Clinical trial NCT02140580: OPTIMIST-A Trial: Minimally-invasive Surfactant Therapy in Preterm Infants 25-28 Weeks Gestation on CPAP
Official title: Multicentre Randomised Controlled Trial of Minimally-invasive Surfactant Therapy in Preterm Infants 25-28 Weeks Gestation on Continuous Positive Airways Pressure
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Bronchopulmonary Dysplasia
Keywords: Minimally-invasive surfactant therapy
Lead sponsor: Menzies Institute for Medical Research
Sponsor class: OTHER
Collaborators: name: Royal Hobart Hospital
name: Royal Women's Hospital, Melbourne, Australia
name: Endeavor Health
name: Monash Medical Centre
name: Mercy Hospital for Women, Australia
name: Auckland City Hospital
name: Middlemore Hospital, New Zealand
name: Zekai Tahir Burak Women's Health Research and Education Hospital
name: Kapiolani Medical Center For Women & Children
name: The Cooper Health System
name: Yale University
name: West Virginia University Hospital
name: Uludag University Hospital
name: Ziv Medical Center
name: Bnai Zion Medical Center
name: University Medical Centre Ljubljana
name: Dunedin Hospital
name: Kanuni Sultan Suleyman Training and Research Hospital
name: University Medical Center Groningen
name: University of Southern California
First posted: 2014-05-16
Enrollment: 486
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: Trial question: Does administration of exogenous surfactant using a minimally-invasive technique improve outcome in preterm infants 25-28 weeks gestation treated with continuous positive airway pressure (CPAP)? Trial hypothesis: That early surfactant administration via a minimally-invasive technique to preterm infants on CPAP will result in a lesser duration of mechanical respiratory support, and a higher incidence of survival without bronchopulmonary dysplasia. Trial design: Multicentre, randomised, masked, controlled trial in inborn preterm infants 25-28 weeks gestation, aged less than 6 hours, requiring CPAP because of respiratory distress, with an FiO2 of \>=0.3 and CPAP pressure 5-8. Infants randomised to surfactant treatment receive 200 mg/kg of poractant alfa (Curosurf) administered under direct laryngoscopy using a surfactant instillation catheter, followed by reinstitution of CPAP. Controls continue on CPAP. The intervention is masked from the clinical team. Care thereafter is as per usual in both groups, other than the requirement to adhere to intubation criteria. The primary outcome is incidence of death or BPD. Secondary outcomes include incidence of death, major neonatal morbidities (BPD, intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotising enterocolitis), pneumothorax and patent ductus arteriosus; need for intubation and surfactant therapy; durations of mechanical respiratory support, intubation, CPAP, intubation and CPAP, high flow nasal cannula (HFNC), oxygen therapy, intensive care stay and hospitalisation; hospitalisation cost; applicability and safety of the MIST procedure; and outcome at 2 years. The sample size is 303/group, allowing detection of a 33% difference in the primary outcome with 90% power. The trial commenced at Royal Hobart Hospital December 2011 and Royal Women's Hospital during 2012, and will ultimately be conducted over 5 years in multiple centres internationally.

Detailed description: 1. OPTIMIST-A TRIAL SUMMARY RESEARCH QUESTION Does administration of exogenous surfactant using a minimally-invasive technique improve outcome in preterm infants 25-28 weeks gestation treated with continuous positive airway pressure (CPAP)?

BACKGROUND Nasal CPAP is often very effective in preterm infants as the initial means of respiratory support, but a sub-group of infants, most with features of respiratory distress syndrome, fail on CPAP and require intubation and ventilation in the first 72 hours. When compared to those in whom CPAP is successful, infants failing CPAP have a substantially longer duration of respiratory support, and a higher risk of adverse outcomes. Decreasing the risk of CPAP failure would thus seem advantageous, and may be achievable with minimally invasive surfactant therapy (MIST), in which surfactant is administered to a spontaneously breathing infant who then remains on CPAP. A technique of MIST (the "Hobart method") using a semi-rigid surfactant instillation catheter has been shown to be feasible in preterm infants on CPAP, and appears to have the potential to alter respiratory course and outcome. This method of MIST now requires evaluation in randomised controlled trials.

RESEARCH DESIGN Multicentre, randomised, masked, controlled trial.

RECRUITMENT Entry criteria Inborn preterm infants 25-28 weeks gestation, aged less than 6 hours, who were not intubated at birth but require CPAP or NIPPV because of respiratory distress, with a CPAP pressure of 5-8 cm H2O and FiO2 ≥0.30.

Exclusion criteria Infants will be excluded if in imminent need of intubation, or if there is a congenital anomaly or alternative cause for respiratory distress.

RANDOMISATION With parental consent, eligible infants will be randomly allocated using a web-based randomisation server, with stratification by study centre, to receive exogenous surfactant via the Hobart MIST technique, or to continue on CPAP.

INTERVENTION Infants randomised to surfactant treatment will receive a dose of poractant alfa (Curosurf) administered under direct laryngoscopy using a surfactant instillation catheter, at a dosage of 200 mg/kg. CPAP will thereafter be reinstituted. Controls will continue on CPAP. The intervention will be masked from the clinical team.

POST-INTERVENTION MANAGEMENT Other than the requirement to adhere to intubation criteria in the first week, and in some cases perform a room air trial at 36 weeks corrected gestation, management after intervention will be at the discretion of the clinical team. Titration of CPAP pressure is encouraged, with a permitted maximum of 8 cm H2O. Nasal IPPV (bi-level CPAP) is allowable. Early caffeine therapy is expected.

Criteria for intubation: Enrolled infants on CPAP will be intubated if FiO2 ≥0.45, or if there is unremitting apnoea or persistent acidosis. These criteria apply during the first week of life, and to the first episode of intubation only.

