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Clinical Trial Results:
A Multicenter, Randomized, Open-Label, Controlled Trial to Assess the Safety and Tolerability of Lucinactant for Inhalation in Preterm Neonates 26 to 28 Weeks PMA.

Summary
EudraCT number	2015-005624-26
Trial protocol	PL
Global end of trial date	09 Jul 2017

Results information
Results version number	v2(current)
This version publication date	15 Dec 2022
First version publication date	27 Oct 2022
Other versions	v1
Version creation reason	Correction of full data set Correction of attachments
Summary report(s)	03-CL-1401_CSR 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

03-CL-1401

ISRCTN number

US NCT number

NCT02528318

WHO universal trial number (UTN)

Sponsor organisation name

Windtree Therapeutics, Inc.

Sponsor organisation address

2600 Kelly Road, Warrington, United States, 18976

Public contact

Steven G. Simonson, MD, MS, Windtree Therapeutics, Inc., +1 (215) 488-9300, psimmons@windtreetx.com

Scientific contact

Steven G. Simonson, MD, MS, Windtree Therapeutics, Inc., +1 (215) 488-9300, psimmons@windtreetx.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?

Analysis stage

Final

Date of interim/final analysis

01 Nov 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Jul 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study is to evaluate the safety and tolerability of lucinactant for inhalation, administered as an aerosolized dose in 4 escalating doses to preterm, neonates 26 to 28 completed weeks PMA with receiving nCPAP for RDS compared with neonates receiving nCPAP alone.

Protection of trial subjects

A Safety Review Committee was established to review safety data for this study. SRC was formed to evaluate the degree of risk involved in study subject participation within each dosing group to determine if study continuation in accordance with the current protocol held the potential to institute any undue harm, or threat to the safety and welfare of study subjects. After all active subject within Dosing Group 1 completed Study Day 7, a safety assessment (AEs incl. ADEs, SAEs and additional safety endpoints) was performed. Dosing was allowed to continue to the next higher dosing group (ie. Dosing Group II) immiediately following completion of nerollment within the current dosing group. The SRC provided recommendations following their review of the safety data. This process of continuing to the next higher dosing group and reviewing safety and tolerability was to be continued for the 100 and 150mg TPL/kg group. Subject were followed for safety evaluations until the subect were 36 weeks PMA or were discharged. A final visit ocured at 36 weeks PMA or at time of discharge or withdrawal for all subjects.

Background therapy

Standard of care (nCPAP alone)

Evidence for comparator

Actual start date of recruitment

01 Oct 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 5

Country: Number of subjects enrolled

Canada: 16

Country: Number of subjects enrolled

Chile: 1

Country: Number of subjects enrolled

United States: 26

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

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

Screening details

1.Signed ICF from legally representative 2.Gestational age 26 to 28 weeks PMA 3. Implementation of controlled nCPAP within 90min after birth 4.Spontaneous breathing 5.Chest radiograph consistent with RDS 6.Within first 20hours after birth, required nCPAP of5-6cm H2O and FiO2 of 0,25-0,50 that was clinically indicated for min. 30mins

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

This study was an open-label study to determine the safety and tolerability of lucinactant for inhalation. No blinding or masking procedures were implemented.

Are arms mutually exclusive

Yes

50mg/kg

Arm description

Lucinactant for inhalation 50 mg total phospholipids (TPL)/kg with nCPAP (drug-device combination product) 1 repeat dose allowed if repeat dosing criteria are met.

