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Clinical Trial Results:
A RANDOMIZED, OPEN, MULTINATIONAL, MULTICENTRE, 2-PART STUDY IN SPONTANEOUSLY BREATHING PRETERM NEONATES WITH MILD TO MODERATE RESPIRATORY DISTRESS SYNDROME TO INVESTIGATE THE SAFETY, TOLERABILITY AND EFFICACY OF INHALED NEBULISED PORACTANT ALFA (PORCINE SURFACTANT, CUROSURF®) IN COMPARISON WITH nCPAP ALONE.

Summary
EudraCT number	2016-004547-36
Trial protocol	HU CZ GB AT FR PL IT
Global end of trial date	05 May 2020

Results information
Results version number	v1(current)
This version publication date	02 Apr 2021
First version publication date	02 Apr 2021
Other versions
Summary report(s)	CURONEB CSR ADDENDUM Synopsis

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CCD-01534CA1-01

ISRCTN number

US NCT number

NCT03235986

WHO universal trial number (UTN)

Sponsor organisation name

Chiesi Farmaceutici S.p.A.

Sponsor organisation address

Via Palermo 26/A, Parma, Italy, 43122

Public contact

Clinical Trial Transparency, CHIESI FARMACEUTICI S.p.A., clinicaltrials_info@chiesi.com

Scientific contact

Clinical Trial Transparency, CHIESI FARMACEUTICI S.p.A., clinicaltrials_info@chiesi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

11 Feb 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

05 May 2020

Global end of trial reached?

Yes

Global end of trial date

05 May 2020

Was the trial ended prematurely?

Yes

Main objective of the trial

Part I objective: To assess the safety and tolerability of three single ascending doses of nebulised Curosurf®. Part II objective: To compare the efficacy of nebulised Curosurf®, administered at low dose (dose 1*) or high dose (dose 2), during nasal continuous positive airway pressure (nCPAP), versus (v) nCPAP alone in terms of incidence of respiratory failure in the first 72 hours of life in spontaneously breathing preterm neonates with mild to moderate respiratory distress syndrome (RDS). *Note: actual doses used were: 200 mg/kg as low dose and 400 mg/kg as high dose.

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and all other requirements of local laws. In both parts of the study, from screening (Day -1) to Day 7: • Neonatal concomitant medication and adverse events (AEs) were recorded during all periods; peri-dosing AEs and adverse drug reactions (ADRs) were assessed; • Peripheral oxygen saturation (SpO2) and fraction of inspired oxygen (FiO2) were measured and respiratory support evaluated during all periods; • Vital signs were measured during all periods; • Blood gas analysis was performed up to Day 7; • Supplemental oxygen use and respiratory failure were monitored during all periods except Day -1. • SpO2 and FiO2 were measured, respiratory support evaluated, respiratory failure monitored and neonatal concomitant medication and AEs recorded at 28 days post-natal age (PNA), at discharge home and at either 36 weeks post-menstrual age (PMA) or between 28 and 56 days PNA (depending on gestational age); • Presence of bronchopulmonary dysplasia (BPD) was assessed at either discharge home, 36 weeks PMA or between 28 and 56 days PNA, as appropriate; • Assessment of development and health status was performed at 24 months (±3 months) corrected age (Part I only). Data from this assessment are the subject of an addendum, the synopsis of which is appended. An independent safety monitoring board (ISMB) was convened to evaluate safety and preliminary efficacy during the study. In Part I, neonates were enrolled in 3 cohorts, planned to receive escalating doses of Curosurf®. After a stop to evaluate the first 7-day safety data of each cohort, the ISMB’s positive decision triggered the continuation of the dose escalation scheme to the next dose. Similarly, in Part II, the ISMB reviewed the safety profile of Curosurf® after enrolment of every 40 neonates.

Background therapy

Not applicable.

Evidence for comparator

In both parts of the study, neonates received single doses of nebulised Curosurf® (200, 400 and 600 mg/kg in Part I and 200 and 400 mg/kg in Part II) in addition to nCPAP. Guidelines for treatment of RDS available at the time of study preparation recommended early initiation of non-invasive respiratory support (e.g. nCPAP) with early rescue surfactant in case of worsening of respiratory parameters (FiO2 > 0.40 for neonates of > 26 weeks gestational age). On this basis, the control group in this study was composed of preterm neonates receiving nCPAP alone, i.e. standard of care.

