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

Sponsor

Ramesh K Agarwal (Other)

Overall Status

Unknown status

CT.gov ID

NCT02774044

Collaborator

Maulana Azad Medical College, New Delhi (Other), Lady Hardinge Medical College (Other), Chacha Nehru Bal Chikitsalya, Delhi (Other), Postgraduate Institute of Medical Education and Research, Chandigarh (Other), King Edward Memorial Hospital, Mumbai (Other), Lokmanya Tilak Municipal General Hospital, Mumbai (Other), Institute of Child health and Hospital for Children, Chennai (Other), Jawaharlal Institute of Postgraduate Medical Education & Research (Other), All India Institute of Medical Sciences, New Delhi (Other), St Johns Medical College Hospital, Bangalore, India (Other), King Edward Memorial Hospital, Pune (Other), Government Medical College, Chandigarh (Other), Wellcome Trust (Other)

900

Enrollment

Arms

Duration (Months)

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Respiratory Distress Syndrome	Drug: Cadisurf Drug: Survanta	Phase 2/Phase 3

Detailed Description

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

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.
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.
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.

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%.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

900 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Evaluating the Efficacy and Safety of an Innovative and Affordable Goat Lung Surfactant for the Treatment of Respiratory Distress Syndrome in Preterm Neonates: a Multi-site Randomized Clinical Trial

Study Start Date :

Jun 1, 2016

Anticipated Primary Completion Date :

Feb 1, 2019

Anticipated Study Completion Date :

May 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cadisurf (goat lung surfactant extract) Neonates in the intervention group will be intratracheally administered 100 mg/kg of GLSE (CADISURF®).	Drug: Cadisurf Cadisurf Intratracheal suspension is a sterile, non-pyrogenic pulmonary surfactant intended for intratracheal use only. It is a natural lung extract containing phospholipids and surfactant-associated proteins. The resulting composition provides 25 mg/mL phospholipids and less than 1.0 mg/ml protein. It is suspended in 0.9% sodium chloride solution. Cadisurf contains no preservatives. Each ml of Cadisurf contains 25 mg of phospholipids. It is a creamy white suspension supplied in single-use glass vials containing 8 mL (200 mg phospholipids). Other Names: Goat lung surfactant extract
Active Comparator: Survanta (Beractant)	Drug: Survanta Other Names: Beractant

Arm

Intervention/Treatment

Experimental: Cadisurf (goat lung surfactant extract)

Neonates in the intervention group will be intratracheally administered 100 mg/kg of GLSE (CADISURF®).

Drug: Cadisurf

Cadisurf Intratracheal suspension is a sterile, non-pyrogenic pulmonary surfactant intended for intratracheal use only. It is a natural lung extract containing phospholipids and surfactant-associated proteins. The resulting composition provides 25 mg/mL phospholipids and less than 1.0 mg/ml protein. It is suspended in 0.9% sodium chloride solution. Cadisurf contains no preservatives. Each ml of Cadisurf contains 25 mg of phospholipids. It is a creamy white suspension supplied in single-use glass vials containing 8 mL (200 mg phospholipids).

Other Names:

Goat lung surfactant extract

Active Comparator: Survanta (Beractant)

Drug: Survanta

Other Names:

Beractant

Outcome Measures

Primary Outcome Measures

BPD free survival [36 weeks post menstrual age]
Survival free from BPD defined as per the definition provided by NIH

Secondary Outcome Measures

Area under the curve for (AUC) for oxygen requirement (FiO2) requirement in first 48 h [48 hours after surfactant replacement therapy]
The oxygen requirement will be recorded every hour using a standardized protocol and AUC for first 48 hrs will be calculated. The outcome would be recorded by the study staff and AUC calculated in a subset of 250 infants.
Pulmonary haemorrhage [48 hours after surfactant replacement therapy]
Occurrence of bleeding/blood stained secretions from the trachea within 48 hr of surfactant administration
Any air leak within 72 hours of administration of surfactant [72 hours after surfactant replacement therapy]
Occurrence of any airleak -pneumothorax, PIE or pneumomediastinum in chest X-ray (done when clinically suspected)
IVH grade 3 or 4 [72±24 hrs]
Grade 3 or 4 IVH as per Papille/Volpe classification
Periventricular Leukomalacia (PVL)-cystic and non-cystic [72±24 hrs]
PVL as per deVries classification
PVL-cystic and non-cystic [28±7days]
PVL as per deVries classification
Sepsis [7 days of age]
Occurrence of any episode of sepsis (culture positive or culture negative) from the time of enrolment until 7 days of age
Respiratory support at 72 h [72 hours of age]
Mechanical ventilation/CPAP/HFNC/free flow oxygen/none at the two time points (point assessments)
Respiratory support at 7 days of age [7 days of age]
Mechanical ventilation/CPAP/HFNC/free flow oxygen/none at the two time points (point assessments)
Retinopathy of prematurity (ROP) [Eyes of the babies would be examined by the ophthalmologists starting from 4 wk of life]
ROP requiring laser as per ICROP classification
Neonatal Mortality [first 28 days of life]
Death of a neonate in first 28 days of life
Duration of mechanical ventilation and CPAP [36 weeks postmenstrual age]
Cumulative duration of mechanical ventilation and CPAP until discharge/death
Duration of hospital stay [36 weeks postmenstrual age]
Duration of hospital stay

Eligibility Criteria

Criteria

Ages Eligible for Study:

26 Weeks to 32 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Gestational age ≤32 completed weeks
Onset of respiratory distress within six hours of age
If baby meets criteria for surfactant replacement therapy:
FiO2 needed is 40% or higher while the baby is on CPAP to maintain pre-ductal oxygen saturation between 90% to 95% or
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:

Gestation below 26 wk
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
Major congenital malformations
Prophylactic surfactant administration, i.e. administration of surfactant before the infant develops respiratory distress
Air leak or pulmonary hemorrhage prior to enrollment
Shock requiring vasopressor support prior to enrollment