A Double Blind, Randomized, Controlled Study to Evaluate CHF 5633 (Synthetic Surfactant) and Poractant Alfa in Neonates With Respiratory Distress Syndrome (RDS) (POC)

A DOUBLE BLIND, RANDOMIZED, CONTROLLED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF SYNTHETIC SURFACTANT (CHF 5633) IN COMPARISON TO PORCINE SURFACTANT (PORACTANT ALFA, CUROSURF®) IN THE TREATMENT OF PRETERM NEONATES WITH RESPIRATORY DISTRESS SYNDROME

A multicenter, double blind, randomized, single dose, active-controlled study to investigate the efficacy and safety of synthetic surfactant (CHF 5633) in comparison to porcine surfactant (Poractant alfa, Curosurf ®) in the treatment of preterm neonates with respiratory distress syndrome. Main objectives of this study are to investigate the short term efficacy profile of CHF 5633 vs. porcine surfactant (Poractant Alfa, Curosurf®) in terms of reduced oxygen requirement and ventilatory support and to evaluate the mid-term efficacy profile in terms of reduced incidence of bronchopulmonary dysplasia (BPD) and mortality/BPD rate at 36 weeks post menstrual age (PMA), mortality rate at 28 days and 36 weeks PMA, RDS-associated mortality through 14 days of age and other major co-morbidities of prematurity.

Inclusion criteria are: Written parental informed consent, inborn preterm neonates of either sex with a gestational age of 24+0 weeks up to 29+6 weeks, clinical course consistent with RDS, requirement of endotracheal surfactant administration within 24 hours from birth, fraction of inspired oxygen (FiO2) ≥0.30 for babies 24+0 to 26+6 weeks and FiO2 ≥0.35 for babies 27+0 to 29+6 weeks to maintain arterial oxygen saturation by pulse oximetry (SpO2) between 88-95%.

Study Overview

• Status: Completed
• Conditions: Respiratory Distress Syndrome, Newborn
• Intervention / Treatment: Drug: CHF5633; Drug: Poractant alfa

• Study Type: Interventional
• Enrollment (Actual): 123
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States
      • University of South Alabama - USA Children's and Women's Hospital
  • California
    • Los Angeles, California, United States
      • LAC + USC Medical Center, Keck School of Medicine
    • Orange, California, United States
      • UC Irvine Medical Center
    • San Diego, California, United States
      • Sharp Mary Birch Hospital
  • Connecticut
    • Hartford, Connecticut, United States
      • Connecticut Children's Medical Center
  • Florida
    • Plantation, Florida, United States
      • Plantation General Hospital (Sheridan Clinical Research, Inc.)
  • Georgia
    • Augusta, Georgia, United States
      • Jatinder Bhatia
  • Indiana
    • Indianapolis, Indiana, United States
      • Indiana University School of Medicine
    • South Bend, Indiana, United States
      • Memorial Hospital of South Bend
  • Kentucky
    • Louisville, Kentucky, United States
      • University of Louisville Research Foundation, Inc.
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital For Children at Tufts Medical Center
    • Springfield, Massachusetts, United States
      • Baystate Children's Hospital / Baystate Medical Center
  • New York
    • Mineola, New York, United States
      • Winthrop University Hospital
    • New York, New York, United States
      • Kings County Hospital Center
    • Valhalla, New York, United States
      • Sergio G. Golombek
  • North Carolina
    • Greenville, North Carolina, United States
      • Martha Naylor
  • Ohio
    • Cincinnati, Ohio, United States
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States
      • Case Western Reserve University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Krishnamurthy Sekar
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Hahnemann University Hospital
  • Texas
    • El Paso, Texas, United States
      • Texas Tech University Health Sciences Center
  • Washington
    • Tacoma, Washington, United States
      • MultiCare Institute for Research & Innovation
  • West Virginia
    • Morgantown, West Virginia, United States
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent obtained by parents/legal representative (according to local regulation) prior to any study-related procedures
2. Inborn preterm neonates of either sex with a gestational age of 24+0 weeks up to 29+6 weeks
3. Clinical course consistent with RDS
4. Requirement of endotracheal surfactant administration within 24 hours from birth
5. Fraction of inspired oxygen (FiO2) ≥0.30 for babies 24+0 to 26+6 weeks and FiO2 ≥0.35 for babies 27+0 to 29+6 weeks to maintain SpO2 between 88-95%

