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

Primary Purpose

Bronchiolitis, Viral

Status
Terminated
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Curosurf 80Mg/Ml Intratracheal Suspension
Ambient Air
Sponsored by
Azienda Ospedaliera Universitaria Integrata Verona
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bronchiolitis, Viral

Eligibility Criteria

40 Weeks - 12 Months (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Azienda Ospedaliera Universitaria Integrata Verona

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Surfactant replacement (Curosurf)

Ambient Air

Arm Description

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

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

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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
Number of cases requiring new intubation
Number of cases requiring new intubation after previous extubation in 14 days from randomization.
Number of days of patients in PICU
Number of days of patients in PICU
Number of days of hospitalization
Number of days of hospitalization.
Number of days free from oxygen supplementation
Number of days free from oxygen supplementation
Values of the Oxygen Saturation Index (OSI)
Changes in the Oxygen Saturation Index (OSI)
Values of the mechanical ventilation parameter (MAP) during invasive mechanical respiratory support
Changes in the ventilatory parameter (MAP) during invasive mechanical respiratory support
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
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)
Rate of deaths
Rate of deaths before 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

Full Information

First Posted
April 9, 2019
Last Updated
April 12, 2021
Sponsor
Azienda Ospedaliera Universitaria Integrata Verona
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1. Study Identification

Unique Protocol Identification Number
NCT03959384
Brief Title
Efficacy and Safety of Curosurf® in Patients Invasively Ventilated for Severe Bronchiolitis Under 12 Months of Age
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Terminated
Why Stopped
Due to COVID19 hospital admissions by patients with moderate-severe bronchiolitis have drastically decreased from 02/2020 to date. Moreover, many centers that had initially joined the study project had great difficulties in the activation phase
Study Start Date
January 9, 2019 (Actual)
Primary Completion Date
April 9, 2021 (Actual)
Study Completion Date
April 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Azienda Ospedaliera Universitaria Integrata Verona

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchiolitis, Viral

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
multicenter, double-blind, placebo-controlled, randomized trial
Masking
ParticipantOutcomes Assessor
Masking Description
Patient's parents and the doctors/nurses responsible for the patient's care will be blinded. At each center only a physician and a nurse will know and prepare the drug or placebo, being subsequently not clinically involved in the care of that particular patient. The assignment of the type of treatment will be communicated by the Coordinator centre in an individual way and reserved to the researcher attending the patient's bed. The same medical researcher will then take care of administering the treatment assigned to the patient, masking the procedure with appropriate precautions. The preparation and administration of treatment can be done with the help of a nurse who does not have to disclose the type of treatment assigned. Thereafter, such a nurse will not be involved in the patient's care until the conclusion of the study. The patient evaluation will be carried out by other physicians and/or nurses who will not be aware of the type of treatment carried out.
Allocation
Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Surfactant replacement (Curosurf)
Arm Type
Experimental
Arm Description
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
Arm Title
Ambient Air
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Curosurf 80Mg/Ml Intratracheal Suspension
Other Intervention Name(s)
phospholipid fraction from porcine lung
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Ambient Air
Intervention Description
Ambient air aspirated in sterile syringes
Primary Outcome Measure Information:
Title
Number of days free from invasive mechanical ventilation
Description
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)
Time Frame
day 14
Secondary Outcome Measure Information:
Title
Number of days free from non-invasive mechanical ventilation in the post-extubation phase
Description
Number of days free from non-invasive mechanical ventilation in the post-extubation phase
Time Frame
day 14
Title
Number of cases requiring new intubation
Description
Number of cases requiring new intubation after previous extubation in 14 days from randomization.
Time Frame
day 14
Title
Number of days of patients in PICU
Description
Number of days of patients in PICU
Time Frame
day 14
Title
Number of days of hospitalization
Description
Number of days of hospitalization.
Time Frame
day 14
Title
Number of days free from oxygen supplementation
Description
Number of days free from oxygen supplementation
Time Frame
day 14
Title
Values of the Oxygen Saturation Index (OSI)
Description
Changes in the Oxygen Saturation Index (OSI)
Time Frame
detected 15 minutes before administration of treatment and at a distance of 2, 6, 12, 24, 36 and 48 hours
Title
Values of the mechanical ventilation parameter (MAP) during invasive mechanical respiratory support
Description
Changes in the ventilatory parameter (MAP) during invasive mechanical respiratory support
Time Frame
detected 15 minutes before administration of treatment and at a distance of 2, 6, 12, 24, 36 and 48 hours
Title
Number of patients undergoing a repeated treatment (Curosurf or placebo)
Description
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
Time Frame
within 24 hours of the first treatment
Title
Number of patients undergoing unconventional or more invasive treatments (HFOV, Nitric Oxide, ECMO)
Description
Number of patients undergoing unconventional or more invasive treatments (HFOV, Nitric Oxide, ECMO)
Time Frame
during the first 14 days
Title
Rate of deaths
Description
Rate of deaths before hospital discharge
Time Frame
(1) Mortality during the first 14 days of hospitalization (2) Mortality from the date of the first intervention until the date of hospital discharge
Title
Number of serious desaturation episodes, severe bradycardia, extreme bradycardia or cardiac arrest, pulmonary hemorrhage, pneumothorax
Description
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
Time Frame
within the first 48 hours after treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Weeks
Maximum Age & Unit of Time
12 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Aged > 40 weeks (correct gestational age) and < 12 months. Patient intubated and mechanically ventilated for at least 6 hours, with expected requirement of ventilatory support of at least 24 hours. Clinical picture strongly suggestive for acute bronchiolitis (fever of probable viral origin, fine crackles, prolonged expiration, lung hyperexpansion on chest X-ray) Moderate or severe pediatric acute respiratory distress syndrome, defined by a Oxygenation Index (OI) > 8 or an Oxygen Saturation Index (OSI) > 7.5 Written informed consent obtained from both parents Exclusion Criteria: 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. Recent phase of oxygen dependency (need for oxygen supplementation to maintain satO2 > 94% in the four weeks preceding hospitalization in Pediatric ICU) Invasive mechanical ventilation for more than 24 hours. Oxygenation index (OI) > 30 Cyanotic congenital heart disease Untreated pneumothorax Neuromuscular diseases Severe Neurological Alterations Other severe congenital anomalies Indication not to attempt resuscitation Patient already recruited for other clinical studies
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paolo Biban, MD
Organizational Affiliation
AOUI Verona
Official's Role
Principal Investigator
Facility Information:
Facility Name
Azienda Ospedaliera Universitaria Integrata Verona
City
Verona
ZIP/Postal Code
37126
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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
Citations:
PubMed Identifier
33077567
Citation
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.
Results Reference
derived

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

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