Respiratory Distress Syndrome, Newborn
Conditions
Keywords
neonates, pulmonary surfactant
Brief summary
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%.
Interventions
DRUGCHF5633
Rescue treatment (if needed)
DRUGPoractant alfa
Rescue treatment (if needed)
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Hours to 24 Hours
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Post-treatment Day 1: 30 min, at 1h, 3h, 6h, 12h, 18h, 24 h; Day 2, 3, 5, and 7 | 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. |
| Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | 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 \[percent\]). 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; |
| Number of Patients With Bronchopulmonary Dysplasia and Mortality | 36 weeks post menstrual age, Day 14 Post-Natal Age, Day 28 Post-Natal Age | 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; |
Other
| Measure | Time frame | Description |
|---|---|---|
| Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Post-treatment Day 1 (24 h), Day 2 (48 h) | 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; |
| Number of Patients With Normal Breathing (Room Air) Within 24 Hours | Post-treatment up to 24 h | 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. |
| 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) | At approximately 5 weeks after the administration of study drug (with a range from 3 to 6 weeks). | 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. |
| Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant) | Day 1 to Day 7 | 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. |
| Time to Reach Normal Breathing (Room Air) Within 24 Hours | Post-treatment Day 1: up to 24 h | 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'. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CHF5633 Single dose within 24 hours from birth.
CHF5633: Rescue treatment (if needed) | 56 |
| Poractant Alfa Single dose within 24 hours from birth.
Poractant alfa: Rescue treatment (if needed) | 57 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 7 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Not treated | 5 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
Baseline characteristics
| Characteristic | Total | CHF5633 | Poractant Alfa |
|---|---|---|---|
| Age, Continuous | 26.86 weeks STANDARD_DEVIATION 1.84 | 27.01 weeks STANDARD_DEVIATION 1.79 | 26.72 weeks STANDARD_DEVIATION 1.9 |
| Age, Customized 24 to 26 Weeks | 58 Participants | 26 Participants | 32 Participants |
| Age, Customized 27 to 29 Weeks | 55 Participants | 30 Participants | 25 Participants |
| APGAR Score | 6.1 units on a scale STANDARD_DEVIATION 1.9 | 6.3 units on a scale STANDARD_DEVIATION 1.8 | 5.9 units on a scale STANDARD_DEVIATION 1.9 |
| Birth weight | 883.0 gram STANDARD_DEVIATION 280.3 | 862.0 gram STANDARD_DEVIATION 247.2 | 903.6 gram STANDARD_DEVIATION 310.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 15 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants | 37 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 42 Participants | 23 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 7 Participants | 8 Participants |
| Race (NIH/OMB) White | 51 Participants | 25 Participants | 26 Participants |
| Region of Enrollment United States | 113 participants | 56 participants | 57 participants |
| Sex: Female, Male Female | 61 Participants | 32 Participants | 29 Participants |
| Sex: Female, Male Male | 52 Participants | 24 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 59 | 7 / 58 |
| other Total, other adverse events | 59 / 59 | 58 / 58 |
| serious Total, serious adverse events | 20 / 59 | 20 / 58 |
Outcome results
Primary
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;
Time frame: Post-treatment Day 1: 30 min, at 1h, 3h, 6h, 12h, 18h, 24 h; Day 2, 3, 5, and 7
Population: Intention-to-Treat Population (ITT). All randomized patients who received at least one dose of study medication and with at least one available evaluation of efficacy after the baseline.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 7 | 29.25 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 30 min | 32.15 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 1 h | 31.41 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 3 h | 29.29 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 6 h | 27.76 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 12 h | 25.28 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 18 h | 26.18 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 24 h | 28.49 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 2 | 29.29 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 3 | 27.54 Fraction of inspired oxygen (percent) |
