Poractant Alfa (Curosurf®)) -- Effect in Adult Patients Diagnosed With 2019 Novel Coronavirus (SARS-COV-19; (Covid-19)) Acute Respiratory Distress Syndrome (ARDS)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and safety of poractant alfa (Curosurf®), administered by endotracheal (ET) instillation in hospitalized adult patients diagnosed with SARS-COV-19 acute respiratory distress syndrome (ARDS).

Detailed Description
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This was a multicentre, open-label, randomized phase II proof-of-concept study. The efficacy and safety of poractant alfa was evaluated in terms of ventilatory free days during the 21 days after randomization, in adult patients diagnosed with ARDS due to SARS-COV-19 infection. Each patient randomized to the study treatment received 3 administrations of Curosurf ® with a 24 hours dosing interval. The assessment collection was up to Day 28, when the evaluation occurred at the Intensive Care Unit (ICU), or by phone call if the patient has already been discharged. Seventy patients were planned to be randomized in the study with a ratio 3:2 (i.e. 42 patients in the poractant alfa arm and 28 in the control arm). The control arm population received Standard of Care (SoC). This study was conducted in United Kingdom (UK), United States of America (US), and Italy. Overall, 13 patients (Curosurf ® group) and 8 patients (control group) were randomised in the study. Due to low recruitment rate the study was terminated early for non-safety reasons. Curosurf® is a pulmonary surfactant of natural origin which, when delivered endotracheally (ET). Curosurf® is currently approved for marketing as treatment of premature neonates with RDS or at risk of Respiratory Distress Syndrome (RDS). Chiesi Farmaceutici S.p.A (Chiesi) conducted this study with its porcine-derived surfactant, Curosurf® (poractant alfa), to evaluate the efficacy and safety in ventilated adult patients who were critically unwell in intensive care with SARS-COV-19 ARDS.

Official Title
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Multicenter, Open-label, Randomised Trial to Assess the Efficacy and Tolerability of Poractant Alfa(Porcine Surfactant, Curosurf®) in Hospitalized Patients With SARS-COV-19 Acute Respiratory Distress Syndrome (ARDS)

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: CUROSURF® (poractant alfa)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants were eligible to be included in the study if the following criteria apply: Male or female ≥18 and ≤ 80 years of age Informed consent for participation in the study (refer to section 15 for detailed inform consent procedure) Positive 2019-nCoV Reverse Transcription Polymerase Chain Reaction (rt-PCR) before randomisation Arterial Partial Pressure of Oxygen/Fraction of Inspired Oxygen (PaO2/FiO2) ratio < 150 mmHg Lung compliance ≤45 ml/cmH20 Intubated and artificially ventilated less than 48 hours before the first poractant alfa administration Exclusion Criteria: Participants were excluded from the study if any of the following criteria apply: Any contraindications to surfactant administration e.g., pulmonary hemorrhage and pneumothorax) Weight < 40kg Stage 4 severe chronic kidney disease (i.e., Estimated Glomerular Filtration Rate (eGFR) < 30) Pregnancy Administration of any nebulized surfactant in the 48 hours before the first poractant alfa administration Extracorporeal membrane oxygenation (ECMO)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

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
Interventional Model Description: Seventy patients will be randomized in the study with a ratio 3:2 (i.e. 42 patients in the poractant alfa arm and 28 in the control arm).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>Patients treated with standard-of-care (SoC), as control cohort | |
| Experimental: Poractant alfa<br>Patients treated with CUROSURF® (poractant alfa), as an add-on to standard-of-care (SoC) | Drug: CUROSURF® (poractant alfa)<br>* Three administrations with a 24 hours dosing interval. Each endotracheal (ET) administration 1, 2, and 3 consisted of poractant alfa bolus: 30mg /kg (Lean Body Weight-LBW) = 0.375ml /kg LBW, diluted with normal saline up to 2ml /kg LBW.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days Alive and Ventilator-free Days | The number of days alive and ventilator-free days, defined as the number of days the patient is not receiving mechanical ventilation over the 21 days following randomisation. Mechanical ventilation was defined as invasive and non-invasive. The patient was defined as free of mechanical ventilation after 12 hours from the suspension of either invasive and non-invasive ventilation. Patients who died or were mechanically ventilated longer than this period were assessed as zero ventilator-free days. | up to 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Alive and Free of Respiratory Failure at Day 28 | The percentage of patients alive and free of respiratory failure (i.e. without need for mechanical ventilation, extracorporeal membrane oxygenation (ECMO), non-invasive ventilation, or high-flow nasal cannula oxygen delivery) at Day 28. | at Day 28 | 
