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Clinical Trial Results:
A MULTINATIONAL, MULTICENTER, MASKED, RANDOMIZED, CONTROLLED STUDY TO ASSESS THE SAFETY AND EFFICACY OF LUCINACTANT FOR INHALATION IN PRETERM NEONATES 26 TO 32 WEEKS GESTATIONAL AGE WITH RESPIRATORY DISTRESS SYNDROME.

Summary
EudraCT number	2015-003519-40
Trial protocol	PL IE NL HU
Global end of trial date	06 Aug 2019

Results information
Results version number	v2(current)
This version publication date	12 Oct 2022
First version publication date	11 Jan 2022
Other versions	v1
Version creation reason	Correction of full data set Summary of attachments not added
Summary report(s)	03-CL-1202 Synopsis v1.1_11JUN2020

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-1202

ISRCTN number

US NCT number

NCT02636868

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, Windtree Therapeutics, Inc., 215 488-9300, ssimonson@windtreetx.com

Scientific contact

Steven G. Simonson, MD, Windtree Therapeutics, Inc., 215 488-9300, ssimonson@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

11 Jun 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Aug 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate the safety and efficacy of lucinactant for inhalation in conjuction with nasal continuous positive airway pressure (nCPAP), in comparison to nCPAP alone, in preterm neonates with RDS, as assessed by the time to, and incidence of, respiratory failure and/or death due to RDS, incidence of bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age (PMA), and change in physiologic parameters (fraction of inspired oxygen [FiO2] and partial pressure of carbon dioxide [PCO2]) over the first 72 hours of life.

Protection of trial subjects

A DMC was established to evaluate the degree of risk involved in study subject participation within each treatment group and to determine if study continuation in accordance with the current protocol holds the potential to institute any undue harm or threat to the safety and welfare of study subjects. Safety and tolerability data from the time all active subjects completed assessments and procedures through 72 hours of life were assessed at pre-specified enrollment milestones. DMC responsibilities, authorities and procedures were documented in a DMC charter endorsed by members of the DMC.

Background therapy

Standard of Care (nCPAP alone)

Evidence for comparator

Preterm neonates who are treated for RDS initially with non-invasive ventilation (including nCPAP) are the appropriate controls for this study, since the addition of aerosolized surfactant would be the only difference in treatment in the active groups compared to the controls. Current guidelines allow use of non-invasive ventilation such as nCPAP as an initial modality for the treatment of RDS in preterm newborns, with the goal of avoiding endotracheal intubation. Each of the 4 components of lucinactant plays a role in its biological activity. Aerosolized vehicles (eg, sterile water or saline) may have an adverse effect on pulmonary function. Thus, no inert placebo exists. Therefore, “sham” treatment, in which the ADS is brought to the subject’s bedside but not used to deliver study drug, is the optimal control. All study treatments (whether active or control) are given only if subjects are stable enough that they do not require intubation. Such subjects would typically be maintained on standard nCPAP or other forms of non-invasive ventilation and since control/sham treatment is equivalent to standard care, it is therefore ethical to administer for initial or repeat dosing.

Actual start date of recruitment

14 Apr 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Poland: 65

Country: Number of subjects enrolled

Hungary: 18

Country: Number of subjects enrolled

Ireland: 3

Country: Number of subjects enrolled

United States: 66

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

Chile: 39

Country: Number of subjects enrolled

Colombia: 16

Worldwide total number of subjects

221

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

221

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

Preterm neonates who successfully met eligibility criteria were randomly assigned to one of 3 treatment groups in a 1:1:1 ratio using centralized allocation electronically. Randomization information was provided to the study drug preparer (eg, pharmacist). The PI, study staff, and attending physicians were masked to treatment assignment.

Screening details

1Signed ICF from legally authorized representative 2 26 0/7 to 32 6/7 compl. weeks gestation PMA 3Sucessful implement. of n/invasive support or ventilation within 90 min after birth 4Spontaneous breathing 5Chest radiograph consistent with RDS 6Within first 20h after birth, requires nCAP of 5-7cm H2O with FiO2>0,25 to 0,4 for minimum 30minutes

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Details of the masking procedure are provided in the 03-CL-1202 Overall Blinding Plan, Blinding Procedure, Blinding Maintenance and Assurance Plan, and Statistical Analysis Plan documents. The blinding plan is outlined as follows: a. Subject safety took precedence over maintenance of study masking. b. Personnel who made or influenced clinical decisions were masked from treatment assignment. c. Each site created a site-specific blinding plan, to be approved by Windtree prior to participation.