Arm type

Experimental

Investigational medicinal product name

Lucinactant for inhalation

Investigational medicinal product code

Other name

AEROSURF®

Pharmaceutical forms

Nebuliser suspension

Routes of administration

Inhalation use

Dosage and administration details

50 mg TPL/kg administered over 30 minutes in conjunction with nCPAP. 1 Repeat dose of 50 mg TPL/kg administered was allowed if repeat dosing criteria were met

75mg/kg

Arm description

Lucinactant inhalation 75 mg TPL/kg with nCPAP (drug-device combination product) 1 repeat dose allowed if repeat dosing criteria are met

Arm type

Experimental

Investigational medicinal product name

Lucinactant for inhalation

Investigational medicinal product code

Other name

AEROSURF®

Pharmaceutical forms

Nebuliser suspension

Routes of administration

Inhalation use

Dosage and administration details

75 mg TPL/kg administered over 45 minutes in conjunction with nCPAP 1 repeat dose of 75 mg TPL/kg was allowed if repeat dosing criteria are met

100 mg/kg

Arm description

Lucinactant fot inhalation 100mg TPL/kg with nCPAP (drug-device combination product) 1 repeat dosing will be allowed if repeat criteria are met.

Arm type

Experimental

Investigational medicinal product name

Lucinactant for inhalation

Investigational medicinal product code

Other name

AEROSURF®

Pharmaceutical forms

Nebuliser suspension

Routes of administration

Inhalation use

Dosage and administration details

100 mg TPL/kg administered over 60 minutes in conjunction with nCPAP 1 repeat dose ok 100 mg TPL/kg was allowed if repeat dosing criteria are met

nCPAP only

Arm description

nCPAP therapy alone

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Started	8	8	8	24
Completed	8	8	8	24

Baseline characteristics

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Reporting group title

50mg/kg

Reporting group description

Lucinactant for inhalation 50 mg total phospholipids (TPL)/kg with nCPAP (drug-device combination product) 1 repeat dose allowed if repeat dosing criteria are met.

Reporting group title

75mg/kg

Reporting group description

Lucinactant inhalation 75 mg TPL/kg with nCPAP (drug-device combination product) 1 repeat dose allowed if repeat dosing criteria are met

Reporting group title

100 mg/kg

Reporting group description

Lucinactant fot inhalation 100mg TPL/kg with nCPAP (drug-device combination product) 1 repeat dosing will be allowed if repeat criteria are met.

Reporting group title

nCPAP only

Reporting group description

nCPAP therapy alone

Reporting group values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only	Total
Number of subjects	8	8	8	24	48
Age categorical
Units: Subjects
<=18 years	8	8	8	24	48
Between 18 and 65 years	0	0	0	0	0
>=65 years	0	0	0	0	0
Gender categorical
Units: Subjects
Female	3	5	5	8	21
Male	5	3	3	16	27
Ethnicity
Units: Subjects
Hispanic or Latino	3	1	2	7	13
Not Hispanic or Latino	5	7	6	17	35
Unknown or not reported	0	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	2	0	1	1	4
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	1	1	2	1	5
White	3	5	4	20	32
More than one race	0	0	0	0	0
Unknown or Not Reported	2	2	1	2	7
Region of Enrollment
Units: Subjects
Canada	1	3	4	8	16
United States	7	3	4	12	26
Poland	0	2	0	3	5
Chile	0	0	0	1	1
Gestational age
Gestational age, based on obstetrician's best estimate
Units: Weeks
arithmetic mean (standard deviation)	27.6 ( 0.61 )	27.2 ( 1.06 )	27.2 ( 0.84 )	27.5 ( 0.76 )	-
Birth Weight
Units: gram(s)
arithmetic mean (standard deviation)	1052 ( 174.7 )	855 ( 84.6 )	839 ( 224.9 )	1005 ( 238.8 )	-
Apgar Score at One Minute
The Apgar Score measures a baby's health by assessing five characteristics (Appearance, Pulse, Grimace, Activity, and Respiration) . Each of the five characteristics are scored from 0 to 2, and the five scores are summed for the Apgar Score. Thus, the Apgar Score ranges from 0 (worst) to 10 (best), and scores over 7 indicate a baby in good health. Apgar Scores are performed at 1 minute and 5 minutes after birth.
Units: Scores on a scale
arithmetic mean (full range (min-max))	5.4 (2 to 9)	5.5 (2 to 8)	6.4 (3 to 8)	5.8 (1 to 9)	-
Apgar Score at Five Minutes
The Apgar Score measures a baby's health by assessing five characteristics (Appearance, Pulse, Grimace, Activity, and Respiration) . Each of the five characteristics are scored from 0 to 2, and the five scores are summed for the Apgar Score. Thus, the Apgar Score ranges from 0 (worst) to 10 (best), and scores over 7 indicate a baby in good health. Apgar Scores are performed at 1 minute and 5 minutes after birth.
Units: Scores on a scale
arithmetic mean (full range (min-max))	7.8 (7 to 9)	6.4 (1 to 9)	8.1 (6 to 9)	7.9 (5 to 9)	-