Actual start date of recruitment

28 Aug 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

24 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 30

Country: Number of subjects enrolled

Czech Republic: 32

Country: Number of subjects enrolled

Hungary: 42

Country: Number of subjects enrolled

Austria: 5

Country: Number of subjects enrolled

Italy: 47

Country: Number of subjects enrolled

Poland: 10

Worldwide total number of subjects

166

EEA total number of subjects

166

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

166

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In Part I, 85 neonates were screened according to inclusion/exclusion criteria, and 37 neonates were randomised. In Part II, 307 neonates were screened according to inclusion/exclusion criteria, and 129 neonates were randomised.

Screening details

In Part I, 48 neonates failed screening (Day -1) due to: inclusion/exclusion criteria (44 neonates), consent withdrawal (1 neonate) and other reasons (3 neonates). In Part II, 178 neonates failed screening (Day -1) due to: inclusion/exclusion criteria (166 neonates), consent withdrawal (1 neonate) and other reasons (11 neonates).

Period 1 title

Study Parts I and II (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part I - 200 mg/kg nebulised Curosurf®

Arm description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 200 mg/kg.

Arm type

Experimental

Investigational medicinal product name

200 mg/kg nebulised Curosurf®

Investigational medicinal product code

Other name

Pharmaceutical forms

Endotracheopulmonary instillation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Part I - 400 mg/kg nebulised Curosurf®

Arm description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 400 mg/kg.

Arm type

Experimental

Investigational medicinal product name

400 mg/kg nebulised Curosurf®

Investigational medicinal product code

Other name

Pharmaceutical forms

Endotracheopulmonary instillation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Part I - 600 mg/kg nebulised Curosurf®

Arm description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 600 mg/kg.

Arm type

Experimental

Investigational medicinal product name

600 mg/kg nebulised Curosurf®

Investigational medicinal product code

Other name

Pharmaceutical forms

Endotracheopulmonary instillation, suspension

Routes of administration

Inhalation use

Dosage and administration details

A single dose of Curosurf® at 600 mg/kg was administered within 60 minutes and 12 hours after birth whilst nCPAP was ongoing. The total duration of nebulisation was variable according to body weight but was not allowed to last more than 90 minutes for the 600 mg/kg dose.

Part I - nCPAP

Arm description

Neonates were randomised to receive nCPAP only.

Arm type

Control

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part II - 200 mg/kg nebulised Curosurf®

Arm description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 200 mg/kg.

Arm type

Experimental

Investigational medicinal product name

200 mg/kg nebulised Curosurf®

Investigational medicinal product code

Other name

Pharmaceutical forms

Endotracheopulmonary instillation, suspension

Routes of administration

Inhalation use

Dosage and administration details

A single dose of Curosurf® at 200 mg/kg was administered within 60 minutes and 12 hours after birth whilst nCPAP was ongoing. The total duration of nebulisation was variable according to body weight but was not allowed to last more than 30 minutes for the 200 mg/kg dose. An additional dose of nebulised Curosurf® at 200 mg/kg was allowed, with re-dosing to occur between 3 and 12 hours after the start of the first dose.

Part II - 400 mg/kg nebulised Curosurf®

Arm description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 400 mg/kg.

Arm type

Experimental

Investigational medicinal product name

400 mg/kg nebulised Curosurf®

Investigational medicinal product code

Other name

Pharmaceutical forms

Endotracheopulmonary instillation, suspension

Routes of administration

Inhalation use

Dosage and administration details

A single dose of Curosurf® at 400 mg/kg was administered within 60 minutes and 12 hours after birth whilst nCPAP was ongoing. The total duration of nebulisation was variable according to body weight but was not allowed to last more than 60 minutes for the 400 mg/kg dose. An additional dose of nebulised Curosurf® at 200 mg/kg was allowed, with re-dosing to occur between 3 and 12 hours after the start of the first dose.

Part II - nCPAP

Arm description

Neonates were randomised to receive nCPAP only.

Arm type

Control

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Part I - 200 mg/kg nebulised Curosurf®	Part I - 400 mg/kg nebulised Curosurf®	Part I - 600 mg/kg nebulised Curosurf®	Part I - nCPAP	Part II - 200 mg/kg nebulised Curosurf®	Part II - 400 mg/kg nebulised Curosurf®	Part II - nCPAP
Started	10	9	9	9	43	43	43
Completed	10	9	9	9	42	40	43
Not completed	0	0	0	0	1	3	0
Adverse event, serious fatal	-	-	-	-	-	1	-
Untreated	-	-	-	-	1	2	-

Baseline characteristics

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Reporting group title

Part I - 200 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 200 mg/kg.

Reporting group title

Part I - 400 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 400 mg/kg.

Reporting group title

Part I - 600 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 600 mg/kg.

Reporting group title

Part I - nCPAP

Reporting group description

Neonates were randomised to receive nCPAP only.

