The purpose of the study is to evaluate the efficacy and safety of Cadisurf (goat lung surfactant extract) as compared to Survanta (beractant) in the treatment of respiratory distress syndrome in preterm neonates (with gestation of 26 to 32 weeks).

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%.

Inclusion Criteria:

• Neonates born at the study sites and fulfilling all of the following criteria will be eligible for enrolment in the study

  1. Gestational age ≤32 completed weeks

  2. Onset of respiratory distress within six hours of age

  3. If baby meets criteria for surfactant replacement therapy:

     1. FiO2 needed is 40% or higher while the baby is on CPAP to maintain pre-ductal oxygen saturation between 90% to 95% or

     2. Baby needs intubation because of CPAP failure or severe respiratory distress (Chest X-ray is not mandatory for deciding the need for SRT). Detailed SOPs will be developed with respect to assessing the eligibility for SRT

        Exclusion Criteria:

        Neonates with any of the following criteria will be excluded:

  1. Gestation below 26 wk
  2. Babies with severe birth asphyxia as defined by the need for chest compressions and/or initial (umbilical arterial/or within 1 hour of birth) pH <7.0
  3. Major congenital malformations
  4. Prophylactic surfactant administration, i.e. administration of surfactant before the infant develops respiratory distress
  5. Air leak or pulmonary hemorrhage prior to enrollment
  6. Shock requiring vasopressor support prior to enrollment