A Study in Preterm Neonates With Respiratory Distress Syndrome (RDS) Comparing CUROSURF® Administration Through Less Invasive Surfactant Administration (LISA) and Conventional Administration

Study Overview
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Brief Summary
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This study compared the administration of porcine surfactant (poractant alfa, Curosurf®) through a less invasive method (LISA), using a thin catheter, CHF 6440 (LISACATH®), during non-invasive ventilation (CPAP, NIPPV, BiPAP) with an approved conventional surfactant administration during invasive ventilation followed by rapid extubation in terms of short term and mid-term safety and efficacy in spontaneously breathing preterm neonates who have clinical signs of respiratory distress syndrome (RDS).

Detailed Description
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This study was an open-label, multicentre, randomized, controlled study of spontaneously breathing neonates with RDS. Neonates were evaluated according to the selection criteria and then randomized to surfactant treatment via LISA or standard administration procedure. The enrolment was staggered: the gestational age was restricted to 27+0 weeks up to 28+6 weeks for the first 15 neonates. Provided no safety concerns were raised, the enrolment was planned to be extended to the whole population (i.e. 25+0 weeks up to 28+6 weeks). Enrolled neonates were evaluated in a main phase of the trial until discharge or 40 weeks post-menstrual age (PMA), whichever came first. Their clinical status and neurodevelopment was to be assessed at 24-month corrected age as a separate stand-alone visit. The Sponsor decided to terminate the study early, due to uncertain sufficient availability of the CHF 6440 catheter.

Official Title
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An Open-Label, Multicenter, Randomized, Controlled Study in Spontaneously Breathing Preterm Neonates With Respiratory Distress Syndrome to Compare Two Procedures for Porcine Surfactant (Poractant Alfa, CUROSURF®) Administration: A Less Invasive Method (LISA) During Non-invasive Ventilation (NIV) and the Conventional Administration During Brief Invasive Ventilation.

Conditions
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Respiratory Distress Syndrome (RDS)

Intervention / Treatment
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* Combination Product: LISA combination product (Curosurf+catheter CHF6440)
* Drug: Curosurf through conventional administration (endotracheal tube)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained by parents/legal representative (according to local regulation) prior to or after birth Preterm neonates of either sex aged ≥30 minutes and <24 hours, spontaneously breathing and stabilized on non-invasive ventilation (NIV). Gestational age of 25+0 weeks up to 28+6 completed weeks, except for the first 15 enrolled neonates in which the gestational age will be restricted to 27+0 weeks up to 28+6 weeks. Clinical course consistent with RDS. Fraction of inspired oxygen (FiO2) ≥0.30 to maintain preductal oxygen saturation (SpO2) between 88-95%. Exclusion Criteria: Need for immediate endotracheal intubation for cardiopulmonary resuscitation or insufficient respiratory drive Use of nasal high frequency oscillatory ventilation (nHFOV) prior to study entry Use of surfactant prior to study entry and need for intratracheal administration of any other treatment (e.g. nitric oxide) Known genetic or chromosomal disorders, major congenital anomalies (congenital heart diseases, myelomeningocele etc) Mothers with prolonged rupture of the membranes (> 21 days duration) Presence of air leaks if identified and known prior to study entry Evidence of severe birth asphyxia (e.g. continued need for resuscitation at 10 minutes after birth, altered neurological state, or neonatal encephalopathy) Neonatal seizures prior to study entry Any condition that, in the opinion of the Investigator, would place the neonate at undue risk Participation in another clinical trial of any medicinal product, placebo, experimental medical device, or biological substance conducted under the provisions of a protocol on the same therapeutic target.

