Two Inodilators Postsurgery in Neonates

April 11, 2012 updated by: Adelina Pellicer, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Madrid, Spain, 28046
        • Hospital Universitario La Paz

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

No older than 1 month (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Newborns undergoing cardiovascular surgery who were in stable pre-operative haemodynamic condition
  • Parental consent given

Exclusion Criteria:

  • Parental consent refused
  • Inodilators contraindicated

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Levosimendan
Drug: Levosimendan
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.
Other Names:
  • Simdax
Active Comparator: Milrinone
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
Drug: Milrinone
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
Other Names:
  • cronotrope

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.
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.
preoperative (baseline) to post-operative day 6.
temperature
Time Frame: preoperative (baseline) to post-operative day 6.
central (axilla) and peripheral (foot) temperature
preoperative (baseline) to post-operative day 6.
arterial oxygen saturation
Time Frame: preoperative (baseline) to post-operative day 6.
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.
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.
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.
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.
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
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
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.
Milrinone and Levosimendan plasma concentration
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.
calculated according to Wernovsky
preoperative (baseline) and then one evaluation every 6 hours until 24 h post-surgery. At 48h post-surgery. At 96 h post-surgery.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Fondo de Investigacion Sanitaria
Hospital Universitario La Paz

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Adelina Pellicer, PhD, Dept. of Neonatology, La Paz University Hospital, Madrid
  • Study Chair: Joan Riera, MBE, Bio-Engineer and Nanotechnology Dept., Polytechnic University of Madrid
  • Study Chair: Paloma López, MD, Dept. of Neonatology, La Paz University Hospital, Madrid
  • Study Chair: María Carmen Bravo, PhD, Dept. of Neonatology, La Paz University Hospital, Madrid
  • Study Chair: Rosario Madero, MD, Division of Biostatistics, La Paz University Hospital, Madrid
  • Study Chair: Jesús Pérez-Rodríguez, PhD, Dept. of Neonatology, La Paz University Hospital, Madrid
  • Study Chair: Carlos Labrandero, MD, Dept. Paediatric Cardiology, La Paz University Hospital, Madrid
  • Study Chair: José Quero, PhD, Dept. of Neonatology, La Paz University Hospital, Madrid
  • Study Chair: Antonio Buño, PhD, Clinical Pathology Service, La Paz University Hospital, Madrid
  • Study Chair: Luis Castro, MD, Dept. Paediatric Anaesthesiology, La Paz University Hospital, Madrid
  • Study Chair: Fernando Cabañas, PhD, Dept. of Neonatology, La Paz University Hospital, Madrid

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2009

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 1, 2010

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 1, 2010

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 31, 2012

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 11, 2012

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 12, 2012

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 12, 2012

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 11, 2012

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • MilevoNeo

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