Are arms mutually exclusive

Yes

40 mg/kg

Arm description

Lucinactant for inhalation 40 mg TPL/kg (administered over 25 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 40 mg TPL/kg were to be given if repeat dosing criteria were met

Arm type

Experimental

Investigational medicinal product name

Lucinactant for inhalation

Investigational medicinal product code

20377

Other name

Aerosurf

Pharmaceutical forms

Inhalation vapour, liquid

Routes of administration

Inhalation use

Dosage and administration details

The study treatment, ‘lucinactant for inhalation,’ consists of the investigational drug lucinactant and the delivery system (ADS). The ADS has two components, the AEROSURF® Delivery Pack (ADP) and the AEROSURF® Control Unit (ACU). Details for study drug preparation and ADS operation were provided in the AEROSURF Investigator’s Brochure and in the ADS Operator’s Manual. Briefly, lyophilized drug was reconstituted immediately before use by adding 10 mL of sterile water for injection to each of 7 vials of lyophilized lucinactant, after which the vials were gently inverted to mix the suspension. The vials were drawn up into a single 60 mL syringe and transferred into the provided ADP syringe, which is then loaded into the ACU. The ADS was brought to the subject’s bedside and connected to the subject’s nCPAP via the patient interface connector. The ADS aerosolized lucinactant through heat and pressure created within the capillary located within the heater assembly.

80 mg/k

Arm description

Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 80 mg TPL/kg were to be given if repeat dosing criteria were met

Arm type

Experimental

Investigational medicinal product name

Lucinactant for inhalation

Investigational medicinal product code

20377

Other name

Aerosurf

Pharmaceutical forms

Inhalation vapour, liquid

Routes of administration

Inhalation use

Dosage and administration details

Control

Arm description

nCPAP alone

Arm type

Standard of Care

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	40 mg/kg	80 mg/k	Control
Started	73	76	72
Completed	73	75	70
Not completed	0	1	2
Adverse event, serious fatal	-	-	2
Adverse event, non-fatal	-	1	-

Baseline characteristics

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Reporting group title

40 mg/kg

Reporting group description

Lucinactant for inhalation 40 mg TPL/kg (administered over 25 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 40 mg TPL/kg were to be given if repeat dosing criteria were met

Reporting group title

80 mg/k

Reporting group description

Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 80 mg TPL/kg were to be given if repeat dosing criteria were met

Reporting group title

Control

Reporting group description

nCPAP alone

Reporting group values	40 mg/kg	80 mg/k	Control	Total
Number of subjects	73	76	72	221
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	73	76	72	221
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age continuous
Units: weeks
arithmetic mean (standard deviation)	30.8 ( 1.24 )	30.7 ( 1.17 )	30.7 ( 1.17 )	-
Gender categorical
Units: Subjects
Female	31	39	37	107
Male	42	37	35	114
Ethnicity
Units: Subjects
Hispanic or Latino	19	24	18	61
Not Hispanic or Latino	54	52	54	160
Unknown or Not Reported	0	0	0	0
Race
Units: Subjects
White	62	64	58	184
Black/African American	4	6	6	16
Asian	1	0	1	2
Other or Unknown	6	6	7	19
Ruptured Membranes
Units: Subjects
Spontaneous	23	16	19	58
Artificial	50	60	53	163
Chorioamnionitis
Units: Subjects
yes	3	3	2	8
no	70	73	70	213
Mode of Delivery
Units: Subjects
Vaginal	17	12	16	45
C-section	56	64	56	176
Birth Status
Units: Subjects
Single Birth	44	53	50	147
Multiple Birth	29	23	22	74
Congenital Anomaly
Units: Subjects
Yes	1	0	0	1
No	72	76	72	220
Region of Enrollment
Units: Subjects
Canada	4	2	3	9
Colombia	4	7	5	16
Netherlands	2	1	2	5
Hungary	6	3	9	18
United States	20	25	21	66
Ireland	1	2	0	3
Poland	23	21	21	65
Chile	13	15	11	39
Steroid Use
Units: Subjects
Used Steroids	68	69	70	207
No Steroids	5	7	2	14
Birth Weight
Units: grams
arithmetic mean (standard deviation)	1557.0 ( 342.38 )	1505.8 ( 378.5 )	1446.4 ( 359.13 )	-
Appearance, Pulse, Grimace, Activity, and Respiration (Apgar) Score at One Minute
Units: scores on a scale
arithmetic mean (standard deviation)	6.7 ( 1.74 )	6.5 ( 1.71 )	6.8 ( 1.61 )	-
Apgar Score at Five Minutes
Units: Scores on a scale
arithmetic mean (standard deviation)	8.1 ( 0.90 )	8.0 ( 1.02 )	8.1 ( 1.00 )	-

