Sildenafil Monotherapy versus Bosentan as an Add-on for persistent pulmonary hypertension of newborn- an exploratory study

Aim of the studyTo evaluate the efficacy and safety of bosentan as an add-on versus sildenafil monotherapy in the management of PPHN

Primary objectiveTo assess the reduction in oxygenation index (OI) in neonates with PPHN receiving bosentan as an add-on versus sildenafil monotherapy at six hours of initiating treatment

Secondary objectives

1.   Reduction in OI at 12, 24 h from baseline

2.   Reduction in TR at 6, 24 and72 hours from baseline

3.   Hemodynamic parameters after the first dose and after 24 h

4.   Need for inotropic agent

5.   Need for rebound use of vasodilators and/or inotropes

6.   Duration of respiratory support and /or mechanical ventilation

7.   Incidence of adverse events: gastric Intolerance, transaminitis and bleeding tendencies

8.   Time to reach full enteral feeds

9.   Co-morbidities IVH, ROP, BPD during hospital stay

10.         Mortality in-hospital and until first 28 days of life

11.         Duration of NICU and hospital stay

Materials and methods

Study design**:**Exploratory RCT; Study siteNeonatal intensive care unit (NICU), AIIMS Rishikesh; **Study duration:**18 months after obtaining clearance from ethics committee and CTRI registration.

Inclusion criteria: All intubated neonate ≥34 weeks gestational age and postnatal age of < 7 days admitted to NICU for respiratory distress will be screened for the eligibility criteria suggesting PPHN- both echocardiographic as well as clinical criteria (as mentioned above). Those neonates who would require intubation purely for hemodynamic compromise or apnea shall not be eligible for the study. Firstly, a screening echocardiography would be performed to record the parameters defining pulmonary hypertension (any two of the following echocardiographic parameters: *I.**Pulmonary Artery pressure (PAP) > 30 mmHg;PAP = Tricuspid regurgitation (TR) gradient + RAP(where RAP is right atrial pressure (usually 5-10 mmHg))**II.Bidirectional flow or right to left shunt at PDA, PFO, ASD, or VSDIII.Ratio of pulmonary artery acceleration time (PAAT) to right ventricular ejection time (RVET): PAAT/RVET <0.3IV.Eccentricity index of LV at end systole > 1V.*Dilated RA and RV). In addition to the echocardiographic features (any 2 of 5), the presence of any one of the three clinical features (OI>10, FiO2 > 0.3 or labile SpO2 with differential pre-, post-ductal SpO2 > 5%) should be satisfied for enrolling the subject in the study.

Exclusion criteria:  Congenital diaphragmatic hernia; Major congenital anomalies including structural heart disease except PDA, PFO, VSD or ASD; Altered GI aspirates

Randomization/Blinding and Intervention •The random sequence will be computer generated, stratified for gestation (34-36 weeks and

= 37 weeks ) •A computer based variable block random sequence will be generated using the online software http://www.sealedenvelope.com by an independent statistician not involved in the study. •All study investigators and health care personnel (except the study nurse) will be blinded. •According to the allocated intervention’ study nurse will prepare the drug/placebo in a 10 ml syringe (as described under Intervention detail) and hand over the prepared drug to the bedside nurse after covering the syringe in silver foil (as bosentan solution is milky). The bedside nurse will cover the feeding tube with silver foil and then administer the corresponding drug/or placebo every 12 hourly without removing the foil over the tube henceforth. 2 ml NS flush will be given after giving drug/placebo. Both group will similarly receive sildenafil solution (as described above)

Statistical method:

•Microsoft Excel 2020 will be used to collate all the data sets for participating neonates •STATA version 14.0 will be used for statistical analysis.

•All analysis will be done on intention to treat basis •Secondary per protocol analysis will also be performed for the primary outcome

•Categorical measurements will be presented as percentages (%) while continuous variables will be presented as mean ± SD. •Fisher Exact test or the Chi-square test will be used to compare categorical variables while Mann Whitney test or student’s t test will be used to compare continuous variables • Two-sided p value of less than 0.05 will be taken as significant. Survival analysis of the neonates, time to wean mechanical ventilation and reach full enteral feeds, etc. will be done using Kaplan Meier survival plot analysis.