Reporting group title

Part II - 200 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 200 mg/kg.

Reporting group title

Part II - 400 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 400 mg/kg.

Reporting group title

Part II - nCPAP

Reporting group description

Neonates were randomised to receive nCPAP only.

Reporting group values	Part I - 200 mg/kg nebulised Curosurf®	Part I - 400 mg/kg nebulised Curosurf®	Part I - 600 mg/kg nebulised Curosurf®	Part I - nCPAP	Part II - 200 mg/kg nebulised Curosurf®	Part II - 400 mg/kg nebulised Curosurf®	Part II - nCPAP	Total
Number of subjects	10	9	9	9	43	43	43	166
Age categorical
Units: Subjects
Preterm newborn infants (gestational age < 37 wks)	10	9	9	9	43	43	43	166
Gender categorical
Units: Subjects
Female	5	2	3	3	20	14	23	70
Male	5	7	6	6	23	29	20	96

Subject analysis set title

Part I - 200 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

The Intention-to-treat population (ITT) was defined as all randomised neonates with a gestational age from 28+0 to 32+6 weeks, who received nCPAP and then started nebulisation with Curosurf® (active treatment group only) and with at least one available evaluation of efficacy after baseline.

Subject analysis set title

Part I - 400 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

The ITT was defined as all randomised neonates with a gestational age from 28+0 to 32+6 weeks, who received nCPAP and then started nebulisation with Curosurf® (active treatment group only) and with at least one available evaluation of efficacy after baseline.

Subject analysis set title

Part I - 600 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - nCPAP - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part II - 200 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part II - 400 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part II - nCPAP - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - 200 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety population (SAF) was defined as all randomised neonates, with a gestational age from 28+0 to 32+6 weeks, who either received nCPAP alone (nCPAP group) or who received nCPAP and then started nebulisation with Curosurf® (active treatment group).

Subject analysis set title

Part I - 400 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

The SAF was defined as all randomised neonates, with a gestational age from 28+0 to 32+6 weeks, who either received nCPAP alone (nCPAP group) or who received nCPAP and then started nebulisation with Curosurf® (active treatment group).

Subject analysis set title

Part I - 600 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part I - nCPAP - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part II - 200 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part II - 400 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part II - nCPAP - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis sets values	Part I - 200 mg/kg nebulised Curosurf® - ITT	Part I - 400 mg/kg nebulised Curosurf® - ITT	Part I - 600 mg/kg nebulised Curosurf® - ITT	Part I - nCPAP - ITT	Part II - 200 mg/kg nebulised Curosurf® - ITT	Part II - 400 mg/kg nebulised Curosurf® - ITT	Part II - nCPAP - ITT	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Number of subjects	9	9	9	9	42	41	43	9	9	9	9	42	41	43
Age categorical
Units: Subjects
Preterm newborn infants (gestational age < 37 wks)	9	9	9	9	42	41	43
Age continuous
Units:
	±	±	±	±	±	±	±	±	±	±	±	±	±	±
Gender categorical
Units: Subjects
Female	4	2	3	3	20	13	23
Male	5	7	6	6	22	28	20

End points

Top of page

Reporting group title

Part I - 200 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 200 mg/kg.

Reporting group title

Part I - 400 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 400 mg/kg.

Reporting group title

Part I - 600 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 600 mg/kg.

Reporting group title

Part I - nCPAP

Reporting group description

Neonates were randomised to receive nCPAP only.

Reporting group title

Part II - 200 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 200 mg/kg.

Reporting group title

Part II - 400 mg/kg nebulised Curosurf®

Reporting group description

Neonates were randomised to receive a single dose of nebulised Curosurf® at 400 mg/kg.

Reporting group title

Part II - nCPAP

Reporting group description

Neonates were randomised to receive nCPAP only.

Subject analysis set title

Part I - 200 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - 400 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - 600 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - nCPAP - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part II - 200 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part II - 400 mg/kg nebulised Curosurf® - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part II - nCPAP - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - 200 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part I - 400 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part I - 600 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part I - nCPAP - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part II - 200 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part II - 400 mg/kg nebulised Curosurf® - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Part II - nCPAP - SAF

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: Percentage of neonates with respiratory failure in the first 72 hours of life - Part II

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End point title

Percentage of neonates with respiratory failure in the first 72 hours of life - Part II

End point description

Note: this was the primary endpoint for Part II of the study, an error in the EudraCT system means that it is presented before endpoints relating to Part I of the study. Respiratory failure was defined as a neonate needing endotracheal surfactant administration and/or mechanical ventilation due to one or more of the following reasons: • FiO2 > 0.40 to maintain SpO2 between 88 and 95% for at least 30 minutes, unless rapid clinical deterioration occurred; • Significant apnoea (more than four episodes of apnoea per hour or more than two episodes of apnoea per hour which required positive pressure ventilation); • Persistent respiratory acidosis despite the initiation of non-invasive respiratory support (partial pressure of carbon dioxide [pCO2] > 65 mmHg/8.5 kPa and pH < 7.20 on blood gas).

