Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus - Full Text View

Purpose

Patent ductus arteriosus (PDA) is a very common condition in immature newborn babies and it has been associated to morbidity and mortality. Ibuprofen is the drug of choice for PDA treatment according to the last version of the Cochrane review. Nowadays the best dose regimen for ibuprofen remains uncertain. The investigators aim to perform a randomized controlled clinical trial to assess whether echocardiographically guided PDA ibuprofen treatment versus standard treatment could reduce the number of doses of ibuprofen without increasing the reopening rate and reducing the side effects associated to this medication.

Condition	Intervention	Phase
Patent Ductus Arteriosus	Drug: Ibuprofen EchoG Drug: Standard ibuprofen treatment	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment
Official Title:	Randomised Controlled Clinical Trial of Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus: a Pilot Study

Resource links provided by NLM:

Drug Information available for: Ibuprofen Ibuprofen sodium Ibuprofen lysinate

U.S. FDA Resources

Further study details as provided by Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz:

Primary Outcome Measures:

PDA re-opening rate [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: No ]
PDA re-opening after echocardiographically documented closure, which the attending physician deemed amenable to additional treatment. Infants with ventilator weaning difficulty, protracted metabolic acidosis or persistent hemodynamic instability were included in this category.

Secondary Outcome Measures:

treatment failure [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: No ]
PDA ≥ 1.5 mm 24 hours after a complete ibuprofen course
need for surgical ligation [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: No ]
need for surgical ligation
need for additional ibuprofen doses [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: No ]
need for additional ibuprofen doses after treatment was completed
urine output [ Time Frame: before the first ibuprofen dose was administered (between 12-72 hours of life) until 24 hours after the last dose of ibuprofen was administered (between 36-168 h of life) ] [ Designated as safety issue: Yes ]
urine output
serum creatinine [ Time Frame: before the first ibuprofen dose was administered (between 12-72 hours of life) until 24 hours after the last dose of ibuprofen was administered (between 36-168 h of life) ] [ Designated as safety issue: Yes ]
serum creatinine
mortality [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: Yes ]
mortality
bronchopulmonary dysplasia [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: Yes ]
bronchopulmonary dysplasia (O2 need at 36 postmenstrual weeks)
necrotising enterocolitis [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: Yes ]
necrotising enterocolitis
intraventricular hemorrhage [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: Yes ]
intraventricular hemorrhage
White matter damage [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: Yes ]
White matter damage
Laser therapy for retinopathy [ Time Frame: Infants will be followed for the duration of hospital stay in the Newborn Unit, an expected average of 4-8 weeks ] [ Designated as safety issue: Yes ]
Laser therapy for retinopathy
peak systolic velocity [ Time Frame: before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered ] [ Designated as safety issue: No ]
peak systolic velocity measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries
end-diastolic velocity [ Time Frame: before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered ] [ Designated as safety issue: No ]
end-diastolic velocity measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries
resistance index [ Time Frame: before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered ] [ Designated as safety issue: No ]
resistance index measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries
pulsatility index [ Time Frame: before each ibuprofen dose should be administered (3 days) and 24 hours after the last dose of ibuprofen was administered ] [ Designated as safety issue: No ]
pulsatility index measured by means of cerebral Doppler ultrasonography in the anterior and middle cerebral arteries

Enrollment:	49
Study Start Date:	May 2009
Study Completion Date:	March 2010
Primary Completion Date:	March 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: EchoG Infants in the experimental group (echoG treatment) received additional doses of ibuprofen only if PDA was still ≥ 1.5 mm at the time of the corresponding ibuprofen dose.	Drug: Ibuprofen EchoG Infants in the experimental group (echoG treatment) received additional doses of ibuprofen only if PDA was still ≥ 1.5 mm at the time of the corresponding ibuprofen dose. Other Name: Echocardiographically guided ibuprofen treatment
ST (standard treatment) Infants received 3 doses of ibuprofen at 24-hour intervals, independently of ductal size, as long as additional doses were not contraindicated.	Drug: Standard ibuprofen treatment Infants received 3 doses of ibuprofen at 24-hour intervals, independently of ductal size, as long as additional doses were not contraindicated. Other Name: Standard ibuprofen treatment

