Curosurf and Survanta Treatment(CAST)of RDS in Very Premature Infants (CAST)

Phase 4 Study of Curosurf (Poractant) and Survanta (Beractant) Surfactant Treatment in Very Premature Infants With Respiratory Distress Syndrome.

Approval of surfactant by the FDA in 1989 for the treatment of Respiratory Distress Syndrome (RDS) in premature infants greatly improved survival rates. Newer surfactants approved by the FDA were more concentrated and had a more rapid onset of action. The overall efficacy of newer surfactants appeared similar until in 2004, Ramanathan and colleagues suggested that a double dose of Curosurf improved survival in infants 25-32 weeks gestational age, compared to infants treated with Survanta, the most commonly used surfactant preparation in the United States. While the data was suggestive, it was not clear that the improvement in survival was reproducible or that Curosurf was responsible for the improved survival rates.

The purpose of this study was to investigate the role of Curosurf in improving lung function and survival rates and reducing the complications of prematurity in very premature infants < 30 weeks gestational age at birth.

Study Overview

• Status: Terminated
• Conditions: Respiratory Distress Syndrome; Patent Ductus Arteriosus; Prematurity
• Intervention / Treatment: Drug: Survanta (beractant); Drug: Curosurf (poractant)

Detailed Description

Specific Aims:

• To determine whether there is a sustained difference in the level of respiratory support during the first 3 days of life in extremely premature infants treated with Curosurf versus Survanta
• To determine whether Curosurf is associated with a higher incidence of hemodynamically significant PDA, compared with Survanta
• To determine whether there is a difference in the cerebral blood flow response to Curosurf versus Survanta
• To determine whether there is a difference in morbidity in very premature infants treated with Curosurf versus Survanta

We reasoned that if Curosurf was primarily responsible for improved survival rates, compared with Survanta, then there should be a sustained improvement in respiratory function in the first three days of life, when the direct pulmonary effects of the surfactant preparations would be most easily detected. It was also possible that Curosurf and Survanta could have effects on other systems that could secondarily affect long-term survival of the infant. These other organ systems would include, but not be limited to, the development of a hemodynamically significant Patent Ductus Arteriosus, Intraventricular Hemorrhage or Periventricular Leukomalacia, or Necrotizing Enterocolitis. We propose to examine how surfactant administration affected the hemodynamic precursors of these common morbidities of very premature infants.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 8 hours (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• <29 6/7 and >24 0/7 weeks gestational age
• Inborn at the participating institution enrolling the patient
• FIO2 >25% and Intubated with mean airway pressure > 5 cm H20
• <8 hours age at randomization
• Signed informed consent from parent(s)

Exclusion Criteria:

• <500 g birth weight
• <24 0/7 weeks gestational age (best estimate)
• Prolonged Premature Rupture of membranes >3 weeks (21 days)
• Apgar score < 3 at 5 minutes
• Impending death anticipated within the first 3 days of life, moribund
• Severe congenital anomalies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Surfactant (beractant, Survanta initial dose 100 mg/kg and subsequent doses 100 mg/kg phospholipids every 6-12 hours, as needed for up to 4 doses), intratracheal administration to very premature infants with RDS requiring mechanical ventilation	Drug: Survanta (beractant); beractant 4.0 ml/kg/dose (100 mg phospholipid/kg/dose, intratracheal, every 6-12 hours as needed for respiratory distress syndrome for initial and subsequent doses, maximum of 4 doses); Other Names: Survanta
Experimental: 2; Surfactant (poractant, Curosurf initial dose 200 mg/kg and subsequent doses 100 mg/kg phospholipids every 12-24 hours as needed for up to 3 doses), intratracheal administration to very premature infants with RDS requiring mechanical ventilation	Drug: Curosurf (poractant); poractant alfa 2.5 ml/kg/dose initial (200 mg phospholipid/kg), and 1.25 ml/kg/dose subsequent (100 mg/kg/subsequent dose), intratracheal, every 12-24 hours as needed for respiratory distress syndrome, maximum of 3 doses); Other Names: Curosurf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison Respiratory Support (Mean Airway Pressure) for Survanta (Beractant) and Curosurf (Poractant) at 48 Hours After Surfactant Administration.	Mean Airway Pressure delivered by mechanical ventilator or nasal CPAP (cm H20) at 48 hours following surfactant administration. A volume cycle ventilator strategy that allowed airway pressure to vary with changes in lung and chest wall compliance was used for mechanically ventilated infants, while inspired oxygen concentration was controlled by the clinical team.	48 hours after surfactant administration
Comparison of Respiratory Support (Mean Airway Pressure) for Curosurf (Poractant) and Survanta (Beractant) 72 Hours After Surfactant Administration	Mean Airway Pressure delivered by mechanical ventilator or nasal CPAP (cm H20) at 72 hours following surfactant administration. A volume cycle ventilator strategy that allowed airway pressure to vary with changes in lung and chest wall compliance was used for mechanically ventilated infants, while oxygen concentration was controlled by the clinical team.	72 hours after surfactant administration
Comparison Respiratory Support (Mean Airway Pressure x Percent Fraction of Inspired Oxygen) for Survanta (Beractant) and Curosurf (Poractant) at 48 Hours After Surfactant Administration.	Mean Airway Pressure x Percent Fraction of Inspired Oxygen (FIO2) at 48 hours after surfactant administration, delivered by mechanical ventilator or nasal CPAP assesses the components of respiratory support primarily affecting blood oxygenation. This index combines these parameters so that a systematic difference in clinical management of mean airway pressure or FIO2 between groups is not mistaken for a drug effect.	48 hours after surfactant administration
Comparison Respiratory Support (Mean Airway Pressure x Percent Fraction of Inspired Oxygen) for Survanta (Beractant) and Curosurf (Poractant) at 72 Hours After Surfactant Administration.	Mean Airway Pressure x Percent Fraction of Inspired Oxygen (FIO2) at 72 hours after surfactant administration, delivered by mechanical ventilator or nasal CPAP assesses the components of respiratory support primarily affecting blood oxygenation. This index combines these parameters so that a systematic difference in clinical management of mean airway pressure or FIO2 between groups is not mistaken for a drug effect.	72 hours after surfactant administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Infants Successfully Extubated at 48 Hours for Curosurf (Poractant) and Survanta (Beractant) Groups	Subjects successfully extubated and no longer needing positive pressure endotracheal mechanical ventilation at 48 hours after surfactant administration helps to explain the difference in mean airway pressure observed between groups.	48 hours after surfactant administration
Comparison of Infants Successfully Extubated at 72 Hours for Curosurf (Poractant) and Survanta (Beractant) Groups	Subjects successfully extubated and no longer needing positive pressure endotracheal mechanical ventilation at 72 hours after surfactant administration helps to explain the difference in mean airway pressure observed between groups.	72 hours after surfactant administration
Comparison of Hemodynamically Significant Patent Ductus Arteriosus (PDA) in Patients Treated With Curosurf (Poractant) and Survanta (Beractant)	Hemodynamically significant PDA, considered significant by the clinical team and having at least 2 objective echocardiographic signs (PDA > 1.5 mm diameter, retrograde diastolic flow in the descending aorta, and left atrial enlargement) were tallied. Hemodynamically significant PDA may increase lung water and decrease lung compliance, requiring increased mechanical ventilator support.	Hemodynamically significant PDA at > 2 days
Changes in Blood Flow Through the Patent Ductus Arteriosus (PDA) Following Second Dose of Survanta (Beractant) and Poractant Alfa (Curosurf)	Maximal changes in blood flow were assessed using Doppler echocardiography following the second surfactant dose of Survanta (beractant) or Curosurf (poractant alfa), to determine whether there was a direct effect of surfactant type on PDA size or pulmonary volume overload through the PDA. The hour interval following the second surfactant dose was selected for study, when the subjects were otherwise clinically stable, not needing additional stabilization procedures.	First hour after 2nd surfactant dose
Change in Anterior Cerebral Artery Blood Flow Velocity Following Second Dose of Surfactant	Percent change in Anterior Cerebral Artery blood flow velocity following the second dose of beractant, reflects the change in brain blood flow associated with surfactant administration. Blood flow velocity is measured by range gated Doppler ultrasound and brain blood flow changes in proportion to changes in arterial carbon dioxide levels, induced by surfactant administration. Variability in brain blood flow is associated with increased risk for intraventricular hemorrhage.	One hour following second surfactant dose at 12-24 hours after initial dose
Patients With Bronchopulmonary Dysplasia (Supplemental Oxygen at 36 Week Post Menstrual Age)	Patients with Bronchopulmonary Dysplasia (BPD), had chronic lung disease requiring supplemental oxygen support at >/= 36 weeks post menstrual age, were tallied. BPD is a chronic lung disease that develops, at least in part, as a consequence of NICU respiratory management of premature infants with Respiratory Distress Syndrome.	36 weeks post menstrual age
Bronchopulmonary Dysplasia (Supplemental Oxygen at 36 Week Post Menstrual Age) or Death Before Discharge From NICU.	Bronchopulmonary Dysplasia + death outcome for all patients enrolled in the study were tallied and used to determine whether neonatal death decreased the frequency of chronic lung disease in one group vs the other.	NICU hospitalization, up to 42 weeks post menstrual age