End point type

Primary

End point timeframe

The first 72 hours of life.

End point values	Part II - 200 mg/kg nebulised Curosurf® - ITT	Part II - 400 mg/kg nebulised Curosurf® - ITT	Part II - nCPAP - ITT
Number of subjects analysed	42	41	43
Units: Percentage of neonates
number (not applicable)	57.1	48.8	58.1

400 mg/kg nebulised Curosurf v nCPAP - Part II

Statistical analysis description

The percentage of neonates with respiratory failure in the first 72 hours of life was compared between 400 mg/kg nebulised Curosurf® and the nCPAP group using a chi-square test. The relative risk with its 95% confidence intervals was also calculated.

Comparison groups

Part II - 400 mg/kg nebulised Curosurf® - ITT v Part II - nCPAP - ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.39

Method

Chi-squared

Parameter type

Relative risk

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.26

Notes
[1] - The comparisons of nebulised Curosurf® dose v nCPAP alone were performed hierarchically starting from the highest dose.

200 mg/kg nebulised Curosurf v nCPAP - Part II

Statistical analysis description

The percentage of neonates with respiratory failure in the first 72 hours of life was compared between 200 mg/kg nebulised Curosurf® and the nCPAP group using a chi-square test. The relative risk with its 95% confidence intervals was also calculated.

Comparison groups

Part II - nCPAP - ITT v Part II - 200 mg/kg nebulised Curosurf® - ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.926

Method

Chi-squared

Parameter type

Relative risk

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

1.42

Notes
[2] - The comparisons of nebulised Curosurf® dose v nCPAP alone were performed hierarchically starting from the highest dose.

Other pre-specified: Percentage of neonates with respiratory failure in the first 72 hours of life - Part I

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End point title

Percentage of neonates with respiratory failure in the first 72 hours of life - Part I

End point description

Respiratory failure was defined as a neonate needing endotracheal surfactant administration and/or mechanical ventilation due to one or more of the following reasons: • FiO2 > 0.40 to maintain SpO2 between 88 and 95% for at least 30 minutes, unless rapid clinical deterioration occurred; • Significant apnoea (more than four episodes of apnoea per hour or more than two episodes of apnoea per hour which required positive pressure ventilation); • Persistent respiratory acidosis despite the initiation of non-invasive respiratory support pCO2 > 65 mmHg/8.5 kPa and pH < 7.20 on blood gas).

End point type

Other pre-specified

End point timeframe

The first 72 hours of life.

End point values	Part I - 200 mg/kg nebulised Curosurf® - ITT	Part I - 400 mg/kg nebulised Curosurf® - ITT	Part I - 600 mg/kg nebulised Curosurf® - ITT	Part I - nCPAP - ITT
Number of subjects analysed	9	9	9	9
Units: Percentage of neonates
number (not applicable)	44.4	66.7	55.6	66.7

600 mg/kg nebulised Curosurf v nCPAP - Part I

Statistical analysis description

The percentage of neonates with respiratory failure in the first 72 hours of life was compared between 600 mg/kg nebulised Curosurf® and the nCPAP group using a Fisher’s exact test. The relative risk with its 95% confidence intervals was also calculated.

Comparison groups

Part I - nCPAP - ITT v Part I - 600 mg/kg nebulised Curosurf® - ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

> 0.999

Method

Fisher exact

Parameter type

Relative risk

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

1.76

Notes
[3] - This analysis was exploratory.

400 mg/kg nebulised Curosurf v nCPAP - Part I

Statistical analysis description

The percentage of neonates with respiratory failure in the first 72 hours of life was compared between 400 mg/kg nebulised Curosurf® and the nCPAP group using a Fisher’s exact test. The relative risk with its 95% confidence intervals was also calculated.

Comparison groups

Part I - nCPAP - ITT v Part I - 400 mg/kg nebulised Curosurf® - ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

> 0.999

Method

Fisher exact

Parameter type

Relative risk

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

1.92

Notes
[4] - This analysis was exploratory.

200 mg/kg nebulised Curosurf v nCPAP - Part I

Statistical analysis description

The percentage of neonates with respiratory failure in the first 72 hours of life was compared between 200 mg/kg nebulised Curosurf® and the nCPAP group using a Fisher’s exact test. The relative risk with its 95% confidence intervals was also calculated.