End points

Top of page

Reporting group title

40 mg/kg

Reporting group description

Lucinactant for inhalation 40 mg TPL/kg (administered over 25 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 40 mg TPL/kg were to be given if repeat dosing criteria were met

Reporting group title

80 mg/k

Reporting group description

Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 80 mg TPL/kg were to be given if repeat dosing criteria were met

Reporting group title

Control

Reporting group description

nCPAP alone

Primary: Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS)

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End point title

Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS)

End point description

Number of participants who had respiratory failure due to RDS or death due to RDS; known as nasal continuous positive airway pressure (nCPAP) failure

End point type

Primary

End point timeframe

72 hours

End point values	40 mg/kg	80 mg/k	Control
Number of subjects analysed	70	72	71
Units: count of participants	31	32	31

Statistical analysis 1

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis is no difference across treatment groups

Comparison groups

40 mg/kg v 80 mg/k v Control

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.363 ^[1]

Method

Regression, Logistic

Confidence interval

Notes
[1] - a priori threshold of statistical significance set at 0.05

Statistical analysis 2

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), nCPAP Only Null hypothesis is no difference across treatment groups

Comparison groups

40 mg/kg v Control

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.36 ^[2]

Method

Regression, Logistic

Confidence interval

Notes
[2] - a priori threshold of statistical significance set at 0.05

Statistical analysis 3

Statistical analysis description

Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis is no difference across treatment groups

Comparison groups

Control v 80 mg/k

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.461 ^[3]

Method

Regression, Logistic

Confidence interval

Notes
[3] - a priori threshold of statistical significance set at 0.05

Secondary: Incidence of Respiratory Failure or Death Due to RDS

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End point title

Incidence of Respiratory Failure or Death Due to RDS

End point description

Incidence of Respiratory Failure or Death Due to RDS by Intubation or Failure Criteria

End point type

Secondary

End point timeframe

72 hours

End point values	40 mg/kg	80 mg/k	Control
Number of subjects analysed	64	44	71
Units: count of participants	28	14	31

Statistical analysis 1

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis is no difference across treatment groups

Comparison groups

80 mg/k v Control v 40 mg/kg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.401 ^[4]

Method

Regression, Logistic

Confidence interval

Notes
[4] - a priori threshold of statistical significance set at 0.05

Statistical analysis 2

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), nCPAP Only Null hypothesis is no difference across treatment groups

Comparison groups

40 mg/kg v Control

Number of subjects included in analysis

135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.372 ^[5]

Method

Regression, Logistic

Confidence interval

Notes
[5] - a priori threshold of statistical significance set at 0.05

Statistical analysis 3

Statistical analysis description

Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis is no difference across treatment groups

Comparison groups

Control v 80 mg/k

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.648 ^[6]

Method

Regression, Logistic

Confidence interval

Notes
[6] - a priori threshold of statistical significance set at 0.05

Secondary: Time to nCPAP Failure

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End point title

Time to nCPAP Failure

End point description

Time from birth to nCPAP Failure

End point type

Secondary

End point timeframe

72 hours

End point values	40 mg/kg	80 mg/k	Control
Number of subjects analysed	70	72	71
Units: hours
least squares mean (standard error)	39.3 ( 2.06 )	44.8 ( 2.69 )	70.7 ( 2.44 )