End points

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Reporting group title

50mg/kg

Reporting group description

Lucinactant for inhalation 50 mg total phospholipids (TPL)/kg with nCPAP (drug-device combination product) 1 repeat dose allowed if repeat dosing criteria are met.

Reporting group title

75mg/kg

Reporting group description

Lucinactant inhalation 75 mg TPL/kg with nCPAP (drug-device combination product) 1 repeat dose allowed if repeat dosing criteria are met

Reporting group title

100 mg/kg

Reporting group description

Lucinactant fot inhalation 100mg TPL/kg with nCPAP (drug-device combination product) 1 repeat dosing will be allowed if repeat criteria are met.

Reporting group title

nCPAP only

Reporting group description

nCPAP therapy alone

Primary: Number of Participants With Peri-Dosing Adverse Events - Initial Dose

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End point title

Number of Participants With Peri-Dosing Adverse Events - Initial Dose ^[1]

End point description

Number of Participants with adverse events that were experienced during the initial study treatment Peri-dosing events are events that occur during study treatment. Since this was an open-label study, no peri-dosing events were recorded for nCPAP alone. Any adverse events that occurred during the corresponding time for nCPAP alone were recorded as adverse events but not peri-dosing events.

End point type

Primary

End point timeframe

Randomization to 24 Hours Post Randomization

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Because no a priori statistical analyses were conducted in this study, no statistical analysys have been specified

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24 ^[2]
Units: Participants
number (not applicable)
Bradycardia	0	2	1	0
Desaturation	1	2	3	0
Gagging/regurgitation	0	0	0	0
Apnea	1	1	1	0
Pallor	0	0	0	0

Notes
[2] - There was no dosing in this group (no intervention, standard of care)

No statistical analyses for this end point

Primary: Number of Participants With Air Leak

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End point title

Number of Participants With Air Leak ^[3]

End point description

Number of participants with air leak (includes pneumothorax, pulmonary interstitial emphysema (PIE), pneumomediastinum, pneumopericardium, subcutaneous emphysema) This dose-escalation study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group or received 150 mg/kg.

End point type

Primary

End point timeframe

7 days

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Because no a priori statistical analyses were conducted in this study, no statistical analysys have been specified

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24
Units: Participants
number (not applicable)	3	0	2	4

No statistical analyses for this end point

Secondary: Number of Participants With Worsening of Respiratory Status Criteria

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End point title

Number of Participants With Worsening of Respiratory Status Criteria

End point description

Number of participants with worsening in one of 12 respiratory status criteria through 72 hours post randomization (need for additional surfactant therapy, desaturation < 80%, heart rate < 100 bpm, sustained fraction of inspired oxygen (FiO2) > 0.50, arterial carbon dioxide (PCO2) > 65 mmHg, sustained apnea, persistent arterial pH < 7.2, intubation for any reason, nCPAP > 7 cmH2O, initiation of intermittent positive pressure ventilation, death, principal investigator determination of worsening status). Intent-to-treat population. This dose-escalation study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group or received 150 mg/kg.