Comparison groups

Part I - nCPAP - ITT v Part I - 200 mg/kg nebulised Curosurf® - ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.637

Method

Fisher exact

Parameter type

Relative risk

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

1.58

Notes
[5] - This analysis was exploratory.

Other pre-specified: Number of neonates with AEs - Part I

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End point title

Number of neonates with AEs - Part I

End point description

An AE was defined as any untoward medical occurrence in a patient or clinical trial neonate administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Only treatment-emergent AEs were considered in this analysis.

End point type

Other pre-specified

End point timeframe

All AEs which started between treatment start (for active treatment) or after randomisation (for control) and discharge or 36 weeks PMA (whichever was sooner).

End point values	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF
Number of subjects analysed	9	9	9	9
Units: Neonates	9	9	9	9

No statistical analyses for this end point

Other pre-specified: Percentage of neonates with AEs - Part I

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End point title

Percentage of neonates with AEs - Part I

End point description

As per the endpoint 'Number of neonates with AEs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with AEs - Part I'.

End point values	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF
Number of subjects analysed	9	9	9	9
Units: Percentage of neonates
number (not applicable)	100.0	100.0	100.0	100.0

No statistical analyses for this end point

Other pre-specified: Number of AEs - Part I

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End point title

Number of AEs - Part I

End point description

As per the endpoint 'Number of neonates with AEs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with AEs - Part I'.

End point values	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF
Number of subjects analysed	9	9	9	9
Units: Events	34	51	52	59

No statistical analyses for this end point

Other pre-specified: Number of neonates with ADRs - Part I

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End point title

Number of neonates with ADRs - Part I

End point description

An ADR was defined as an untoward and unintended responses to an investigational product related to any dose administered. All AEs judged by either the reporting Investigator or the Sponsor as having a reasonable causal relationship to an investigational product qualified as ADRs. The expression “reasonable causal relationship” meant to convey in general that there were facts (evidence) or arguments meant to suggest a causal relationship. The definition covered also medication errors and uses outside what was foreseen in the protocol, including misuse and abuse of the product. Only treatment-emergent ADRs were considered in this analysis.

End point type

Other pre-specified

End point timeframe

All ADRs which started between treatment start (for active treatment) or after randomisation (for control) and discharge or 36 weeks PMA (whichever was sooner).

End point values	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF
Number of subjects analysed	9	9	9	9
Units: Neonates	0	0	0	0

No statistical analyses for this end point

Other pre-specified: Percentage of neonates with ADRs - Part I

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End point title

Percentage of neonates with ADRs - Part I

End point description

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point values	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF
Number of subjects analysed	9	9	9	9
Units: Percentage of neonates
number (not applicable)	0.0	0.0	0.0	0.0

No statistical analyses for this end point

Other pre-specified: Number of ADRs - Part I

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End point title

Number of ADRs - Part I

End point description

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point values	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF
Number of subjects analysed	9	9	9	9
Units: Events	0	0	0	0

No statistical analyses for this end point

Other pre-specified: Number of neonates with AEs - Part II

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End point title

Number of neonates with AEs - Part II

End point description

As per the endpoint 'Number of neonates with AEs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with AEs - Part I'.

End point values	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Number of subjects analysed	42	41	43
Units: Neonates	38	33	40

No statistical analyses for this end point

Other pre-specified: Percentage of neonates with AEs - Part II

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End point title

Percentage of neonates with AEs - Part II

End point description

As per the endpoint 'Number of neonates with AEs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with AEs - Part I'.

End point values	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Number of subjects analysed	42	41	43
Units: Percentage of neonates
number (not applicable)	90.5	80.5	93.0

No statistical analyses for this end point

Other pre-specified: Number of AEs - Part II

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End point title

Number of AEs - Part II

End point description

As per the endpoint 'Number of neonates with AEs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with AEs - Part I'.

End point values	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Number of subjects analysed	42	41	43
Units: Events	173	162	152

No statistical analyses for this end point

Other pre-specified: Number of neonates with ADRs - Part II

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End point title

Number of neonates with ADRs - Part II

End point description

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point values	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Number of subjects analysed	42	41	43
Units: Neonates	0	0	0

No statistical analyses for this end point

Other pre-specified: Percentage of neonates with ADRs - Part II

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End point title

Percentage of neonates with ADRs - Part II

End point description

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point values	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Number of subjects analysed	42	41	43
Units: Percentage of neonates
number (not applicable)	0.0	0.0	0.0

No statistical analyses for this end point

Other pre-specified: Number of ADRs - Part II

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End point title

Number of ADRs - Part II

End point description

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point type

Other pre-specified

End point timeframe

As per the endpoint 'Number of neonates with ADRs - Part I'.