| Number of Days Alive and Ventilator-Free at Day 28 | The number of days alive and ventilator-free (i.e. free of any mechanical ventilation for at least 12 hours) at Day 28. | at Day 28 | 
| Mortality at Day 21 and Day 28 | Mortality at Day 21 and Day 28 of the study by treatment group. | at Day 21 and at Day 28 | 
| Number of Days Alive and Free From Invasive Ventilation at Day 21 and Day 28 | The number of days alive and free from invasive ventilation at Day 21 and Day 28 is presented by treatment group. | Day 21 and Day 28 | 
| Number of Days Alive and Free From Non-Invasive Ventilation at Day 21 and Day 28 | The number of days alive and free from non-invasive ventilation at Day 21 and Day 28 is presented by treatment group. | Day 21 and Day 28 | 
| Percentage of Patients With Improvement in Severity Status at Day 28 or Discharge (Severity Score: Mild, Moderate, Severe, or Death) | The severity status of patients at baseline and at Day 28/Discharge and the percentage of patients with improvement in severity status (i.e. a decrease of at least 1 point in severity status) at Day 28/Discharge relative to baseline is presented. Severity was assessed using a point score system: Severity score was defined as mild, moderate, severe (see below*), or death and was based on PaO2/FiO2 ratio and patient status at Day 28/Discharge and numerically rated from 1-4, respectively. An improvement in severity was defined as a decrease of at least 1 point between baseline and Day 28/Discharge. At Day 28 the last follow up evaluation took place on the ICU if, still requiring critical care, or by phone call if the patient has been discharged from ICU by that time. *Mild: 200 mmHg < PaO2/FiO2 ratio ≤300 mmHg; Moderate: 100 mmHg < PaO2/FiO2 ratio ≤200 mmHg; Severe: PaO2/FiO2 ratio ≤100 mmHg | Day 28 or Discharge, whichever comes first | 
| Change From Baseline in Arterial Partial Pressure of Oxygen / Fraction of Inspired Oxygen (PaO2/FiO2) Ratio at Each Timepoint | Change from baseline in PaO2/FiO2 ratio measured at each timepoint following administration of each dose in the treatment and control group. The change was calculated from two time points as the value at the later time point minus the value at baseline. Partial pressure of oxygen (PaO2) is the oxygen pressure in arterial blood. The fraction of inspired oxygen (FiO2) is the concentration of oxygen in the gas mixture. The fraction of inspired oxygen (PaO2/FiO2) ratio is widely used in ICUs as an indicator of oxygenation status. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation, and Day 28 | 
| Percentage of Patients Alive and With PaO2/FiO2 Ratio Improvement >20% Compared to Baseline at Each Timepoint | The percentages of patients in categories of PaO2/FiO2 ratio improvement compared to baseline (>20%) at all timepoints post-baseline are summarised by treatment group. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Change From Baseline in Fraction of Inspired Oxygen (FiO2) at Each Timepoint | The FiO2 at baseline and at selected timepoints post-baseline was measured. Results are shown as changes from baseline, summarised by treatment group. The change was calculated from two time points as the value at the later time point minus the value at baseline. The unit for the variable is percent (%) and what is reported is an absolute change. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Length of ICU Stay (Days) at Day 28 | The length of ICU stay (days) at Day 28 is presented by treatment by treatment group. Patients who died or were mechanically ventilated longer than this period were assigned with 28 days. | up to 28 days | 
| Percentage of Patients Alive and Out of Intensive Care Unit (ICU) at Day 28 | The percentage of patients alive and out of ICU at Day 28 is presented by treatment group. | Day 28 | 
| Delta Sequential Organ Failure Assessment (SOFA) Score and Sub-component Measure at Day 3 and Day 28 | The Sequential Organ Failure Assessment (SOFA) score is a scoring system that assesses the performance of several organ systems in the body. The SOFA score was used to determine the extent of organ failure at Day 3 and Day 28/Discharge with respect to a pre-randomisation assessment. The total score was derived from six sub-scores system categories: respiratory, neurological, cardiovascular, hepatic, coagulation, and renal systems; respective sub-scores were calculated primarily considering PaO2/FiO2 ratio, Glasgow Coma Scale, mean arterial pressure (MAP) or requirement for vasopressor administration, bilirubin levels, platelet levels and creatinine levels or daily urine output. A score of 0, 1, 2, 3, or 4) was assigned to each of the six system category. The total score ranged from 0 (min) to 24 (max) points. To be considered organ failure free, a patient had to have a score of 0. | Day 3 and Day 28 or discharge -- whichever comes first | 