Exclusion Criteria:

1. Use of surfactant prior to study entry and need for intratracheal administration of any other treatment (e.g. nitric oxide)
2. Known genetic or chromosomal disorders, major congenital anomalies (cardiac malformations, myelomeningocele etc)
3. Maternal drug abuse (heroin, methadone, methamphetamine, or cocaine) or significant alcohol consumption during pregnancy
4. Mothers with prolonged rupture of the membranes (>21 days duration)
5. Strong suspicion of congenital pneumonia/infection, sepsis
6. Presence of air leaks prior to study entry
7. Evidence of severe birth asphyxia
8. Neonatal seizures prior to study entry
9. Any condition that, in the opinion of the Investigator, would place the neonate at undue risk
10. Participation in another clinical trial of any placebo, drug or biological substance conducted under the provisions of a protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CHF5633; Single dose within 24 hours from birth	Drug: CHF5633; Rescue treatment (if needed)
Active Comparator: Poractant alfa; Single dose within 24 hours from birth	Drug: Poractant alfa; Rescue treatment (if needed)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio	SpO2/FiO2 ratio The oxygen requirement and ventilatory support were assessed through arterial oxygen saturation, measured by pulse oximetry (SpO2 [%]) and ventilator settings, by measuring fraction of inspired oxygen (FiO2[%]) and SpO2/FiO2. Results are shown as change from baseline, summarized at post-treatment timepoints. Definitions: SpO2=Arterial Oxygen saturation by pulse oximetry; FiO2=Fraction of inspired oxygen; Baseline=The last pre-dose measurement taken on Day -1.	Post-treatment Day 1: 30 min, at 1h, 3h, 6h, 12h, 18h, 24 h; Day 2, 3, 5, and 7
Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7	Fraction of inspired oxygen (FiO2) (percent) during the first 24 h and up to Day 7. Fraction of inspired oxygen (FiO2 [percent]). Results are shown as change from baseline, summarized at post-treatment time points. Definitions: FiO2=Fraction of inspired oxygen (percent); Baseline=The last pre-dose measurement taken on Day -1;	Post-treatment Day 1: 30 min, at 1h, 3h, 6h, 12h, 18h, 24 h; Day 2, 3, 5, and 7
Number of Patients With Bronchopulmonary Dysplasia and Mortality	Bronchopulmonary dysplasia and mortality. Results summarize the following items: Number of patients who died and the number of patients who had bronchopulmonary dysplasia (BPD) were assessed by treatment, at 36 weeks post menstrual age (PMA). Number of patients who died by Day 28 post-natal age (PNA). Number of patients with respiratory distress syndrome (RDS)-associated mortality by Day 14 post-natal age (PNA). Definitions: BPD=Bronchopulmonary dysplasia; Mortality/BPD incidence=The incidence of neonates dead within 36-week PMA or alive at 36-week PMA with a diagnosis of BPD; PMA=Post menstrual age; PNA=Post-natal age; RDS=Respiratory distress syndrome;	36 weeks post menstrual age, Day 14 Post-Natal Age, Day 28 Post-Natal Age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Normal Breathing (Room Air) Within 24 Hours	Normal breathing (room air) within 24 hours The number of patients with at least one reading of FiO2 equal to 21% (i.e. corresponding to room air for oxygen concentration) within 24 hours from first dose of surfactant was evaluated.	Post-treatment up to 24 h
Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant)	Number of patients with the need for re-dosing (use of rescue surfactant). The number of patients requiring at least one surfactant rescue dose (i.e. re-dosing with the study drug) at any time during the study was evaluated.	Day 1 to Day 7
