Efficacy and Safety of Goat Lung Surfactant for the Treatment of Respiratory Distress Syndrome in Preterm Neonates

Title: Evaluating the Efficacy and Safety of an Innovative and Affordable Lung Surfactant for the treatment of Respiratory Distress Syndrome (RDS) in preterm neonates: a multi-site randomized clinical trial

Phase of Development: Phase II/ III

Indication: Respiratory Distress Syndrome

Primary Objective: To compare the incidence of survival without bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age in preterm neonates (≤32 wk) with RDS randomized to receive intratracheal administration (100 mg/kg) of either goat lung surfactant extract (GLSE) or the standard preparation (Beractant; Survanta; Abbott, USA)

Secondary Objective: 1 To compare area under curve (AUC) for oxygen requirement (FiO2) requirement in first 48 h of surfactant administration

2 To compare incidence of safety outcomes namely air leaks, pulmonary hemorrhage, intraventricular hemorrhage, neonatal mortality, sepsis and retinopathy of prematurity

Study Design: A multicentric, non-inferiority randomized controlled trial (RCT) in preterm infants with RDS.

Study Centers: The study would be conducted at 12-14 academic centers of India.

Study population: A total of approximately 900 eligible preterm neonates will be enrolled in the study.

Planned No. of subjects: N~900 to be enrolled by 12-14 centers

Investigational Product : GLSE (Lung Surfactant Extract) Cadisurf 25

Dosage and site of administration: Dosage: Neonates in the intervention group will be administered 100 mg/kg of GLSE. Those in the control group will be administered 100 mg/kg of Beractant (Survanta®, Abbott, USA).

Site of Administration: Intratracheal

Expected Duration of Participation of each Subject: 4-10 Weeks

Expected duration of study 3 years

Methodology The study would be conducted at 12-14 study sites. The dedicated study teams under the leadership of site Principal Investigator (PI) at each site would implement the study protocol as per uniform standard operating procedures (SOPs). Written informed consent will be taken from the legally authorized representative (LAR) of the subject. Subjects will be enrolled based on the inclusion/exclusion criteria depicted in the institute ethics committee (IEC) \& Central drugs standard control organization (CDSCO) approved protocol. After satisfying inclusion/exclusion criteria subjects will be randomized either GLSE arm or Beractant (Survanta®, Abbott, USA) arm. The duration of the hospitalization would be 4-10 weeks. Enrolled infants would be monitored by the study team round the clock as per standard procedures. The study infants would be followed up until death or 36 weeks of postmenstrual age (PMA). Adverse events \& serious adverse events will be recorded \& reported as per the regulatory guidelines of India.

The study infants would be followed up until 36 weeks of PMA. The study would be conducted at 12-14 study sites. The study will be conducted in a highly supervised clinical setting with immediate availability of clinicians experienced with intubation, ventilator management and general care of premature infants. Infants receiving surfactant will be frequently monitored with arterial or transcutaneous measurement of systemic O2 and CO2. The dedicated study teams at each site would implement the study protocol as per uniform standard operating procedures (SOPs).

Primary Study Endpoint • BPD free survival

Blinding Procedures

1. Random sequence The random sequence will be generated using web based algorithm for 1:1 allocation and stratification by site and gestation (<28 and 28-32 weeks) in permuted blocks of random sizes. The block sizes will be blinded to the investigators.
2. Allocation concealment The vials of two surfactant products would be packaged in identical cardboard boxes (by CDSA) and sequentially numbered as per the allocation sequence for two gestation strata (8 mL vials for strata 26-27 weeks and 28-32 weeks, respectively) for each site.
3. Implementation The randomization sequence would be generated by an independent statistician and will be kept in safe custody and undisclosed to investigators. Dedicated research teams would track, ascertain the eligibility and randomize the infants and measure the outcomes. The clinical team would administer surfactant blinded to research team.
4. Blinding Clinicians would be aware of the type of surfactant product received by the neonate given the different physical appearance of the product and the vial of Cadisurf® and Survanta®. Clinicians would administer the surfactant to the baby while the baby's bed is cordoned off from rest of NICU by cloth screen. The parents and the research staff responsible for outcome assessment would be kept blinded to the interventions. The allocation would be concealed in the dataset so that the researchers can analyse data without information of the allocation.

Interim analysis Interim analyses, if desired by the Data Safety Monitoring Board (DSMB), are proposed at enrolment of 5%, 33% and 66% of the target sample size. The DSMB would only have access to the results of such analyses. Interim analysis will be conducted using O'Brien-Fleming spending function and a type I error rate of 5%.