Statistical analysis 1

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no difference across treatments

Comparison groups

40 mg/kg v 80 mg/k v Control

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.996 ^[7]

Method

Logrank

Confidence interval

Notes
[7] - a priori threshold of statistical significance set at 0.05

Statistical analysis 2

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), nCPAP Only Null hypothesis of no difference across treatments

Comparison groups

40 mg/kg v Control

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.951 ^[8]

Method

Logrank

Confidence interval

Notes
[8] - a priori threshold of statistical significance set at 0.05

Statistical analysis 3

Statistical analysis description

Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no difference across treatments

Comparison groups

Control v 80 mg/k

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.995 ^[9]

Method

Logrank

Confidence interval

Notes
[9] - a priori threshold of statistical significance set at 0.05

Secondary: Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling

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End point title

Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling

End point description

The measure tests the differences between treatments on respiratory failure or death due to RDS using Poisson distribution modeling, which accounts for the time over which the event could have occurred.

End point type

Secondary

End point timeframe

72 hours

End point values	40 mg/kg	80 mg/k	Control
Number of subjects analysed	70	72	71
Units: count of participants	31	32	31

Statistical analysis 1

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no difference between treatment groups

Comparison groups

80 mg/k v 40 mg/kg v Control

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.312 ^[10]

Method

Regression, Linear

Confidence interval

Notes
[10] - A priori threshold of statistical significance set at 0.10

Statistical analysis 2

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), nCPAP Only Null hypothesis of no difference between treatment groups

Comparison groups

40 mg/kg v Control

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.094 ^[11]

Method

Regression, Linear

Confidence interval

Notes
[11] - A priori threshold of statistical significance set at 0.10

Statistical analysis 3

Statistical analysis description

Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no difference between treatment groups

Comparison groups

Control v 80 mg/k

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.414 ^[12]

Method

Regression, Linear

Confidence interval

Notes
[12] - A priori threshold of statistical significance set at 0.10

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Top of page

End point title

Incidence of Respiratory Failure or Death Due to RDS

End point description

Incidence of Respiratory Failure or Death due to RDS by Intubation or Failure Criteria

End point type

Secondary

End point timeframe

28 days

End point values	40 mg/kg	80 mg/k	Control
Number of subjects analysed	70	72	71
Units: count of participants	35	32	31

Statistical analysis 1

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no difference between treatment groups

Comparison groups

40 mg/kg v 80 mg/k v Control

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.099 ^[13]

Method

Regression, Logistic

Confidence interval

Notes
[13] - A priori statistical significance of 0.05

Statistical analysis 2

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), nCPAP Only Null hypothesis of no difference between treatment groups

Comparison groups

40 mg/kg v Control

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.09 ^[14]

Method

Regression, Logistic

Confidence interval

Notes
[14] - A priori statistical significance of 0.05

Statistical analysis 3

Statistical analysis description

Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no difference between treatment groups

Comparison groups

Control v 80 mg/k

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.461 ^[15]

Method

Regression, Logistic

Confidence interval

Notes
[15] - A priori statistical significance of 0.05

Secondary: Number of Participants With Bronchopulmonary Dysplasia (BPD)

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End point title

Number of Participants With Bronchopulmonary Dysplasia (BPD)

End point description

Summarizes the number of participants with BPD or alive without BPD

End point type

Secondary

End point timeframe

36 weeks post-menstrual age (PMA)

End point values	40 mg/kg	80 mg/k	Control
Number of subjects analysed	70	72	71
Units: count of participants
BPD	7	7	10
Alive without BPD	62	64	59

Statistical analysis 1

Statistical analysis description

Aerosolized Lucinactant (40 mg TPL/kg), Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no treatment between treatments

Comparison groups

40 mg/kg v 80 mg/k v Control

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

= 0.534

Method

ANOVA

Confidence interval

Notes
[16] - A priori threshold for statistical significance set at 0.05

Statistical analysis 2

Statistical analysis description

Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no treatment between treatments

Comparison groups

80 mg/k v Control

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.48 ^[17]

