Randomised Placebo-controlled Trial of Early Targeted Treatment of Patent Ductus Arteriosus with Paracetamol in Extremely Low birth Weight Infants - A Pilot Study (ETAPA Phase 1)

Extremely low birth weight infants (ELBW, birth weight less than 1000g) have been identified as those at highest risk of the recognised adverse associations of early large Patent Ductus Arteriosus (PDA). Evidence is emerging to support the early targeted treatment of those ELBW infants that are unlikely to achieve spontaneous PDA closure. The efficacy and basic safety of Paracetamol in the treatment of Patent Ductus Arteriosus (PDA) is established, and Paracetamol has been shown to be as effective as Indomethacin and Ibuprofen for PDA closure, with reduced associated adverse effects. The aim of the ETAPA trial is to determine whether early targeted treatment of PDA with Paracetamol in Extremely Low Birth Weight (ELBW) infants results in significant reduction of adverse outcomes attributable to systemic hypoperfusion associated with early large PDA (peri/intraventricular haemorrhage (PIVH), necrotising enterocolitis (NEC) and death). The objective of this pilot study (Phase 1) and Thesis was to assess the feasibility of the early targeted approach in this trial, assess the suitability of the enrolment criteria, and refine the trial Protocol before proceeding to the multi-centre, international randomised trial (Phase 2). This is a parallel group, randomised, double-blinded, placebo-controlled trial. Phase 1, the internal pilot study involved 30 ELBW infants. These infants will be included in the total of 218 participants in the trial, at the end of Phase 2. ELBW infants with PDA diameter more than 1.5 mmm and non-restrictive left to right PDA flow between 6 and 12 hours of age were eligible for enrolment. Participants were randomised to Paracetamol or placebo (1:1) administered 6-hourly, until ductal closure as determined by serial 48-hourly functional targeted neonatal echocardiography (fnECHO) assessment, to a maximum of six completed days. Based on our inclusion/exclusion criteria we expected to enrol approximately 60% of the ELBW infants admitted to the participating centres. Criteria for progression of the trial to Phase 2 included per protocol treatment of over 75% of participants in Phase 1.

Fifty-two ELBW infants were admitted to the participating NICU’s during Phase 1, 41 were consented and screened (79%), with 30 infants randomised (58%). Median gestation was 25.9 weeks (IQR 25.3 - 27.4) and median birth weight was 780g (IQR 637 - 909). No participants were unblinded, and none received open-label treatment during the trial intervention period. All participants received the investigative medicinal product (IMP) as per protocol. Of the non-randomised infants, five infants had PDA ≤1.5mm and/or restrictive flow. PDA was closed spontaneously before discharge in all of these infants. The remaining six non-randomised infants had clinical or echocardiographic evidence of persistent pulmonary hypertension of the newborn (PPHN) and/or bidirectional shunt on targeted functional neonatal echocardiography (fnECHO), with high mortality (83.%) and morbidity in this group (combined outcome of PIVH/NEC/Death of 83%).

This internal pilot study (Phase 1) of the ETAPA trial has confirmed the estimated enrolment to the trial and the trial protocol has been adhered to. No patients were unblinded, none received open-label treatment during the trial intervention period, and there were no serious adverse events (SAEs) attributable to the IMP, Paracetamol. The results to date indicate that our trial selection criteria are appropriate for targeting infants that might benefit most from early targeted treatment of PDA.