Ages Eligible for Study
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Minimum Age: 30 Minutes
Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Curosurf LISA<br>Single dose of poractant alfa 200 mg/kg via brief insertion of a thin catheter (CHF 6440) into the trachea in neonates with RDS. A second surfactant dose at 100 mg/kg will be administered with the same technique as the first dosage administration if needed. After the first and second surfactant administration, neonates could receive a third surfactant dose at 100 mg/kg through a standard technique if needed. | Combination Product: LISA combination product (Curosurf+catheter CHF6440)<br>* Curosurf administration through brief insertion of a thin catheter into the trachea<br>|
| Active Comparator: Curosurf Endotracheal Tube<br>Single dose of poractant alfa 200 mg/kg via the conventional intubation with endotracheal tube in neonates with RDS. A second surfactant dose at 100 mg/kg will be administered with the same technique as the first dosage administration if needed. After the first and second surfactant administration, neonates could receive a third surfactant dose at 100 mg/kg through a standard technique if needed. | Drug: Curosurf through conventional administration (endotracheal tube)<br>* Curosurf through conventional administration (endotracheal tube), followed by rapid extubation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Study Treatment Administration: Number of Participants Who Received 1, 2, or 3 Doses of Treatment | Extent of exposure to study treatment is summarized by treatment group. Number of participants who received 1, 2, or 3 doses of treatment. All neonates received the first administration of Curosurf® 200 mg/kg. In case of lack of efficacy or clinical deterioration, a second dose of Curosurf® 100 mg/kg was administered using the same technique as the first dose. Neonates could receive a third Curosurf® 100 mg/kg dose if needed, administered using a standard technique. Results are presented as the number of neonates who received 1, 2, or 3 doses of Curosurf®, administered. | First 72 hours of life. | 
| Safety: Study Treatment Administration: Number of Participants for Whom the First Attempt Failed to Insert the Catheter/Endotracheal Tube | Number of participants for whom the first attempt failed to insert the catheter/endotracheal tube and the percentage of neonates with first failed attempt, is presented by treatment group. | At first surfactant administration, up to Day 1. | 
| Safety: Study Treatment Administration: Number of Maneuvers Discontinued Due to Neonate's Severe Destabilization | Number of manoeuvres (attempts) discontinued, due to neonate's severe destabilization is presented by treatment group. | At first surfactant administration, up to Day 1 or at second administration, up to 2 days. | 
| Safety: Study Treatment Administration: Number of Attempts to First Successful Insertion | Number of attempts required to achieve first successful insertion is presented by treatment group. | At first surfactant administration, up to Day 1 or at second administration, up to 2 days. | 
| Safety: Study Treatment Administration: Number of Device Misallocation for LISA Administration Group (Esophageal Insertion) | Number of device misallocation for LISA administration group (esophageal insertion). Data was not collected from participants in the Curosurf Endotracheal Tube -- the control arm of the study, because it is not applicable. | At first surfactant administration, up to Day 1 or at second administration, up to 2 days. | 
| Safety: Study Treatment Administration: Duration of Surfactant Administration | Duration of surfactant administration is presented by treatment group. | At first surfactant administration, up to Day 1 or at second administration, up to 2 days. | 
| Safety: Study Treatment Administration: Duration of the Whole Procedure | Duration of the whole procedure (starting from the insertion of laryngoscope up to the removal of the catheter/ETT), is presented by treatment group. | At first surfactant administration, up to Day 1 or at second administration, up to 2 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Duration of Oxygen Alone Supplementation and Any Non-Invasive Ventilation (NIV) | The duration of oxygen alone supplementation and any non-invasive ventilation (NIV) during the study are presented by treatment group. PMA=Post-Menstrual Age PNA=Post-Natal Age | First 72 hours of life, Up to 28 days Post-Natal Age (PNA), Up to 36 weeks Post-Menstrual Age (PMA). | 
| Efficacy: Neonates Needing Additional 2 or 3 Doses of Surfactant | A summary of the percentage of neonates requiring at least one additional dose of surfactant, and respective statistical analysis, is presented by treatment group i.e. 2 or 3 doses of surfactant . | First 72 hours of life. | 
| Efficacy: Neonates Needing Additional Surfactant Doses | A summary of the percentage of neonates requiring at least one additional dose of surfactant, and respective statistical analysis, is presented by treatment group. | First 72 hours of life. | 
