OPTIMIST-A Trial: Minimally-invasive Surfactant Therapy in Preterm Infants 25-28 Weeks Gestation on CPAP

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.

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.