Efficacy and Safety of Curosurf® in Patients Invasively Ventilated for Severe Bronchiolitis Under 12 Months of Age

Efficacy and Safety of Curosurf® in Patients Under 12 Months of Age Requiring Invasive Mechanical Ventilation for Acute Respiratory Distress Syndrome in the Course of Bronchiolitis: A Randomized, Double-blind, Placebo-controlled Trial

Background. Viral bronchiolitis is a common cause of hospitalization for acute respiratory insufficiency in young infants. Despite several RCT have tested the effectiveness of various agents, currently there is no proven specific therapy for bronchiolitis, treatment remaining mostly supportive. Based on available studies, exogenous surfactant replacement in bronchiolitis is likely to have a promising safety and efficacy profile. Primary objective. To evaluate whether Curosurf treatment is effective compared to placebo (air) in reducing the duration of invasive mechanical ventilation in the first 14 days of hospitalization, in infants less than 12 months suffering from acute hypoxemic bronchiolitis. Methods. a multicenter, double-blind, placebo-controlled, randomized trial. 19 Italian PICUs will enroll children less than12 months with hypoxemic acute bronchiolitis, with need for invasive mechanical ventilation. Once the patient has been recruited, randomization should occur as quickly as possible. The first dose of Curosurf or placebo should be administered within 60 minutes of randomization. The treatment may be repeated once, not before 12 hours and not later than 24 hours after the initial dose. The assignment of the type of treatment will be communicated by the Coordinator center to the researcher attending the patient's bed. The same medical researcher will then take care of administering the assigned treatment, masking the procedure with appropriate precautions, for example with screens or closing the patient's room whenever possible. The preparation and administration of treatment, medication or placebo, can be done by a nurse who must not disclose the assigned treatment and will not be involved in the patient's care until the conclusion of the study. Patient evaluation will be carried out by other physicians and/or nurses who will not be aware of the assigned treatment. Regardless the received treatment, all patients will be assisted according to standard practice of the Unit. For the purposes of the study, several parameters will be collected 15 minutes before, and 2, 6, 12, 24, 36, 48 hours after administration of the drug: oxygenation indexes such as OI, OSI, PaO2 and SatO2; Invasive ventilation parameters, i.e. current volume, positive end expiratory pressure, peak pressure, respiratory rate, FiO2 and mean airway pressure; and ventilation indexes such as PaCO2 and End Tidal CO2. If it is necessary to repeat the treatment, the above parameters will be re-collected with the same timepoints. During the study all the AE/ADR will be recorded.

Study Overview

• Status: Terminated
• Conditions: Bronchiolitis, Viral
• Intervention / Treatment: Drug: Curosurf 80Mg/Ml Intratracheal Suspension; Other: Ambient Air

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria integrata Verona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 months to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged > 40 weeks (correct gestational age) and < 12 months.
2. Patient intubated and mechanically ventilated for at least 6 hours, with expected requirement of ventilatory support of at least 24 hours.
3. Clinical picture strongly suggestive for acute bronchiolitis (fever of probable viral origin, fine crackles, prolonged expiration, lung hyperexpansion on chest X-ray)
4. Moderate or severe pediatric acute respiratory distress syndrome, defined by a Oxygenation Index (OI) > 8 or an Oxygen Saturation Index (OSI) > 7.5
5. Written informed consent obtained from both parents

Exclusion Criteria:

1. Severe prematurity (gestational age < 32 weeks). Patients with gestational age less than 32 weeks will be excluded because they are considered at high risk for respiratory pathology following their severe prematurity. This consideration does not apply in successive gestational ages. Therefore patients with mild prematurity, i.e. with gestational age equal to or greater than 32 weeks, are not to be excluded.
2. Recent phase of oxygen dependency (need for oxygen supplementation to maintain satO2 > 94% in the four weeks preceding hospitalization in Pediatric ICU)
3. Invasive mechanical ventilation for more than 24 hours.
4. Oxygenation index (OI) > 30
5. Cyanotic congenital heart disease
6. Untreated pneumothorax
7. Neuromuscular diseases
8. Severe Neurological Alterations
9. Other severe congenital anomalies
10. Indication not to attempt resuscitation
11. Patient already recruited for other clinical studies

