separate central line started intraoperatively and was increased step-wise at predefined time points: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission providing the patient was in stable haemodynamic condition; dose 3, starting after 2 hours of stability with dose 2, and maintained up to 48 hours IND infusion started. Accordingly, patients randomised to MR received 0.5 , 0.75 and 1 microg/kg per min | Drug | Milrinone |
| LevosimendanAlso: SimdaxBefore surgery patients received levosimendan (levosimendan 2.5 mg/ml). Intravenous continuous infusion of the study drug through a separate central line started intraoperatively and was increased step-wise at predefined time points: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission providing the patient was in stable haemodynamic condition; dose 3, starting after 2 hours of stability with dose 2, and maintained up to 48 hours IND infusion started. Accordingly, patients randomised to LEVO received 0.1 , 0.15 and 0.2 microg/kg per min, for doses 1, 2 and 3, respectively. | Drug | Levosimendan |
Primary outcome
Perfusion-oxygenation
Time frame: NIRS evaluation started immediately after surgery and was maintained during 24 h. At 48 h after surgery, a new NIRS evaluation during 4 hours. At 96 h post-surgery, during 4h.
Changes in cerebral and thigh oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), total haemoglobin (THb) and tissue oxygenation index (TOI). The cerebral and peripheral intravascular oxygenation as c∆HbD was also assessed.
11 secondary outcomes
Blood gases
Time frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
Blood pressure
Time frame: preoperative (baseline) to post-operative day 6.
temperature
Time frame: preoperative (baseline) to post-operative day 6.
arterial oxygen saturation
Time frame: preoperative (baseline) to post-operative day 6.
cooximetry
Time frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
lactate
Time frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
glucose
Time frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
haemoglobin concentration
Time frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery.
Biochemical markers
Time frame: baseline, at 24h after surgery and on day 6 post-surgery
Inodilators concentration
Time frame: Basal, two hours after dose 2; and at 24 and 48h from the start of the IND infusion in infants receiving IND dose 3. Beyond that period (open study), daily samples were obtained for LEVO up to day 7 postsurgery, and at 10 and 14 days.
inotrope score
Time frame: preoperative (baseline) and then one evaluation every 6 hours until 24 h post-surgery. At 48h post-surgery. At 96 h post-surgery.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Apr 2012.
- Background: PubMed 20881438Bravo MC, Lopez P, Cabanas F, Perez-Rodriguez J, Perez-Fernandez E, Quero J, Pellicer A. Acute effects of levosimendan on cerebral and systemic perfusion and oxygenation in newborns: an observational study. Neonatology. 2011;99(3):217-23. doi: 10.1159/000314955. Epub 2010 Sep 25.
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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.
Adelina Pellicer, PhD principal investigator
Dept. of Neonatology, La Paz University Hospital, Madrid
Joan Riera, MBE study chair
Bio-Engineer and Nanotechnology Dept., Polytechnic University of Madrid
Paloma López, MD study chair
Dept. of Neonatology, La Paz University Hospital, Madrid
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Milrinone and Levosimendan in people with Low Cardiac Output Syndrome, run by Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz at 1 site in Spain.
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 2 inclusion and 2 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: finished, as of the sponsor's last update on 12 Apr 2012. 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 Spain. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Perfusion-oxygenation (time frame: NIRS evaluation started immediately after surgery and was maintained during 24 h. At 48 h after surgery, a new NIRS evaluation during 4 hours. At 96 h post-surgery, during 4h.). 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 NCT01576094, 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 12 Apr 2012.