| CHF5633 | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 5 | 28.06 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 5 | 26.32 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 18 h | 28.10 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 30 min | 34.08 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 3 | 29.07 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 1 h | 28.96 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 24 h | 29.50 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 3 h | 28.87 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 7 | 28.02 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 6 h | 28.16 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 2 | 29.20 Fraction of inspired oxygen (percent) |
| Poractant Alfa | Fraction of Inspired Oxygen (FiO2) (Percent) During the First 24 h and up to Day 7 | Day 1, 12 h | 28.05 Fraction of inspired oxygen (percent) |
Comparison: Day 1, 30 min post dosep-value: 0.51995% CI: [-7.87, 3.99]Mixed model for repeated measurements
Comparison: Day 1, 1 h post dosep-value: 0.28295% CI: [-2.04, 6.93]Mixed model for repeated measurements
Comparison: Day 1, 3 h post dosep-value: 0.85495% CI: [-4.04, 4.86]Mixed model for repeated measurements
Comparison: Day 1, 6 h post dosep-value: 0.86195% CI: [-5, 4.19]Mixed model for repeated measurements
Comparison: Day 1, 12 h post dosep-value: 0.11795% CI: [-6.24, 0.7]Mixed model for repeated measurements
Comparison: Day 1, 18 h post dosep-value: 0.18595% CI: [-4.79, 0.94]Mixed model for repeated measurements
Comparison: Day 1, 24 h post dosep-value: 0.67895% CI: [-5.82, 3.8]Mixed model for repeated measurements
Comparison: Day 2, post dose~SpO2/FiO2 was compared between treatments at the remaining post-treatment time points (i.e., Days 2, 3, 5, 7): analyzed using mixed model including treatment, investigational site and gestational age group as fixed effects and pre-dose ratio as covariate.p-value: 0.96195% CI: [-3.49, 3.67]Mixed Models Analysis
Comparison: Day 3, post dosep-value: 0.54495% CI: [-6.53, 3.46]Mixed Models Analysis
Comparison: Day 5, post dosep-value: 0.49295% CI: [-3.28, 6.76]Mixed Models Analysis
Comparison: Day 7, post dosep-value: 0.63495% CI: [-3.9, 6.36]Mixed Models Analysis
Primary
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;
Time frame: 36 weeks post menstrual age, Day 14 Post-Natal Age, Day 28 Post-Natal Age
Population: Intention-to-Treat Population (ITT). All randomized patients who received at least one dose of study medication and with at least one available evaluation of efficacy after the baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CHF5633 | Number of Patients With Bronchopulmonary Dysplasia and Mortality | 36 week PMA Incidence of BPD (Yes) | 31 Participants |
| CHF5633 | Number of Patients With Bronchopulmonary Dysplasia and Mortality | Day 28 (PNA) Mortality | 4 Participants |
| CHF5633 | Number of Patients With Bronchopulmonary Dysplasia and Mortality | 36 week PMA Mortality | 4 Participants |
| CHF5633 | Number of Patients With Bronchopulmonary Dysplasia and Mortality | Day 14 (PNA) RDS-associated mortality | 1 Participants |
| CHF5633 | Number of Patients With Bronchopulmonary Dysplasia and Mortality | 36 week PMA Mortality/BPD | 35 Participants |
| Poractant Alfa | Number of Patients With Bronchopulmonary Dysplasia and Mortality | Day 14 (PNA) RDS-associated mortality | 2 Participants |
| Poractant Alfa | Number of Patients With Bronchopulmonary Dysplasia and Mortality | 36 week PMA Incidence of BPD (Yes) | 32 Participants |
| Poractant Alfa | Number of Patients With Bronchopulmonary Dysplasia and Mortality | 36 week PMA Mortality/BPD | 38 Participants |
| Poractant Alfa | Number of Patients With Bronchopulmonary Dysplasia and Mortality | 36 week PMA Mortality | 6 Participants |
| Poractant Alfa | Number of Patients With Bronchopulmonary Dysplasia and Mortality | Day 28 (PNA) Mortality | 3 Participants |
Comparison: Week 36 PMA Incidence of BPDp-value: 0.81195% CI: [0.81, 1.32]Cochran-Mantel-Haenszel
Comparison: Week 36 PMA Incidence of Mortality/BPDp-value: 0.97295% CI: [0.81, 1.25]Cochran-Mantel-Haenszel
Comparison: Week 36 PMA Mortalityp-value: 0.61995% CI: [0.23, 2.42]Cochran-Mantel-Haenszel
Comparison: Day 28 PNA Mortalityp-value: 0.60295% CI: [0.35, 6.09]Cochran-Mantel-Haenszel
Comparison: Day 14 PNA RDS-associated mortality in 14 days of lifep-value: 0.60695% CI: [0.06, 5.29]Cochran-Mantel-Haenszel
Primary
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.