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: Surfactant replacement (Curosurf); Broncho-alveolar lavage (BAL) with 25 mg / kg of Curosurf, diluted 1:10 with physiological solution, divided in two aliquots administered with a endotracheal tube in two different postures (1st BAL on right decubitus, 2nd BAL on left decubitus).; Following supplementation of a dose of 25 mg / kg of Curosurf, diluted with physiological solution 1: 2 (1 ml = 40 mg of surfactant), given in two aliquots with endotracheal tube in two different postures (1st on right decubitus, 2nd on left decubitus). The treatment assigned may be repeated at least 12 hours later and in any case within 24 hours from the first treatment, at the same dosage and with the same method of administration	Drug: Curosurf 80Mg/Ml Intratracheal Suspension; CUROSURF is a natural surfactant obtained from swine lungs containing almost exclusively phospholipids, in particular phosphatidylcholine (about 70% of the total phospholipid content) and about 1% of low molecular weight hydrophobic proteins, specific for surfactant, SP-B and SP -C. CUROSURF will be administered via endotracheopulmunary.; Other Names: phospholipid fraction from porcine lung
Placebo Comparator: Ambient Air; Broncho-alveolar lavage (BAL) with air, administered with a endotracheal tube in two different postures (1st BAL on right decubitus, 2nd BAL on left decubitus).; Following supplementation of air given with endotracheal tube in two different postures (1st on right decubitus, 2nd on left decubitus). The treatment assigned may be repeated at least 12 hours later and in any case within 24 hours from the first treatment, at the same dosage and with the same method of administration	Other: Ambient Air; Ambient air aspirated in sterile syringes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days free from invasive mechanical ventilation	Number of days free from invasive mechanical ventilation within the first 14 days of hospitalization. Ventilation-free days will start after the first successful extubation (at least 48 hours without the need for re-intubation)	day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days free from non-invasive mechanical ventilation in the post-extubation phase	Number of days free from non-invasive mechanical ventilation in the post-extubation phase	day 14
Number of cases requiring new intubation	Number of cases requiring new intubation after previous extubation in 14 days from randomization.	day 14
Number of days of patients in PICU	Number of days of patients in PICU	day 14
Number of days of hospitalization	Number of days of hospitalization.	day 14
Number of days free from oxygen supplementation	Number of days free from oxygen supplementation	day 14
Values of the Oxygen Saturation Index (OSI)	Changes in the Oxygen Saturation Index (OSI)	detected 15 minutes before administration of treatment and at a distance of 2, 6, 12, 24, 36 and 48 hours
Values of the mechanical ventilation parameter (MAP) during invasive mechanical respiratory support	Changes in the ventilatory parameter (MAP) during invasive mechanical respiratory support	detected 15 minutes before administration of treatment and at a distance of 2, 6, 12, 24, 36 and 48 hours
Number of patients undergoing a repeated treatment (Curosurf or placebo)	Number of patients undergoing a repeated treatment (Curosurf or placebo). The repetition of the assigned treatment may take place at least 12 hours apart and in any case within 24 hours of the first treatment, at the same dosage and with the same method of administration	within 24 hours of the first treatment
Number of patients undergoing unconventional or more invasive treatments (HFOV, Nitric Oxide, ECMO)	Number of patients undergoing unconventional or more invasive treatments (HFOV, Nitric Oxide, ECMO)	during the first 14 days
Rate of deaths	Rate of deaths before hospital discharge	(1) Mortality during the first 14 days of hospitalization (2) Mortality from the date of the first intervention until the date of hospital discharge
Number of serious desaturation episodes, severe bradycardia, extreme bradycardia or cardiac arrest, pulmonary hemorrhage, pneumothorax	Number of serious desaturation episodes (SatO2 < 75%), episodes of severe bradycardia (FC < 80/min) , episodes of extreme bradycardia or cardiac arrest with the need for chest compressions and/or administration of drugs for resuscitation, episodes of pulmonary hemorrhage, episodes of pneumothorax	within the first 48 hours after treatment

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Investigators: Principal Investigator: Paolo Biban, MD, AOUI Verona

Publications and helpful links

General Publications

• Biban P, Conti G, Wolfler AM, Carlassara S, Gitto E, Rulli I, Moscatelli A, Micalizzi C, Savron F, Sagredini R, Genoni G, Binotti M, Caramelli F, Fae M, Pettenazzo A, Stritoni V, D'Amato L, Zito Marinosci G, Calderini E, Scalia Catenacci S, Berardi A, Torcetta F, Bonanomi E, Bonacina D, Ivani G, Santuz P. Efficacy and safety of exogenous surfactant therapy in patients under 12 months of age invasively ventilated for severe bronchiolitis (SURFABRON): protocol for a multicentre, randomised, double-blind, controlled, non-profit trial. BMJ Open. 2020 Oct 19;10(10):e038780. doi: 10.1136/bmjopen-2020-038780.

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2019
• Primary Completion (Actual): April 9, 2021
• Study Completion (Actual): April 9, 2021

Study Registration Dates

• First Submitted: April 9, 2019
• First Submitted That Met QC Criteria: May 20, 2019
• First Posted (Actual): May 22, 2019

Study Record Updates

• Last Update Posted (Actual): April 15, 2021
• Last Update Submitted That Met QC Criteria: April 12, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchitis; Bronchiolitis; Bronchiolitis, Viral; Respiratory System Agents; Pulmonary Surfactants; Poractant alfa
• Other Study ID Numbers: SURFABRON

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available
• IPD Sharing Time Frame: Data will be available within 9 months of study completion, up to five years
• IPD Sharing Access Criteria: Data access request will be reviewed by the Steering committee. Requestors wil be required to sign a Data Access Agreement
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

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