End point type

Secondary

End point timeframe

Randomization to 72 Hours Post Randomization

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24
Units: Participants
number (not applicable)	6	7	6	18

No statistical analyses for this end point

Secondary: Bronchopulmonary Dysplasia

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End point title

Bronchopulmonary Dysplasia

End point description

Number of participants with bronchopulmonary dysplasia (BPD) and number of participants alive and without BPD at 36 weeks post-menstrual age (PMA) This dose-escalation study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group or received 150 mg/kg.

End point type

Secondary

End point timeframe

Randomization to 36 weeks PMA

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24
Units: Participants
number (not applicable)
BPD	0	0	0	6
Alive and without BPD	7	7	8	18

No statistical analyses for this end point

Secondary: Number of Participants With Nasal Continuous Positive Airway Pressure (nCPAP) Failure

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End point title

Number of Participants With Nasal Continuous Positive Airway Pressure (nCPAP) Failure

End point description

Participants who required intubation for mechanical ventilation or surfactant administration were defined as having failed nCPAP. This dose-escalation study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group or received 150 mg/kg.

End point type

Secondary

End point timeframe

Randomization to 72 Hours Post Randomization

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24
Units: Participants
number (not applicable)	5	7	5	16

No statistical analyses for this end point

Secondary: Death

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End point title

Death

End point description

Number of participants who died during the study. This dose-escalation study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group or received 150 mg/kg.

End point type

Secondary

End point timeframe

Randomization to 36 weeks PMA

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24
Units: Participants
number (not applicable)	1	1	0	0

No statistical analyses for this end point

Secondary: FiO2

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End point title

FiO2

End point description

Observed and change from baseline measurements for fraction of inspired oxygen (FiO2). Values represent the amount (fraction) of oxygen in the air the participant inspires; the values themselves do not have units. The normal amount of oxygen in air ("room air") is 21%, or 0.21. This dose-escalation study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group or received 150 mg/kg. Safety population

End point type

Secondary

End point timeframe

Randomization to 72 hours post randomization

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24
Units: Fraction of oxygen in inspired air
arithmetic mean (standard deviation)
Baseline (Randomization)	0.31 ( 0.058 )	0.33 ( 0.071 )	0.37 ( 0.072 )	0.32 ( 0.061 )
60 minutes post randomization - observed	0.31 ( 0.064 )	0.35 ( 0.063 )	0.37 ( 0.090 )	0.34 ( 0.159 )
60 minutes post randomization - change from baseli	0.01 ( 0.010 )	0.02 ( 0.024 )	0.01 ( 0.044 )	0.01 ( 0.162 )
3 hours post randomization - observed	0.37 ( 0.191 )	0.37 ( 0.120 )	0.37 ( 0.107 )	0.29 ( 0.082 )
3 hours post randomization - change from baseline	0.06 ( 0.154 )	0.00 ( 0.066 )	0.00 ( 0.047 )	-0.03 ( 0.082 )
12 hours post randomization - observed	0.30 ( 0.114 )	0.30 ( 0.117 )	0.30 ( 0.068 )	0.33 ( 0.181 )
12 hours post randomization - change from baseline	-0.02 ( 0.137 )	-0.07 ( 0.074 )	-0.08 ( 0.090 )	0.00 ( 0.172 )
24 hours post randomization - observed	0.28 ( 0.093 )	0.25 ( 0.044 )	0.28 ( 0.077 )	0.29 ( 0.143 )
24 hours post randomization - change from baseline	-0.03 ( 0.072 )	-0.09 ( 0.046 )	-0.08 ( 0.105 )	-0.04 ( 0.140 )
48 hours post randomization - observed	0.28 ( 0.058 )	0.24 ( 0.038 )	0.23 ( 0.071 )	0.31 ( 0.188 )
48 hours post randomization - change from baseline	-0.03 ( 0.083 )	-0.09 ( 0.075 )	-0.09 ( 0.091 )	-0.02 ( 0.191 )
72 hours post randomization - observed	0.3 ( 0.105 )	0.23 ( 0.023 )	0.25 ( 0.050 )	0.27 ( 0.119 )
72 hours post randomisation - change from baseline	-0.02 ( 0.133 )	-0.10 ( 0.071 )	-0.12 ( 0.066 )	-0.05 ( 0.133 )