Detailed Description:

Patent ductus arteriosus (PDA) is presented in 55 to 70% of the preterm infants with a gestational age lower than 30 weeks or a birth weight lower than 1000 grams. PDA has being associated to mortality or morbidity such as ischemic or hemorrhagic cerebral events, necrotising enterocolitis, renal disfunction or poor pulmonary outcome; however, it is not clear whether these are a consequence of the PDA presence, the treatment implemented for closing it, or the immaturity of these population. PDA standard treatment (ST) consists on three doses of indomethacin or ibuprofen (10-5-5mg/kg) given 24 hours apart, being the surgical closure a second line therapeutic option. In spite of ibuprofen has been pointed as the drug of choice for PDA treatment by the last version of the Cochrane review, side effects have been associated to both medication. Standard ibuprofen treatment is based on a clinical trial where the three-dose protocol seemed to be more effective than one-dose scheme for PDA closure; however, the sample size was not powered to find differences statistically significant, so nowadays the best dose regimen for ibuprofen remains uncertain. Functional echocardiographic assessment is spreading to all over the world. In this scenario, it has been proposed its implementation to guide PDA treatment in order to individualize the number of doses of indomethacin administered as a function of patient's response, limiting the doses and side effects in those where PDA presented an early constriction. The investigators hypothesized whether echocardiographically guided PDA ibuprofen treatment could reduce the number of doses of ibuprofen without increasing the reopening rate and reducing the side effects associated to this medication.

Eligibility

Ages Eligible for Study:	up to 1 Month
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Preterm infants with a gestational age lower than 37 weeks of gestational age
PDA ≥ 1.5 mm
No contraindication to receive ibuprofen
Informed consent signed.

Exclusion Criteria:

Life-threatening congenital defects
Congenital heart disease
Contraindication for ibuprofen administration such as oligoanuria < 1cc/kg/h or recent severe intraventricular bleeding (IVH grade III) or creatinine serum level > 1.5 mg/dl or potential intestinal ischemia.
Informed consent refused

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01593163

Locations

Spain
Department of Neonatology, La Paz University Hospital
Madrid, Spain, 28046

Sponsors and Collaborators

Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Investigators

Principal Investigator:	María Carmen Bravo, PhD MD	Department of Neonatology, La Paz University Hospital
Study Chair:	Fernando Cabañas, PhDMD	Department of Neonatology, La Paz University Hospital
Study Chair:	Joan Riera, Bio-Engineer	Department of Neonatology, La Paz University Hospital
Study Chair:	Elia Pérez-Fernández	Division of Statistics, La Paz University Hospital. Madrid, Spain.
Study Chair:	José Quero, PhDMD	Department of Neonatology, La Paz University Hospital. Madrid, Spain.
Study Chair:	Jesús Pérez-Rodríguez, PhDMD	Department of Neonatology, La Paz University Hospital. Madrid, Spain.
Study Director:	Adelina Pellicer, PhDMD	Department of Neonatology, La Paz University Hospital. Madrid, Spain.

More Information

Publications:

Carmo KB, Evans N, Paradisis M. Duration of indomethacin treatment of the preterm patent ductus arteriosus as directed by echocardiography. J Pediatr. 2009 Dec;155(6):819-822.e1. Epub 2009 Jul 29.

Responsible Party:	Maria Carmen Bravo Laguna, Principal Investigator, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
ClinicalTrials.gov Identifier:	NCT01593163 History of Changes
Other Study ID Numbers:	IbuEchoG
Study First Received:	May 3, 2012
Last Updated:	May 4, 2012
Health Authority:	Spain: Comité Ético de Investigación Clínica

Keywords provided by Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz:

Functional echocardiography
power Doppler cranial ultrasonography
N-terminal probrain natriuretic peptide
Patent ductus arteriosus

Additional relevant MeSH terms:

Ductus Arteriosus, Patent
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Ibuprofen
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents

Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Central Nervous System Agents

ClinicalTrials.gov processed this record on June 18, 2013