| Percentage of Patients Alive and Free of Organ Failure (SOFA Score=0) | The percentage of patients alive and organ failure free (defined as SOFA score=0) at Day 28/Discharge is presented by treatment group. The total score was derived from six sub-scores system categories: respiratory, neurological, cardiovascular, hepatic, coagulation, and renal systems; respective sub-scores were calculated primarily considering PaO2/FiO2 ratio, Glasgow Coma Scale, mean arterial pressure (MAP) or requirement for vasopressor administration, bilirubin levels, platelet levels and creatinine levels or daily urine output. A score of 0, 1, 2, 3, or 4) was assigned to each of the six system category. The total score ranged from 0 (min) to 24 (max) points. To be considered organ failure free, a patient had to have a score of 0. | at day 28 or discharge -- whichever comes first | 
| Ventilatory Parameter: Tidal Volume -- Change From Baseline in Tidal Volume (mL/kg BW) at All Timepoints up to Day 3 (72 Hours) and at Day 28 | Ventilatory parameter: Change from baseline in tidal volume (mL/kg BW) at all timepoints up to Day 3 (72 hours) and at Day 28. The change was calculated from two time points as the value at the later time point minus the value at baseline. Tidal volume is the amount of air that moves in or out of the lungs with each respiratory cycle. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Ventilatory Parameter: Respiratory Rate -- Change From Baseline in Respiratory Rate (Breaths/Minute) at All Timepoints up to Day 3 (72 Hours) and at Day 28 | Ventilatory parameter: Change from baseline in respiratory rate (breaths/minute) at all timepoints up to Day 3 (72 hours) and at Day 28. The change was calculated from two time points as the value at the later time point minus the value at baseline. Respiratory rate is the number of breaths taken per minute. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Ventilatory Parameter: Dynamic Compliance -- Change From Baseline in Dynamic Compliance (mL/cmH2O) at All Timepoints up to Day 3 (72 Hours) and at Day 28 | Ventilatory parameter: Change from baseline in dynamic compliance (mL/cmH2O) at all timepoints up to Day 3 (72 hours) and at Day 28. The change was calculated from two time points as the value at the later time point minus the value at baseline. Dynamic compliance: is the continuous measurement of pulmonary compliance calculated at each point representing schematic changes during rhythmic breathing. Dynamic compliance monitors both elastic and airway resistance. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Ventilatory Parameter: Static Compliance -- Change From Baseline in Static Compliance (mL/cmH2O) at All Timepoints up to Day 3 (72 Hours) and at Day 28 | Ventilatory parameter: static compliance -- change from baseline in static compliance (mL/cmH2O) at all timepoints up to Day 3 (72 hours) and at Day 28. The change was calculated from two time points as the value at the later time point minus the value at baseline. At each time point the number of patients that contributed with a result value is indicated for both study arms. Static Compliance: represents pulmonary compliance at a given fixed volume when there is no airflow, and muscles are relaxed. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Ventilatory Parameter: Positive End-Expiratory Pressure (PEEP) -- Change From Baseline in PEEP (cmH2O) at All Timepoints up to Day 3 (72 Hours) and at Day 28 | Ventilatory parameter: Positive End-Expiratory Pressure -- Change from baseline in PEEP (cmH2O) at all timepoints up to Day 3 (72 hours) and at Day 28. The change was calculated from two time points as the value at the later time point minus the value at baseline. At each time point the number of patients that contributed with a result value is indicated for both study arms. Positive end-expiratory pressure (PEEP) is the positive pressure that will remain in the airways at the end of the respiratory cycle (end of exhalation) that is greater than the atmospheric pressure in mechanically ventilated patients. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Ventilatory Parameter: Peak Inspiratory Pressure -- Change From Baseline in Peak Inspiratory Pressure (cmH2O) at All Timepoints up to Day 3 (72 Hours) and at Day 28 | Ventilatory parameter: Peak Inspiratory Pressure -- Change from baseline in peak inspiratory pressure (cmH2O) at all timepoints up to Day 3 (72 hours) and at Day 28. The change was calculated from two time points as the value at the later time point minus the value at baseline. At each time point the number of patients that contributed with a result value is indicated for both study arms. Peak inspiratory pressure (PIP) is the highest level of pressure applied to the lungs during inhalation. In mechanical ventilation the number reflects a positive pressure in centimetres of water pressure (cmH2O). | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation and Day 28 | 
