Evaluation of early and combined treatment with surfactant and inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension

ISRCTN	ISRCTN13727958
DOI	https://doi.org/10.1186/ISRCTN13727958
Secondary identifying numbers	FONIS SA07I20035

Submission date: 03/09/2019
Registration date: 06/09/2019
Last edited: 26/08/2020

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Neonatal Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Hypoxemic respiratory failure (HRF) is a leading cause of illness and death among term and near term newborns. Few studies have tested surfactant treatment in these patients with conflicting results. The aim of this study is to test whether early use of surfactant in combination with inhaled nitric oxide (iNO) will prevent newborns with moderate hypoxemic respiratory failure from developing severe HRF.

Who can participate?
Term and near-term newborns (35 weeks gestational ages and over) with acute HRF

What does the study involve?
Participants are randomly allocated to one of two groups. The surfactant-iNO group receive the combined treatment of surfactant plus inhaled Nitric Oxide (iNO). The control group receive standard treatment with iNO. Infants of both groups receive standard intensive care, which includes high frequency or conventional mechanical ventilation, inotropic support and sedation. ECMO was considered in patients with a persistent OI>40.

What are the possible benefits and risks of participating?
It is expected that the combined treatment of inhaled Nitric Oxide and surfactant will help to improve oxygenation and prevent the progression to severe HRF. This may reduce mortality and the need for ECMO treatment. Surfactant is a usual therapy for preterms with respiratory distress, occasionally its administration is associated with oxygen desaturation and bleeding, but the incidence of these complications is minimized with careful application and monitoring.

Where is the study run from?
Five level III Neonatal Intensive Care Units in five hospitals in Chile

When is the study starting and how long is it expected to run for?
August 2008 to July 2015

Who is funding the study?
Chilean National Fund for Research in Health (FONIS)

Who is the main contact?
Dr Alvaro González
alvgonza@med.puc.cl

Contact information

Dr Alvaro González
Scientific

Diagonal Paraguay 362, 8° piso
Santiago
8330077
Chile

ORCID ID	0000-0002-0442-9109
Phone	+56 (0)223543887
Email	alvgonza@med.puc.cl

Study information

Study design	Prospective randomized double-blind placebo-controlled clinical trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contacat details to request a participant information sheet
Scientific title	Randomized controlled trial to assess the early addition of exogenous surfactant to inhaled nitric oxide in the treatment of newborns with respiratory failure and pulmonary hypertension
Study acronym	Surfactant plus Nitric Oxide in Neonatal Hypoxic Respiratory Failure
Study objectives	The early addition of exogenous surfactant to the treatment with inhaled Nitric Oxide of newborns with respiratory failure (OI>20) and pulmonary hypertension will improve oxygenation and prevent them from developing severe hypoxemic respiratory failure (OI > 40).
Ethics approval(s)	Approved 08/07/2007, Research Ethics Committee of Medicine School Pontificia Universidad Catolica de Chile (Comité Etico Científico Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 383, Torre 11, Local 4, Santiago, Chile 8330077; Tel: +56 (0)2 23548173; Email: cecmeduc@med.puc.cl), CE# 027807
Health condition(s) or problem(s) studied	Neonatal hypoxic respiratory failure and pulmonary hypertension
Intervention	Enrolled infants were randomized into one of the two study groups using sequential sealed opaque envelopes from a computer-generated randomization list. This allocation sequence was generated centrally by an independent statistician, and sequentially sealed envelopes were sent to each center. Surfactant-iNO group: received treatment with 20 ppm of inhaled Nitric Oxide (INOmax, INO Therapeutics, USA) with up to 2 doses of 100 mg/kg of poractant alfa (Curocerf; Chiesi Farmaceutici, Italy) Control group: received treatment with 20 ppm iNO + placebo (air) and standard intensive care, which in both groups includes high frequency or conventional mechanical ventilation with 100% FiO2., inotropic support and sedation Infants in both groups could receive open-label surfactant if they developed an OI>40 within the first 48 hrs of study. ECMO was considered in patients with a persistent OI>40. Study surfactant combined with iNitric Oxide treatment were used within first 48 hours after study entry, but infants continue receiving standard intensive care later according to local and physician in charge guidelines. Patients were strictly monitored and followed during their whole hospital stay until discharge home.
Intervention type	Mixed
Primary outcome measure	The proportion of infants developing treatment failure during the first 48 hours of study treatment, defined as an oxygenation index (OI) ≥ 40
Secondary outcome measures	1. Proportion of infants requiring ECMO or death recorded during hospital stay 2. Oxygen and ventilatory requirements recorded during hospital stay
Overall study start date	01/08/2008
Completion date	31/07/2015

Eligibility

Participant type(s)	Patient
Age group	Neonate
Sex	Both
Target number of participants	100
Total final enrolment	100
Key inclusion criteria	1. Near term infants (35 weeks gestation) with birth weights > 2000 g and who are less than 72 hours old 2. Infants requiring mechanical ventilation with hypoxemic respiratory failure with an OI > 20, calculated on two consecutive measurements of post ductal arterial blood gases without acidosis (pH > 7.25) and efforts will be done to adjust ventilatory support to reach a PCO2 < 60 3. A previous echocardiogram will be performed to rule out a cardiac anomaly and evaluate the presence of pulmonary hypertension (a tricuspid insufficiency jet with an estimated systolic pulmonary artery pressure ≥ 2/3 of systemic systolic arterial blood pressure and/or evidence of right-to-left shunting through foramen ovale or ductus arteriosus)
Key exclusion criteria	1. Life-threatening congenital anomalies 2. Congenital heart disease 3. Congenital diaphragmatic hernia 4. Other forms of lung hypoplasia syndromes 5. Suspected or confirmed chromosomal abnormality 6. Postnatal age > 72 hours
Date of first enrolment	01/03/2009
Date of final enrolment	30/04/2014

Locations

Countries of recruitment

Chile

Study participating centres

Hospital Clinico Pontificia Universidad Catolica de Chile

Marcoleta 367
Santiago
8330077
Chile

Hospital Regional Guillermo Grant Benavente, Concepción

San Martin 1436
Concepción
4070038
Chile

Hospital Dr Luis Tisné

Avenida Las Torres 5150
Santiago
8640002
Chile

Hosptal Dr Sóteo del Río

Avenida Concha y Toro 3459
Puente Alto
Santiago
8207257
Chile

Hospital San José

San José 1196
Independencia
Santiago
8380419
Chile

Sponsor information

Pontificia Universidad Católica de Chile
University/education

Department of Neonatology
School of Medicine
Diagonal Paraguay 362, 8° piso
Santiago
8330077
Chile

Phone	+56 (0)23543887
Email	jfabres@med.puc.cl
Website	https://medicina.uc.cl
"ROR"	https://ror.org/04teye511

Funders

Funder type

Government

Chilean Fund for Health Research (FONIS): SA07I20035

No information available

Results and Publications

Intention to publish date	15/11/2019
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Results were presented in part at Pediatric Academic Societies meetings in Chile and internationally, and will be published at Pediatric Journal.
IPD sharing plan	Deidentified individual participant data will be made available, in addition to study protocols, the statistical analysis plan, and the informed consent form. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to alvgonza@med.puc.cl

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	13/08/2020	26/08/2020	Yes	No

Editorial Notes

26/08/2020: The following changes were made to the trial record:
1. Publication reference added.
2. The total final enrolment was added.
06/09/2019: Trial's existence confirmed by institutional review board and funder.