End point values	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Number of subjects analysed	42	41	43
Units: Events	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from the signature of the patient information sheet/informed consent form (PIS/ICF; or from birth if the PIS/ICF was signed before birth) until the neonate’s study participation ended.

Adverse event reporting additional description

Treatment-emergent AEs were defined as AEs that started after treatment start (for active treatment) or randomisation (for control). Only treatment-emergent AEs are presented in this analysis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Part I - 200 mg/kg nebulised Curosurf® - SAF

Reporting group description

Reporting group title

Part I - 400 mg/kg nebulised Curosurf® - SAF

Reporting group description

Reporting group title

Part I - 600 mg/kg nebulised Curosurf® - SAF

Reporting group description

Reporting group title

Part I - nCPAP - SAF

Reporting group description

Reporting group title

Part II - 200 mg/kg nebulised Curosurf® - SAF

Reporting group description

Reporting group title

Part II - 400 mg/kg nebulised Curosurf® - SAF

Reporting group description

Reporting group title

Part II - nCPAP - SAF

Reporting group description

Serious adverse events	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	8 / 42 (19.05%)	3 / 41 (7.32%)	5 / 43 (11.63%)
number of deaths (all causes)	0	0	0	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0	0	1	0
Vascular disorders
Neonatal hypotension
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiopulmonary failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Nervous system disorders
Intraventricular haemorrhage neonatal
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage neonatal
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Necrotising enterocolitis neonatal
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neonatal gastrointestinal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 42 (4.76%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meconium ileus
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	3 / 42 (7.14%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Neonatal infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis neonatal
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part I - 200 mg/kg nebulised Curosurf® - SAF	Part I - 400 mg/kg nebulised Curosurf® - SAF	Part I - 600 mg/kg nebulised Curosurf® - SAF	Part I - nCPAP - SAF	Part II - 200 mg/kg nebulised Curosurf® - SAF	Part II - 400 mg/kg nebulised Curosurf® - SAF	Part II - nCPAP - SAF
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 9 (100.00%)	9 / 9 (100.00%)	9 / 9 (100.00%)	9 / 9 (100.00%)	38 / 42 (90.48%)	33 / 41 (80.49%)	40 / 43 (93.02%)
Vascular disorders
Neonatal hypotension
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	3 / 42 (7.14%)	4 / 41 (9.76%)	0 / 43 (0.00%)
occurrences all number	0	0	0	0	4	4	0
Pregnancy, puerperium and perinatal conditions
Jaundice neonatal
subjects affected / exposed	0 / 9 (0.00%)	4 / 9 (44.44%)	4 / 9 (44.44%)	4 / 9 (44.44%)	17 / 42 (40.48%)	17 / 41 (41.46%)	27 / 43 (62.79%)
occurrences all number	0	5	4	4	19	26	34
General disorders and administration site conditions
Catheter site discharge
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary dysplasia
subjects affected / exposed	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 9 (0.00%)	7 / 42 (16.67%)	6 / 41 (14.63%)	4 / 43 (9.30%)
occurrences all number	1	1	1	0	7	6	4
Infantile apnoea
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	2 / 9 (22.22%)	11 / 42 (26.19%)	6 / 41 (14.63%)	4 / 43 (9.30%)
occurrences all number	0	2	2	3	15	11	8
Neonatal hypoxia
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 9 (22.22%)	7 / 42 (16.67%)	4 / 41 (9.76%)	5 / 43 (11.63%)
occurrences all number	0	3	1	3	9	4	5
Neonatal respiratory failure
subjects affected / exposed	4 / 9 (44.44%)	6 / 9 (66.67%)	5 / 9 (55.56%)	7 / 9 (77.78%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	4	8	5	7	0	0	0
Pulmonary congestion
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Neonatal tachypnoea
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	3 / 41 (7.32%)	2 / 43 (4.65%)
occurrences all number	0	0	0	0	1	3	2
Psychiatric disorders
Selective eating disorder
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Blood bilirubin increased
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	2 / 41 (4.88%)	0 / 43 (0.00%)
occurrences all number	0	2	0	0	0	2	0
Blood iron decreased
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Blood phosphorus decreased
subjects affected / exposed	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	2	1	2	1	0	0	1
Blood potassium decreased
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	1	0	0	0	0	0	1
C-reactive protein increased
subjects affected / exposed	0 / 9 (0.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences all number	0	2	1	0	0	2	1
Cardiac murmur
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	3 / 41 (7.32%)	0 / 43 (0.00%)
occurrences all number	0	0	0	0	1	3	0
Haematocrit decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	0	1	2	0	0	0	1
PCO2 increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences all number	1	0	1	0	0	1	0
Congenital infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Congenital pneumonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Patent ductus arteriosus