| Ventilatory Parameter: Plateau Pressure -- Change From Baseline in Plateau Pressure (cmH2O) at All Timepoints up to Day 3 (72 Hours) and at Day 28 | Ventilatory parameter: Plateau Pressure -- Change from baseline in plateau pressure (cmH2O) at all timepoints up to Day 3 (72 hours) and at Day 28. The change was calculated from two time points as the value at the later time point minus the value at baseline. At each time point the number of patients that contributed with a result value is indicated for both study arms. Plateau pressure is the pressure that is applied by the mechanical ventilator to the small airways and alveoli. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation, and Day 28 | 
| Blood Gas Analysis Acid-base Balance Parameters: Change From Baseline in Blood Gas Analysis Acid-base Balance Parameters -- pH | Change from baseline in blood gas analysis acid-base balance parameters -- pH. The change was calculated from two time points as the value at the later time point minus the value at baseline. Arterial blood gas was measured at 6, 12, 24, 30, 36, 48, 54, 60 and 72 hours after randomisation and up to Day 28 or till the patient was discharged from the ICU - whichever occurred earlier. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation, and Day 28 | 
| Change From Baseline in Blood Gas Analysis Acid-base Balance Parameter -- Partial Pressure of Carbon Dioxide (pCO2) | Change from baseline in blood gas analysis acid-base balance parameter -- pCO2. The change was calculated from two time points as the value at the later time point minus the value at baseline. Arterial blood gas was measured at 6, 12, 24, 30, 36, 48, 54, 60 and 72 hours after randomisation and up to Day 28 or till the patient was discharged from the ICU - whichever occurred earlier. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation, and Day 28 | 
| Change From Baseline in Blood Gas Analysis Acid-base Balance Parameter -- Partial Pressure of Oxygen (pO2) | Change from baseline in blood gas analysis acid-base balance parameter -- pO2. The change was calculated from two time points as the value at the later time point minus the value at baseline. Arterial blood gas was measured at 6, 12, 24, 30, 36, 48, 54, 60 and 72 hours after randomisation and up to Day 28 or till the patient was discharged from the ICU - whichever occurred earlier. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation, and Day 28 | 
| Change From Baseline in Blood Gas Analysis Acid-base Balance Parameter -- Bicarbonate (HCO3) | Change from baseline in blood gas analysis acid-base balance parameter -- Bicarbonate (HCO3). The change was calculated from two time points as the value at the later time point minus the value at baseline. Measured at 6-12-24h after each poractant alfa administration up to 72 hours and at similar timepoints in the control group (6, 12, 24, 30, 36, 48, 54, 60 and 72 hours after randomisation) and then every 24 hours till the patient is discharged from the ICU | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation, and Day 28 | 
| Change From Baseline in Blood Parameter -- Lactate | Change from baseline in blood parameter -- Lactate The change was calculated from two time points as the value at the later time point minus the value at baseline. At each time point the number of patients that contributed with a result value is indicated for both study arms. Arterial blood lactate was measured at 6, 12, 24, 30, 36, 48, 54, 60, and 72 hours after randomisation and up to Day 28 or till the patient was discharged from the ICU - whichever occurred earlier. | up to 28 days: 6, 12, 24, 30, 36, 48, 54, 60, 72 hours after randomisation, and Day 28 | 
| Mortality -- TEAEs Leading to Death | The incidence of treatment-emergent adverse event (TEAEs) leading to death is presented by treatment group. | up to day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute respiratory distress syndrome, ARDS, Adults, Surfactant, Poractant alfa (porcine surfactant, Curosurf®),, Curosurf®, Coronavirus disease (COVID-19), Coronavirus 2019 Disease