FOLLOWUP: At 2 years corrected age, parents of each infant will complete a brief health assessment and a validated child development assessment (PARCA-R, Dev Med Child Neurol 2004;46:389-97) administered as a web-based questionnaire located on a secure server. The infant-specific link to the questionnaire, and reminders where necessary, will be sent electronically to the parents by research personnel at each Site, thus maintaining confidentiality. No identifying details will be revealed in the completion of the questionnaire.

OUTCOMES Primary outcome: Incidence of composite outcome of death or physiological bronchopulmonary dysplasia (BPD).

Secondary outcomes: Incidence of death, major neonatal morbidities (BPD, intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotising enterocolitis), pneumothorax and patent ductus arteriosus; need for intubation and surfactant therapy; durations of mechanical respiratory support, intubation, CPAP, intubation and CPAP, high flow nasal cannula (HFNC), oxygen therapy, intensive care stay and hospitalisation; hospitalisation cost; applicability and safety of the MIST procedure; and outcome at 2 years.

SAMPLE SIZE 606 infants (303 per group), giving 90% power to detect a 33% reduction in death or BPD from the anticipated rate of 38% in the control arm, α = 0.05.

TRIAL PLAN The OPTIMIST trials will commence at RHH Hobart and RWH Melbourne during 2011. All Australasian neonatal units, and selected international centres including those in the Vermont- Oxford Network, will be invited to join the trials. A full complement of participating centres is expected by early 2014. Recruitment will thereafter proceed at full rate until completion, which is estimated to take up to 4 years.

Eligibility criteria: Inclusion Criteria:

* Gestational age 25-28 completed weeks
* Requiring CPAP or non-invasive positive pressure ventilation with signs of early respiratory distress.
* CPAP pressure of 5-8 cm H2O and FiO2 \>=0.30.
* Less than 6 hours of age.
* Agreement of the Treating Physician in charge of the infant's care.
* Signed parental consent.

Exclusion Criteria:

* Previously intubated, or in imminent need of intubation
* Congenital anomaly or condition that might adversely affect breathing.
* Identifiable alternative cause for respiratory distress (e.g. congenital pneumonia or pulmonary hypoplasia).
* Lack of availability of an OPTIMIST treatment team.

Primary outcomes:
measure: Death or physiological bronchopulmonary dysplasia
timeFrame: 36 weeks post menstrual age
Secondary outcomes:
measure: Mortality
timeFrame: 36 weeks post menstrual age
measure: Major morbidity
timeFrame: 36 weeks post menstrual age
measure: Pneumothorax
timeFrame: 36 weeks post menstrual age
measure: Duration of respiratory support
timeFrame: During first hospitalisation (average assessment period 14 weeks)
measure: Bronchopulmonary dysplasia
timeFrame: 36 weeks post menstrual age
measure: Duration of bradycardia and hypoxaemia during intervention
timeFrame: During intervention
measure: Discomfort during intervention
timeFrame: During intervention
Other outcomes:
measure: Hospitalisation cost
timeFrame: First hospitalisation (average assessment period 14 weeks)
Locations:
city: New Haven
country: United States
facility: Yale-New Haven Children's Hospital
state: Connecticut
city: Honolulu
country: United States
facility: Kapi'olani Medical Center for Women and Children
state: Hawaii
city: Evanston
country: United States
facility: NorthShore Health University HealthSystem Evanston Hospital
state: Illinois
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Morgantown
country: United States
facility: West Virginia University Hospital
state: West Virginia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Melbourne
country: Australia
facility: Royal Womens Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Haifa
country: Israel
facility: Bnai Zion Medical Center
city: Tsefat
country: Israel
facility: Ziv Medical Center
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Zaloska
country: Slovenia
facility: University Medical Center, Ljubljana
state: Ljubljana
city: Gorukle
country: Turkey
facility: Uludag University Hospital
state: Bursa
city: Ankara
country: Turkey
facility: Zekai Tahir Burak Hospital
Study officials:
affiliation: Menzies Institute of Medical Research, University of Tasmania
name: Peter A Dargaville, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dargaville PA, Aiyappan A, De Paoli AG, Kuschel CA, Kamlin CO, Carlin JB, Davis PG. Minimally-invasive surfactant therapy in preterm infants on continuous positive airway pressure. Arch Dis Child Fetal Neonatal Ed. 2013 Mar;98(2):F122-6. doi: 10.1136/archdischild-2011-301314. Epub 2012 Jun 9.
citation: Dargaville PA, Aiyappan A, Cornelius A, Williams C, De Paoli AG. Preliminary evaluation of a new technique of minimally invasive surfactant therapy. Arch Dis Child Fetal Neonatal Ed. 2011 Jul;96(4):F243-8. doi: 10.1136/adc.2010.192518. Epub 2010 Oct 21.
citation: Dargaville PA. Innovation in surfactant therapy I: surfactant lavage and surfactant administration by fluid bolus using minimally invasive techniques. Neonatology. 2012;101(4):326-36. doi: 10.1159/000337346. Epub 2012 Jun 1.
citation: Dargaville PA. CPAP, Surfactant, or Both for the Preterm Infant: Resolving the Dilemma. JAMA Pediatr. 2015 Aug;169(8):715-7. doi: 10.1001/jamapediatrics.2015.0909. No abstract available.
citation: Dargaville PA, Kamlin CO, De Paoli AG, Carlin JB, Orsini F, Soll RF, Davis PG. The OPTIMIST-A trial: evaluation of minimally-invasive surfactant therapy in preterm infants 25-28 weeks gestation. BMC Pediatr. 2014 Aug 27;14:213. doi: 10.1186/1471-2431-14-213.