Time frame: Post-treatment Day 1: 30 min, at 1h, 3h, 6h, 12h, 18h, 24 h; Day 2, 3, 5, and 7
Population: Intention-to-Treat Population (ITT). All randomized patients who received at least one dose of study medication and with at least one available evaluation of efficacy after the baseline.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 18 h | 3.82 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 1 h | 3.36 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 24 h | 3.72 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 6 h | 3.77 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 2 | 3.61 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 3 | 3.75 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 30 min | 3.33 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 5 | 3.83 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 12 h | 3.89 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 7 | 3.74 SpO2/FiO2 ratio |
| CHF5633 | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 3 h | 3.58 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 7 | 3.73 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 30 min | 3.31 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 1 h | 3.55 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 3 h | 3.68 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 6 h | 3.87 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 12 h | 3.78 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 18 h | 3.74 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 1, 24 h | 3.64 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 3 | 3.78 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 5 | 3.88 SpO2/FiO2 ratio |
| Poractant Alfa | Oxygen Requirement and Ventilatory Support -- SpO2/FiO2 Ratio | Day 2 | 3.63 SpO2/FiO2 ratio |
Comparison: Day 1, 30 min post dose.~SpO2/FiO2 and FiO2 (%) over the first 24 hours: analyzed using a linear mixed model for repeated measures (MMRM) including treatment, timepoint, treatment by timepoint interaction, investigational site and gestational age (GA) group as fixed effects, and predose values as covariates. The adjusted mean difference between treatments, and their 95% confidence intervals (CIs) at each timepoint and averaged over the first 24 hours were estimated by the model.p-value: 0.9395% CI: [-0.4, 0.44]Mixed model for repeated measurements
Comparison: Day 1, 1 h post dosep-value: 0.34695% CI: [-0.59, 0.21]Mixed model for repeated measurements
Comparison: Day 1, 3 h post dosep-value: 0.54995% CI: [-0.43, 0.23]Mixed model for repeated measurements
Comparison: Day 1, 6 h post dosep-value: 0.53995% CI: [-0.43, 0.23]Mixed model for repeated measurements
Comparison: Day 1, 12 h post dosep-value: 0.49195% CI: [-0.21, 0.43]Mixed model for repeated measurements
Comparison: Day 1, 18 h post dosep-value: 0.62395% CI: [-0.22, 0.37]Mixed model for repeated measurements
Comparison: Day 1, 24 h post dosep-value: 0.60895% CI: [-0.25, 0.43]Mixed model for repeated measurements
Comparison: Day 2, post dose~SpO2/FiO2 was compared between treatments at the remaining post-treatment time points (i.e., Days 2, 3, 5, 7): analyzed using mixed model including treatment, investigational site and gestational age group as fixed effects and pre-dose ratio as covariate.p-value: 0.86995% CI: [-0.35, 0.3]Mixed Models Analysis
Comparison: Day 3, post dosep-value: 0.83395% CI: [-0.38, 0.31]Mixed Models Analysis
Comparison: Day 5, post dosep-value: 0.77295% CI: [-0.39, 0.29]Mixed Models Analysis
Comparison: Day 7, post dosep-value: 0.96395% CI: [-0.33, 0.35]Mixed Models Analysis
Other Pre-specified
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;
Time frame: Post-treatment Day 1 (24 h), Day 2 (48 h)
Population: Intention-to-Treat Population (ITT). All randomized patients who received at least one dose of study medication and with at least one available evaluation of efficacy after the baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 8,Day 2, 48 h | 821.16 pg/mg total protein | Standard Deviation 5978.87 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 6, Day 1, 24 h | -200.074 pg/mg total protein | Standard Deviation 761.436 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Myeloperoxidase, Day 1, 24 h | 267337.7 pg/mg total protein | Standard Deviation 399695.4 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 1β, Day 2, 48 h | 3.681 pg/mg total protein | Standard Deviation 154.736 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Myeloperoxidase, Day 2, 48 h | 310323.0 pg/mg total protein | Standard Deviation 419874 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 6, Day 2, 48 h | -129.368 pg/mg total protein | Standard Deviation 954.282 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Tumor Necrosis Factor-Alpha, Day 1, 24 h | -16.047 pg/mg total protein | Standard Deviation 42.924 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 1β, Day 1, 24 h | -38.535 pg/mg total protein | Standard Deviation 93.111 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Tumor Necrosis Factor-Alpha, Day 2, 48 h | 2.899 pg/mg total protein | Standard Deviation 71.215 |