No statistical analyses for this end point

Secondary: Number of Participants With Complications of Prematurity

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End point title

Number of Participants With Complications of Prematurity

End point description

Number of participants with pre-specified common complications of prematurity. The study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150mg/kg group or received a 150mg/kg dose. Safety population.

End point type

Secondary

End point timeframe

Randomization to 36 weeks PMA

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	8	8	8	24
Units: Participants
number (not applicable)
Subject with any complication	8	7	7	22
Acquired sepsis	2	2	2	5
Apnea	8	5	6	19
Cystic Periventricular Leukomalcia	0	0	0	1
Patent Ductus Arteriosus	3	3	4	10
Pulmonary Hemorrhage	1	0	1	1
Intraventicular Hemorrhage	0	1	3	4
Necrotizing Enterocolitis	1	1	1	1
Retinopathy of Prematurity	2	1	1	9

No statistical analyses for this end point

Other pre-specified: nCPAP Failure Without Treatment Interruptions

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End point title

nCPAP Failure Without Treatment Interruptions

End point description

Number of subjects requiring mechanical ventilation or surfactant administration (nCPAP failure) but did not have a treatment interruption The study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group.

End point type

Other pre-specified

End point timeframe

Randomization to 72 Hours Post Randomization

End point values	50mg/kg	75mg/kg	100 mg/kg	nCPAP only
Number of subjects analysed	7	3	6	24
Units: Participants
number (not applicable)	4	3	3	16

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From randomization to 36 weeks PMA

Adverse event reporting additional description

This dose-escalation study was terminated after completion of the 100 mg/kg group for administrative purposes. No participants were enrolled in the 150 mg/kg group or received 150 mg/kg.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

50 mg/kg

Reporting group description

Lucinactant for inhalation 50 mg TPL/kg with nCPAP 1 repeat dose allowed if repeat dosing criteria are met. Lucinactant for inhalation: Lucinactant for inhalation refers to the active investigational agent, lucinactant, in combination with the investigational delivery device (drug-device combination product)

Reporting group title

75 mg/kg

Reporting group description

Lucinactant for inhalation 75 mg TPL/kg with nCPAP 1 repeat dose allowed if repeat dosing criteria are met. Lucinactant for inhalation: Lucinactant for inhalation refers to the active investigational agent, lucinactant, in combination with the investigational delivery device (drug-device combination product)

Reporting group title

100 mg/kg

Reporting group description

Lucinactant for inhalation 100 mg TPL/kg with nCPAP 1 repeat dose allowed if repeat dosing criteria are met. Lucinactant for inhalation: Lucinactant for inhalation refers to the active investigational agent, lucinactant, in combination with the investigational delivery device (drug-device combination product)