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	2 / 9 (22.22%)	5 / 42 (11.90%)	6 / 41 (14.63%)	8 / 43 (18.60%)
occurrences all number	0	1	4	2	5	6	8
Cardiac disorders
Bradycardia neonatal
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 42 (4.76%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	1	2	0	0
Neonatal tachycardia
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences all number	0	0	1	0	0	1	1
Nervous system disorders
Cerebral cyst
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Intraventricular haemorrhage neonatal
subjects affected / exposed	2 / 9 (22.22%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 42 (2.38%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences all number	2	0	1	0	1	1	0
Blood and lymphatic system disorders
Anaemia neonatal
subjects affected / exposed	2 / 9 (22.22%)	3 / 9 (33.33%)	0 / 9 (0.00%)	3 / 9 (33.33%)	9 / 42 (21.43%)	5 / 41 (12.20%)	5 / 43 (11.63%)
occurrences all number	2	4	0	4	17	8	7
Coagulopathy
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Retinopathy of prematurity
subjects affected / exposed	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 42 (2.38%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	2	0	0	1	1	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences all number	0	0	3	0	0	1	0
Constipation
subjects affected / exposed	0 / 9 (0.00%)	2 / 9 (22.22%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	3	3	1	0	0	0
Gastric haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	0	0	1	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	1 / 42 (2.38%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	0	0	0	2	1	0	1
Infantile vomiting
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 42 (2.38%)	3 / 41 (7.32%)	6 / 43 (13.95%)
occurrences all number	0	0	0	1	1	3	6
Meconium ileus
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	1	0	0	1	1	0	0
Necrotising enterocolitis neonatal
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	0	0	0	1	0	0	1
Umbilical hernia
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	1	0	0
Hepatobiliary disorders
Hyperbilirubinaemia neonatal
subjects affected / exposed	5 / 9 (55.56%)	1 / 9 (11.11%)	3 / 9 (33.33%)	1 / 9 (11.11%)	6 / 42 (14.29%)	2 / 41 (4.88%)	6 / 43 (13.95%)
occurrences all number	5	1	3	1	6	2	6
Renal and urinary disorders
Oliguria
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 42 (2.38%)	1 / 41 (2.44%)	1 / 43 (2.33%)
occurrences all number	0	0	0	1	1	1	1
Musculoskeletal and connective tissue disorders
Hypotonia neonatal
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Osteopenia
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	3 / 42 (7.14%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	0	1	0	0	3	0	1
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	1 / 43 (2.33%)
occurrences all number	0	0	0	1	0	0	1
Conjunctivitis
subjects affected / exposed	1 / 9 (11.11%)	2 / 9 (22.22%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	1	3	2	1	0	0	0
Conjunctivitis bacterial
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 42 (4.76%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences all number	1	0	0	0	2	1	0
Neonatal infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	6 / 42 (14.29%)	3 / 41 (7.32%)	7 / 43 (16.28%)
occurrences all number	0	0	0	0	6	4	9
Neonatal pneumonia
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	1	0	0
Ophthalmia neonatorum
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	3 / 42 (7.14%)	1 / 41 (2.44%)	6 / 43 (13.95%)
occurrences all number	0	0	0	0	4	1	6
Pneumonia viral
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Sepsis neonatal
subjects affected / exposed	4 / 9 (44.44%)	0 / 9 (0.00%)	2 / 9 (22.22%)	2 / 9 (22.22%)	6 / 42 (14.29%)	3 / 41 (7.32%)	1 / 43 (2.33%)
occurrences all number	5	0	2	4	7	3	1
Skin infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Staphylococcal sepsis
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 42 (2.38%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0	1	1	0
Staphylococcal skin infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 42 (0.00%)	4 / 41 (9.76%)	1 / 43 (2.33%)
occurrences all number	0	0	0	1	0	5	2
Hyperkalaemia
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 42 (2.38%)	1 / 41 (2.44%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0	1	1	0
Hypernatraemia
subjects affected / exposed	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 42 (0.00%)	2 / 41 (4.88%)	1 / 43 (2.33%)
occurrences all number	1	0	1	0	0	2	1
Hypoglycaemia neonatal
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 42 (4.76%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	0	0	1	3	0	0
Hypokalaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 42 (2.38%)	2 / 41 (4.88%)	0 / 43 (0.00%)
occurrences all number	0	0	0	1	2	2	0
Hyponatraemia
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	2	1	0	0	0
Metabolic acidosis
subjects affected / exposed	0 / 9 (0.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 9 (0.00%)	3 / 42 (7.14%)	4 / 41 (9.76%)	1 / 43 (2.33%)
occurrences all number	0	2	1	0	4	5	1
Neonatal hypocalcaemia
subjects affected / exposed	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 9 (22.22%)	3 / 42 (7.14%)	2 / 41 (4.88%)	4 / 43 (9.30%)
occurrences all number	0	1	1	2	3	2	4
Neonatal hyponatraemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 42 (4.76%)	2 / 41 (4.88%)	2 / 43 (4.65%)
occurrences all number	0	0	0	1	2	3	2