| CHF5633 | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 8, Day 1, 24 h | 389.86 pg/mg total protein | Standard Deviation 5240.76 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Tumor Necrosis Factor-Alpha, Day 2, 48 h | -25.573 pg/mg total protein | Standard Deviation 78.934 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 1β, Day 1, 24 h | -39.896 pg/mg total protein | Standard Deviation 134.659 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 1β, Day 2, 48 h | -40.564 pg/mg total protein | Standard Deviation 158.194 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 6, Day 1, 24 h | -792.196 pg/mg total protein | Standard Deviation 2657.394 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 6, Day 2, 48 h | -1089.753 pg/mg total protein | Standard Deviation 3222.013 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 8,Day 2, 48 h | -243.71 pg/mg total protein | Standard Deviation 6425.9 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Myeloperoxidase, Day 1, 24 h | 52663.5 pg/mg total protein | Standard Deviation 264660.9 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Myeloperoxidase, Day 2, 48 h | 508378.1 pg/mg total protein | Standard Deviation 381999.8 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Tumor Necrosis Factor-Alpha, Day 1, 24 h | -19.985 pg/mg total protein | Standard Deviation 67.539 |
| Poractant Alfa | Concentration of Biomarkers of Inflammation in Tracheal Aspirates | Interleukin 8, Day 1, 24 h | -843.74 pg/mg total protein | Standard Deviation 4720.36 |
Other Pre-specified
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.
Time frame: At approximately 5 weeks after the administration of study drug (with a range from 3 to 6 weeks).
Population: Safety Population. All randomized patients who took at least one dose of study medication and who had the assessment done on 28 day PNA.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CHF5633 | 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) | Antibody to SP-B (CHF 5736.03) | 100 Titre (dilution with 0.050 absorbance) |
| CHF5633 | 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) | Antibody to SP-C (CHF 4902.03) | 12.5 Titre (dilution with 0.050 absorbance) |
| Poractant Alfa | 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) | Antibody to SP-B (CHF 5736.03) | 100 Titre (dilution with 0.050 absorbance) |
| Poractant Alfa | 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) | Antibody to SP-C (CHF 4902.03) | 12.5 Titre (dilution with 0.050 absorbance) |
Other Pre-specified
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.
Time frame: Post-treatment up to 24 h
Population: Intention-to-Treat Population (ITT). All randomized patients who received at least one dose of study medication and with at least one available evaluation of efficacy after the baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CHF5633 | Number of Patients With Normal Breathing (Room Air) Within 24 Hours | 38 Participants |
| Poractant Alfa | Number of Patients With Normal Breathing (Room Air) Within 24 Hours | 43 Participants |
p-value: 0.40995% CI: [0.3, 1.57]Fisher Exact
Other Pre-specified
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.
Time frame: Day 1 to Day 7
Population: Intention-to-Treat Population (ITT). All randomized patients who received at least one dose of study medication and with at least one available evaluation of efficacy after the baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CHF5633 | Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant) | Patients receiving rescue at any time during the study | 19 Participants |
| CHF5633 | Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant) | 1 rescue dose given | 11 Participants |
| CHF5633 | Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant) | 2 rescue doses given | 8 Participants |
| Poractant Alfa | Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant) | 2 rescue doses given | 5 Participants |
| Poractant Alfa | Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant) | Patients receiving rescue at any time during the study | 17 Participants |
| Poractant Alfa | Number of Patients With the Need for Re-dosing (Use of Rescue Surfactant) | 1 rescue dose given | 12 Participants |
Comparison: The percentage of patients requiring at least one rescue surfactant dose.p-value: 0.68995% CI: [0.55, 2.67]Fisher Exact
Other Pre-specified
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'.
Time frame: Post-treatment Day 1: up to 24 h
Population: Intention-to-Treat Population (ITT). All randomized patients who received at least one dose of study medication and with at least one available evaluation of efficacy after the baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CHF5633 | Time to Reach Normal Breathing (Room Air) Within 24 Hours | 2.980 hour |
| Poractant Alfa | Time to Reach Normal Breathing (Room Air) Within 24 Hours | 2.320 hour |
p-value: 0.935Wilcoxon (Mann-Whitney)