Reporting group title

nCPAP alone

Reporting group description

nCPAP therapy alone

Serious adverse events	50 mg/kg	75 mg/kg	100 mg/kg	nCPAP alone
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 8 (50.00%)	3 / 8 (37.50%)	2 / 8 (25.00%)	6 / 24 (25.00%)
number of deaths (all causes)	1	1	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Hepatic haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal injury
Additional description: Laryngeal trauma due to intubation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic liver injury
Additional description: Liver laceration
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Shock
Additional description: refractory shock
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Intraventricular haemorrhage neonatal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising enterocolitis neonatal
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Neonatal respiratory distress syndrome
subjects affected / exposed	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neonatal respiratory failure
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia neonatal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastric perforation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoea neonatal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neonatal respiratory failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis neonatal
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	50 mg/kg	75 mg/kg	100 mg/kg	nCPAP alone
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 8 (100.00%)	8 / 8 (100.00%)	8 / 8 (100.00%)	24 / 24 (100.00%)
Vascular disorders
Haemangioma
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1	0	1
Hypertension
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Hypotension
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 8 (0.00%)	4 / 24 (16.67%)
occurrences all number	1	2	0	7
Pregnancy, puerperium and perinatal conditions
Agitation neonatal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 24 (0.00%)
occurrences all number	0	0	1	0
Bradycardia neonatal
subjects affected / exposed	0 / 8 (0.00%)	5 / 8 (62.50%)	3 / 8 (37.50%)	9 / 24 (37.50%)
occurrences all number	0	7	5	9
Fixed bowel loop
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Intraventricular haemorrhage neonatal
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	2 / 24 (8.33%)
occurrences all number	0	1	1	2
Jaundice neonatal
subjects affected / exposed	5 / 8 (62.50%)	3 / 8 (37.50%)	1 / 8 (12.50%)	11 / 24 (45.83%)
occurrences all number	5	3	1	12
Necrotising enterocolitis neonatal
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 24 (4.17%)
occurrences all number	0	1	1	1
Neonatal respiratory distress syndrome
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	2 / 8 (25.00%)	9 / 24 (37.50%)
occurrences all number	1	2	3	12
Periventricular haemorrhage neonatal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Retinopathy of prematurity
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	9 / 24 (37.50%)
occurrences all number	2	1	1	9
Small for dates baby
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
General disorders and administration site conditions
Endotracheal intubation complication
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 24 (4.17%)
occurrences all number	0	0	1	1
Face oedema
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Hypothermia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	2
Oedema
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	3	0	0	1
Pain
alternative assessment type: Systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Apnoea neonatal
subjects affected / exposed	7 / 8 (87.50%)	4 / 8 (50.00%)	6 / 8 (75.00%)	19 / 24 (79.17%)
occurrences all number	7	5	9	21
Bronchopulmonary dysplasia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	7 / 24 (29.17%)
occurrences all number	0	0	0	8
Chronic respiratory failure
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Hypercapnia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	1	0	4
Nasal discomfort
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1	0	1
Nasal inflammation
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	3	0	0	2
Nasal mucosal ulcer
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Neonatal respiratory failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Neonatal tachypnoea
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	2 / 24 (8.33%)
occurrences all number	1	0	1	3
Pneumothorax
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Pulmonary haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 24 (4.17%)
occurrences all number	0	0	1	1
Pulmonary hypertension
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Pulmonary interstitial emphysema syndrome
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	3 / 24 (12.50%)
occurrences all number	3	0	1	3
Pulmonary oedema neonatal
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	1	0	2
Respiratory acidosis
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	2	0	0	2
Respiratory alkalosis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	0	0	2
Respiratory tract haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 24 (0.00%)
occurrences all number	0	0	1	0
Investigations
Anticonvulsant drug level above therapeutic
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Blood urea increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Cardiac murmur
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	2	1	0	1
Coagulation time prolonged
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 24 (0.00%)
occurrences all number	0	0	1	0
Neutrophil count increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Oxygen saturation decreased
subjects affected / exposed	2 / 8 (25.00%)	4 / 8 (50.00%)	6 / 8 (75.00%)	9 / 24 (37.50%)
occurrences all number	3	6	11	11
PO2 increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Reticulocyte count increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Injury, poisoning and procedural complications
Blister
alternative assessment type: Systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Ear abrasion
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Infusion site extravasation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Laceration