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Were there any global substantial amendments to the protocol? Yes

10 Nov 2017

A global and substantial amendment (protocol version 2.0, dated 01 August 2017) clarified the following: 1. Section 3.1.1: Change in stopping rules and addition of plan to disseminate safety data among study sites, as per UK-specific protocol version 1.1; 2. Section 3.3: Change in the definition of end of trial; 3. Section 6: Alignment of the protocol with the nebuliser instructions for use; 4. Section 7: Timing to perform BPD assessment to be aligned with the BPD definition; 5. Addition of mean blood pressure (MBP) recording.

30 Apr 2018

A global and substantial amendment (protocol version 3.0, dated 08 February 2018) clarified the following: 1. Section 5.1: Change in concomitant medications recording instructions; 2. Sections 10.1 and 10.8: Change in recording of AEs; 3. Section 7.1.2: Cerebral echography to be additionally performed within 6 hours from randomisation/start of nebulisation; 4. Blood gas analysis: Better clarification of sampling time points; 5. Neonates with 26+0 to 27+6 weeks gestational age were removed from the study population. All protocol sections were impacted.

24 Jan 2019

A global and substantial amendment (protocol version 4.0, dated 16 November 2018) clarified the following: 1. Sections 3, 6 and 7: inclusion of re-dosing when indicated; 2. Sections 8 and 9: addition of efficacy and safety parameters related to re-dosing; 3. Section 10: clarifications for AE recording; 4. Section 12: statistical analysis updated in line with changes in Sections 8 and 9. Hierarchical testing defined.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
24 Mar 2020	Recruitment was halted as of 24 March 2020 due to the COVID-19 emergency.	23 Apr 2020
23 Apr 2020	A notification of permanent recruitment stop was submitted on 23 April 2020 following the ISMB recommendation to stop the study. This recommendation was based on the evaluation of the safety profile of the first 120 randomised neonates in Part II of the study as there was a change in the benefit-risk balance driven by a negligible efficacy profile. The study was considered as terminated early because the planned sample size of 252 neonates was not reached. The last visit of the last enrolled patient was held on 05 May 2020.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The early termination of Part II of the study led to a smaller sample size analysed than originally foreseen (120 neonates v the 252 neonates planned).

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of neonates with respiratory failure in the first 72 hours of life - Part II

Primary: Percentage of neonates with respiratory failure in the first 72 hours of life - Part II

Other pre-specified: Percentage of neonates with respiratory failure in the first 72 hours of life - Part I

Other pre-specified: Percentage of neonates with respiratory failure in the first 72 hours of life - Part I

Other pre-specified: Number of neonates with AEs - Part I

Other pre-specified: Number of neonates with AEs - Part I

Other pre-specified: Percentage of neonates with AEs - Part I

Other pre-specified: Percentage of neonates with AEs - Part I

Other pre-specified: Number of AEs - Part I

Other pre-specified: Number of AEs - Part I

Other pre-specified: Number of neonates with ADRs - Part I

Other pre-specified: Number of neonates with ADRs - Part I

Other pre-specified: Percentage of neonates with ADRs - Part I

Other pre-specified: Percentage of neonates with ADRs - Part I

Other pre-specified: Number of ADRs - Part I

Other pre-specified: Number of ADRs - Part I

Other pre-specified: Number of neonates with AEs - Part II

Other pre-specified: Number of neonates with AEs - Part II

Other pre-specified: Percentage of neonates with AEs - Part II

Other pre-specified: Percentage of neonates with AEs - Part II

Other pre-specified: Number of AEs - Part II

Other pre-specified: Number of AEs - Part II

Other pre-specified: Number of neonates with ADRs - Part II

Other pre-specified: Number of neonates with ADRs - Part II

Other pre-specified: Percentage of neonates with ADRs - Part II

Other pre-specified: Percentage of neonates with ADRs - Part II

Other pre-specified: Number of ADRs - Part II

Other pre-specified: Number of ADRs - Part II

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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