Time to Reach Normal Breathing (Room Air) Within 24 Hours	Time to reach normal breathing (room air) within 24 hours. The median time to reach normal breathing (room air) within 24 hours from first dose of surfactant was evaluated. These are the patients who contributed to the results in the outcome measure 'Normal Breathing (room air) within 24 hours'.	Post-treatment Day 1: up to 24 h
Concentration of Biomarkers of Inflammation in Tracheal Aspirates	The inflammatory status of the patients was assessed (in a subgroup of babies who required endotracheal intubation for mechanical ventilation, when feasible). This was performed by measuring the concentration of specific biomarkers of inflammation in tracheal aspirates. The biomarkers measured were: Interleukin 1β, Interleukin 6, Interleukin 8, Myeloperoxidase, and Tumor Necrosis Factor-Alpha. The total protein content in tracheal aspirates was measured as an endogenous marker of dilution to calculate the extent to which epithelial lining fluid (ELF) was diluted during the tracheal aspirate procedure. To adjust for variation during the collection of tracheal aspirates, the measured cytokines values were normalized to the total protein. Results are presented as change from baseline in pg/mg total protein and were evaluated by descriptive statistics. Definition: Baseline=The last pre-dose measurement taken on Day -1;	Post-treatment Day 1 (24 h), Day 2 (48 h)
Immunogenicity: Assessment of Antibodies to Surfactant Protein B (SP-B) Analogue (CHF 5736.03) and to Surfactant Protein C (SP-C) Analogue (CHF 4902.03)	Immunogenicity was assessed by measuring antibodies to SP-B analogue (CHF 5736.03) and to SP-C analogue (CHF 4902.03), contained in CHF 5633. Results are expressed as the titre (i.e. serum dilution) at which the sample had an absorbance of 0.069 (background) for SP-C Analogue (CHF 4902.03) CHF or an absorbance of 0.05 for SP-B Analogue (CHF 5736.03) in a microplate reader. The positive control serum was diluted in buffer solution and the maximum binding for the positive control was determined at dilutions < 1/12.5 for SPC and <1/100 for SPB. Test samples for immunogenicity were analyzed by using negative and positive controls. By definition, titer <12.5 for CHF-4902.03 and <100 for CHF-5736.02 show that the test serum had an absorbance equal to background at the same dilution at which the positive control had the maximum binding, implying absence of antibodies.	At approximately 5 weeks after the administration of study drug (with a range from 3 to 6 weeks).

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Rangasamy Ramanathan, MD, Division of Neonatology, Department of Pediatrics, LAC+USC Medical Center and Good Samaritan Hospital, Keck School of Medicine of USC, Los Angeles, CA, USA

Publications and helpful links

General Publications

• Ramanathan R, Biniwale M, Sekar K, Hanna N, Golombek S, Bhatia J, Naylor M, Fabbri L, Varoli G, Santoro D, Del Buono D, Piccinno A, Dammann CE. Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial. J Pediatr. 2020 Oct;225:90-96.e1. doi: 10.1016/j.jpeds.2020.06.024. Epub 2020 Jun 14. Erratum In: J Pediatr. 2020 Nov 10;: J Pediatr. 2022 May;244:262.

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2016
• Primary Completion (Actual): May 24, 2018
• Study Completion (Actual): May 24, 2018

Study Registration Dates

• First Submitted: May 20, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (Estimate): May 22, 2015

Study Record Updates

• Last Update Posted (Actual): August 13, 2021
• Last Update Submitted That Met QC Criteria: July 19, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: neonates, pulmonary surfactant
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory System Agents; Pulmonary Surfactants; Poractant alfa
• Other Study ID Numbers: CCD-05633AA1-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No