| Efficacy: Preductal Oxygen Saturation/Fraction of Inspired Oxygen (SpO2/FiO2) Ratio | The mean SpO2/FiO2 ratio values at timepoints up to and including 120 hours post-treatment, and respective statistical analyses, are summarized by treatment group. | Pre-procedure, at time 0 (T0, end of surfactant instillation) and post treatment after T0 at 5, 15, 30 minutes, at 1, 6, 12, 24, 48, 72, and 120 hours, on Day 28 PNA, 36 weeks PMA. | 
| Efficacy: Fraction of Inspired Oxygen (FiO2) | The FiO2 values at timepoints up to and including 120 hours post-treatment and the changes from pre-procedure to each of those timepoints are presented by treatment group. The fraction of inspired oxygen (FiO2) is the concentration of oxygen in the gas mixture. | Pre-procedure, at time 0 (T0, end of surfactant instillation) and post treatment after T0 at 5, 15, 30 minutes, at 1, 6, 12, 24, 48, 72, and 120 hours, on Day 28 PNA, 36 weeks PMA. | 
| Efficacy: Preductal Oxygen Saturation (SpO2) | The mean SpO2 values at timepoints up to and including 120 hours post-treatment are summarized by treatment group. Oxygen saturation (SpO2) is a measurement of how much oxygen the blood is carrying as a percentage of the maximum it could carry. | Pre-procedure, at time 0 (T0, end of surfactant instillation) and post treatment after T0 at 5, 15, 30 minutes, at 1, 6, 12, 24, 48, 72, and 120 hours, on Day 28 PNA, 36 weeks PMA. | 
| Efficacy: Percentage of Neonates Needing Any Intubation Procedure, Outside the Initial Surfactant Administration Period | The percentage of neonates needing any intubation procedure, outside the initial surfactant administration period (i.e., excluding endotracheal intubation[s] that were required for surfactant administration in the Conventional administration arm), in the first 72 hours of life, in the first 28 days post-natal age (PNA), and within 36 weeks Post-menstrual age (PMA), and respective statistical analyses, are presented. | First 72 hours of life, up to 28 days post-natal age (PNA), Up to 36 weeks Post-menstrual age (PMA) | 
| Efficacy: Median Duration of Invasive Mechanical Ventilation During the Study | The duration of invasive ventilation (MV) in the first 28 days PNA, and within 36 weeks PMA, are presented by treatment group. Participants who actually received invasive ventilation are reported in the table below. | Up to 28 days PNA, Up to 36 weeks PMA | 
| Efficacy: Duration of Invasive Mechanical Ventilation During the Study | The duration of invasive ventilation (MV) in the first 72 hours of life and respective statistical analyses, are presented by treatment group. | First 72 hours of life | 
| Efficacy: Percentage of Neonates Needing Invasive Mechanical Ventilation (MV) During the Study | The percentage of neonates needing invasive mechanical ventilation (MV) in the first 72 hours of life, in the first 28 days post-natal age (PNA), and within 36 weeks Post-Menstrual Age (PMA), and respective statistical analyses, are presented by treatment group. | First 72 hours of life, Up to 28 days Post-Natal Age (PNA), Up to 36 weeks PMA | 
| Efficacy: Blood Gas Analysis Parameters -- pH | The blood gas analysis for blood pH at all timepoints and the changes from pre-procedure to each timepoint are presented. Results for pH values are based on a scale of 0 to 14. A pH value of 7 is neutral, pH less than 7 is acidic, and pH greater than 7 is basic. | First 72 hours of life (1h, 6h, 24h, 48h, 72h) | 
| Efficacy: Blood Gas Analysis Parameters -- Partial Pressure of Carbon Dioxide (pCO2) | The blood gas analysis partial pressure of carbon dioxide (pCO2) at all timepoints and the changes from pre-procedure to each timepoint are presented. | First 72 hours of life (1h, 6h, 24h, 48h, 72h) | 
| Efficacy: Blood Gas Analysis Parameters -- Partial Pressure of Oxygen (pO2) | The blood gas analysis partial pressure of oxygen (pO2) at all timepoints and the changes from pre-procedure to each timepoint are presented. | First 72 hours of life (1h, 6h, 24h, 48h, 72h) | 
| Efficacy: Blood Analysis Parameter -- Bicarbonate (HCO3^-) | The blood concentration of bicarbonate (HCO3^-) at all timepoints and the changes from pre-procedure to each timepoint are presented. | First 72 hours of life (1h, 6h, 24h, 48h, 72h) | 
| Efficacy: Blood Analysis Parameter -- Base Excess | The blood base excess at all timepoints and the changes from pre-procedure to each timepoint are presented. Base excess is defined as the amount of acid that must be added to each litre of fully oxygenated blood to return the pH to 7.40 at a temperature of 37°C and a pCO2 of 40 mmHg (5.3 kPa). The value is reported as a concentration in units of milliequivalent per liter (mEq/L), with positive numbers indicating an excess of base and negative a deficit. | First 72 hours of life (1h, 6h, 24h, 48h, 72h) | 
| Efficacy: Blood Analysis Parameter -- Lactate | The blood concentration of lactate at all timepoints and the changes from pre-procedure to each timepoint are presented. | First 72 hours of life (1h, 6h, 24h, 48h, 72h) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CUROSURF®, Less Invasive Surfactant administration, LISPAP, Neonates, Newborns, Respiratory Distress Syndrome (RDS)