Collaborators and Investigators

• Sponsor: Alan Fujii
• Collaborators: Dey LP
• Investigators: Principal Investigator: Alan M Fujii, MD, Boston Medical Center

Publications and helpful links

General Publications

• Fujii AM, Editorial. Is There Really A Clinical Difference In Surfactant Preparations? J Perinatol 2010; 30:698; doi:10,1038/jp.2010.90
• Fujii A. Editorial. Are all animal derived surfactants the same? The e-NeoResearch 2011; 1 (1); 50-51.
• Fujii AM, Carillo M. Animal-derived surfactant treatment of respiratory distress syndrome in premature neonates: a review. Drugs Today (Barc). 2009 Sep;45(9):697-709.
• Fujii AM, Patel SM, Allen R, Doros G, Guo CY, Testa S. Poractant alfa and beractant treatment of very premature infants with respiratory distress syndrome. J Perinatol. 2010 Oct;30(10):665-70. doi: 10.1038/jp.2010.20. Epub 2010 Mar 25. Erratum In: J Perinatol. 2012 May;32(5):395.
• Fujii A, Allen R, Doros G, O'Brien S. Patent ductus arteriosus hemodynamics in very premature infants treated with poractant alfa or beractant for respiratory distress syndrome. J Perinatol. 2010 Oct;30(10):671-6. doi: 10.1038/jp.2010.21. Epub 2010 Mar 25.
• Fujii AM, Bailey J, Doros G, Sampat K, Sikes NC, Mason M, Kaiser JR. Cerebral Blood Flow Responses to Beractant and Poractant Administration. Journal of Neonatal-Perinatal Medicine 2009; 2:27-34

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: December 17, 2007
• First Submitted That Met QC Criteria: October 3, 2008
• First Posted (Estimate): October 6, 2008

Study Record Updates

• Last Update Posted (Estimate): October 3, 2011
• Last Update Submitted That Met QC Criteria: September 28, 2011
• Last Verified: October 1, 2008

More Information

Terms related to this study

• Keywords: Surfactant; Very Premature; RDS
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Congenital Abnormalities; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Heart Defects, Congenital; Cardiovascular Abnormalities; Infant, Premature, Diseases; Syndrome; Premature Birth; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Ductus Arteriosus, Patent; Respiratory System Agents; Pulmonary Surfactants; Poractant alfa; Beractant
• Other Study ID Numbers: H-23371

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No