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Skin abrasion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Tracheal injury
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 24 (0.00%)
occurrences all number	0	1	1	0
Cardiac septal defect
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Hydrocele
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Patent ductus arteriosus
subjects affected / exposed	3 / 8 (37.50%)	3 / 8 (37.50%)	4 / 8 (50.00%)	10 / 24 (41.67%)
occurrences all number	3	3	4	10
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Tachycardia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 24 (0.00%)
occurrences all number	0	1	1	0
Nervous system disorders
Hypotonia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Lethargy
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Periventricular leukomalacia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Seizure
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	2
Blood and lymphatic system disorders
Anaemia neonatal
subjects affected / exposed	6 / 8 (75.00%)	4 / 8 (50.00%)	2 / 8 (25.00%)	12 / 24 (50.00%)
occurrences all number	6	6	2	16
Bandaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	0	0	1
Coagulopathy
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	0	0	1
Leukocystosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Leukopenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	2
Neutropenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	0	0	1
Thrombocytopenia
subjects affected / exposed	2 / 8 (25.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	4 / 24 (16.67%)
occurrences all number	2	2	0	4
Thrombocytosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Constipation
subjects affected / exposed	5 / 8 (62.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	2 / 24 (8.33%)
occurrences all number	13	0	1	2
Gastric haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Gastric hypomotility
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal hypomotility
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Haematemesis
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	2	0	0	0
Inguinal hernia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	2
Salivary hypersecretion
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Umbilical hernia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 24 (0.00%)
occurrences all number	0	1	1	0
Vomiting
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	0	0	1
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	0	0	3
Gallbladder disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Skin and subcutaneous tissue disorders
Dermatitis diaper
subjects affected / exposed	4 / 8 (50.00%)	2 / 8 (25.00%)	1 / 8 (12.50%)	1 / 24 (4.17%)
occurrences all number	5	2	1	1
Rash
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	2
Renal and urinary disorders
Azotaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Haematuria
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Oliguria
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	1	0	2
Renal failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	3
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1	0	1
Bacterial disease carrier
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 24 (0.00%)
occurrences all number	0	0	2	0
Conjunctivitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Enterococcal sepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Fungal skin infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Nosocomial infection
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Pneumonia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	1	0	3
Pneumonia klebsiella
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Pneumonia staphylococcal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Sepsis neonatal
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 8 (12.50%)	4 / 24 (16.67%)
occurrences all number	1	1	1	4
Septic shock
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Urinary tract infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	0	0	2
Urinary tract infection enterococcal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Urosepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 24 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Electrolyte imbalance
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Feeding intolerance
subjects affected / exposed	3 / 8 (37.50%)	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 24 (4.17%)
occurrences all number	3	1	1	1
Fluid retention
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	0	0	1
Hypercalcaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	1	0	0	1
Hyperchloraemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	1	0	0	3
Hyperglycaemia
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	1	2	0	5
Hyperkalaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	2
Hypermagnesaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	1	0	0	0
Hypernatraemia
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 8 (0.00%)	4 / 24 (16.67%)
occurrences all number	1	2	0	5
Hypertriglyceridaemia
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	1	1	0	3
Hypoalbuminaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	0	0	3
Hypocalcaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	2
Hypochloraemia
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	2	1	0	4
Hypokalaemia
subjects affected / exposed	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	2	0	4
Hypomagnesaemia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1	0	1
Hyponatraemia
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	7 / 24 (29.17%)
occurrences all number	3	0	0	7
Hypophosphataemia
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 24 (4.17%)
occurrences all number	2	0	0	1
Hypovolaemia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Metabolic acidosis
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	5 / 24 (20.83%)
occurrences all number	3	0	0	5
Metabolic alkalosis
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Osteopenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	0	0	2
Vitamin D deficiency
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 24 (0.00%)
occurrences all number	0	1	0	0
Hypoglycaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	0	0	3

