MULTICENTRE RANDOMISED CONTROLLED TRIAL
OF MINIMALLY-INVASIVE SURFACTANT THERAPY IN
PRETERM INFANTS 25-28 WEEKS GESTATION
ON CONTINUOUS POSITIVE AIRWAY PRESSURE

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.

To determine whether administration of exogenous surfactant using a
minimally-invasive technique improves outcome in preterm infants 25-28 weeks
gestation treated with continuous positive airway pressure (CPAP).

Multicentre, randomised, masked, controlled trial. 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.
Once consent has been obtained, the infant will be randomised by the OPTIMIST
Treatment Team, after handover of care from the treating clinicians. Enrolled
infants will be randomised into surfactant via MIST* and *standard care*
groups, with an allocation ratio of 1:1, using a webbased randomisation
procedure that will require confirmation of eligibility criteria and consent
before revealing the randomly determined allocation. The randomisation schedule
and web-based OPTIMIST-A trial protocol will be provided by the Clinical
Epidemiology and Biostatistics Unit at the Murdoch Childrens Research
Institute. The randomisation will be in randomly permuted blocks of variable
length, stratified by study centre, and by gestational age. For the OPTIMIST-A
trial there will be two gestational age strata (25-26 weeks and 27-28 weeks).
Twins and higher order multiples will be randomised independently. Infants who
are unstable and in need of intubation should not be randomised, even if
consent has been obtained; such infants will not be considered to have been
enrolled.

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 (after a sham intervention
procedure). The intervention will be masked from the clinical team.

Burden and risks:
Direct laryngoscopy for tracheal catheterisation will be performed with risks
of bradycardia and desaturation. Athough usually self resolving, premedication
with sucrose (buccal) will be given as well as atropine (intravenous and at the
discretion of the OPTIMIST Treatment Team). In addition tot CPAP positive
pressure inflations can be given to restore saturation.

Benefit and group relatedness:
In view of the difficulties associated with intubation for surfactant delivery,
this less invasive mean of delivering surfactant has been pursued.
In addition it is expected in line with other data that respiratory course and
outcomes in infants treated with MIST will be better, i.e., more rapidly
weaning of FiO2, reduced intubation rate < 3 days, and a shorter duration of
oxygen therapy.