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Were there any global substantial amendments to the protocol? Yes

02 Sep 2015

Rationale for protocol amendment - additional requirement of meeting criteria at treatment initiation added - additional clarification on repeat dose - typo corrections - clarification of "completion of study" - SRC approval not required to advance to next dosing level - repeat dosing criteria changed - concomitant medications - additional clarifications added - supplement to the instruction for ADP returns - clarification of when SRC meeting would be held following a death - clarification of peri-dosing events

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
09 Jul 2017	The sponsor of study 03-CL-1401, Windtree Therapeutics, Inc. has made a decision to terminate the dose-escalation study early after the completion of enrollment into Dose Group 3 3. It was anticipated 64 subjects would be enrolled into the study in four dose groups; however, only 48 subjects were enrolled (Dose Groups 1,2,3; n=16 per group). The decision to terminate the study early was taken to incorporate learning from this study into a redesigned trial to continue studying neonates in the 26-28 week gestational age. To this end, sponsor planned to study the 26-28 week GA patients in the amendment (Amendment 2) to the 03-CL-1202 study. A preliminary review of the data through Dose Group 3 has shown no safety signal of concern and the overall safety and tolerability profile was generally similar to the control group treated with nCPAP alone. A maximum tolerated dose was not established, the overall objective of the study was met. Early termination of 03-CL-1401 study has no effect on the overall risk-benefit assessment of lucinactant for inhalation. Last subject randomized into the study was on 16 May 2017 and was followed through study completion, which is 36 weeks PMA (9 July 2017)	-

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

None reported

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Clinical trials

Clinical Trial Results:
A Multicenter, Randomized, Open-Label, Controlled Trial to Assess the Safety and Tolerability of Lucinactant for Inhalation in Preterm Neonates 26 to 28 Weeks PMA.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Peri-Dosing Adverse Events - Initial Dose

Primary: Number of Participants With Peri-Dosing Adverse Events - Initial Dose

Primary: Number of Participants With Air Leak

Primary: Number of Participants With Air Leak

Secondary: Number of Participants With Worsening of Respiratory Status Criteria

Secondary: Number of Participants With Worsening of Respiratory Status Criteria

Secondary: Bronchopulmonary Dysplasia

Secondary: Bronchopulmonary Dysplasia

Secondary: Number of Participants With Nasal Continuous Positive Airway Pressure (nCPAP) Failure

Secondary: Number of Participants With Nasal Continuous Positive Airway Pressure (nCPAP) Failure

Secondary: Death

Secondary: Death

Secondary: FiO2

Secondary: FiO2

Secondary: Number of Participants With Complications of Prematurity

Secondary: Number of Participants With Complications of Prematurity

Other pre-specified: nCPAP Failure Without Treatment Interruptions

Other pre-specified: nCPAP Failure Without Treatment Interruptions

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Open-Label, Controlled Trial to Assess the Safety and Tolerability of Lucinactant for Inhalation in Preterm Neonates 26 to 28 Weeks PMA.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Peri-Dosing Adverse Events - Initial Dose

Primary: Number of Participants With Peri-Dosing Adverse Events - Initial Dose

Primary: Number of Participants With Air Leak

Primary: Number of Participants With Air Leak

Secondary: Number of Participants With Worsening of Respiratory Status Criteria

Secondary: Number of Participants With Worsening of Respiratory Status Criteria

Secondary: Bronchopulmonary Dysplasia

Secondary: Bronchopulmonary Dysplasia

Secondary: Number of Participants With Nasal Continuous Positive Airway Pressure (nCPAP) Failure

Secondary: Number of Participants With Nasal Continuous Positive Airway Pressure (nCPAP) Failure

Secondary: Death

Secondary: Death

Secondary: FiO2

Secondary: FiO2

Secondary: Number of Participants With Complications of Prematurity

Secondary: Number of Participants With Complications of Prematurity

Other pre-specified: nCPAP Failure Without Treatment Interruptions

Other pre-specified: nCPAP Failure Without Treatment Interruptions

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Randomized, Open-Label, Controlled Trial to Assess the Safety and Tolerability of Lucinactant for Inhalation in Preterm Neonates 26 to 28 Weeks PMA.