Method

ANOVA

Confidence interval

Notes
[17] - A priori threshold for statistical significance set at 0.05

Statistical analysis 3

Statistical analysis description

Aerosolized Lucinactant (80 mg TPL/kg), nCPAP Only Null hypothesis of no treatment between treatments

Comparison groups

80 mg/k v Control

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.313 ^[18]

Method

ANOVA

Confidence interval

Notes
[18] - A priori threshold for statistical significance set at 0.05

Adverse events

Top of page

Timeframe for reporting adverse events

Information regarding occurence of AEs was assessed from the time of randomization until completion of Final Study Observation

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

40 mg/kg

Reporting group description

Lucinactant for inhalation 40 mg TPL/kg (administered over 25 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 40 mg TPL/kg were to be given if repeat dosing criteria were met

Reporting group title

Control

Reporting group description

nCPAP alone

Reporting group title

80 mg/k

Reporting group description

Lucinactant for inhalation 80 mg TPL/kg (administered over 50 minutes) in conjunction with nCPAP (n=80) Up to 2 repeat doses of 80 mg TPL/kg were to be given if repeat dosing criteria were met

Serious adverse events	40 mg/kg	Control	80 mg/k
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 70 (22.86%)	20 / 71 (28.17%)	14 / 72 (19.44%)
number of deaths (all causes)	0	2	1
number of deaths resulting from adverse events
Congenital, familial and genetic disorders
Coarctation of the aorta
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Patent ductus arteriosus
subjects affected / exposed	1 / 70 (1.43%)	0 / 71 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Hydrocephalus
subjects affected / exposed	1 / 70 (1.43%)	0 / 71 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Intraventricular haemorrhage neonatal
subjects affected / exposed	1 / 70 (1.43%)	1 / 71 (1.41%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Necrotising enterocolitis neonatal
subjects affected / exposed	0 / 70 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neonatal respiratory distress syndrome
subjects affected / exposed	4 / 70 (5.71%)	0 / 71 (0.00%)	2 / 72 (2.78%)
occurrences causally related to treatment / all	4 / 4	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 70 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Large intestine perforation
subjects affected / exposed	1 / 70 (1.43%)	0 / 71 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Necrotising enterocolitis neonatal
subjects affected / exposed	0 / 70 (0.00%)	2 / 71 (2.82%)	2 / 72 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
apnoea neonatal
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopulmonary dysplasia
subjects affected / exposed	1 / 70 (1.43%)	1 / 71 (1.41%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 70 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	1 / 70 (1.43%)	0 / 71 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 70 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary interstitial emphysema syndrome
subjects affected / exposed	1 / 70 (1.43%)	3 / 71 (4.23%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	1 / 1	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	3 / 70 (4.29%)	7 / 71 (9.86%)	4 / 72 (5.56%)
occurrences causally related to treatment / all	3 / 3	7 / 7	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema neonatal
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	2 / 70 (2.86%)	2 / 71 (2.82%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis staphylococcal
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	1 / 70 (1.43%)	0 / 71 (0.00%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neurological infection
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
nocosomial infection
subjects affected / exposed	1 / 70 (1.43%)	0 / 71 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 70 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	0 / 70 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis neonatal
subjects affected / exposed	2 / 70 (2.86%)	5 / 71 (7.04%)	3 / 72 (4.17%)
occurrences causally related to treatment / all	0 / 3	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic embolus
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 70 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	40 mg/kg	Control	80 mg/k
Total subjects affected by non serious adverse events
subjects affected / exposed	65 / 70 (92.86%)	66 / 71 (92.96%)	69 / 72 (95.83%)
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	4 / 70 (5.71%)	2 / 71 (2.82%)	4 / 72 (5.56%)
occurrences all number	5	2	4
Vascular disorders
Hypotension
subjects affected / exposed	2 / 70 (2.86%)	3 / 71 (4.23%)	4 / 72 (5.56%)
occurrences all number	3	4	4
Pallor
subjects affected / exposed	10 / 70 (14.29%)	3 / 71 (4.23%)	4 / 72 (5.56%)
occurrences all number	11	3	5
Cardiac disorders
Patent ductus arteriosus
subjects affected / exposed	18 / 70 (25.71%)	24 / 71 (33.80%)	24 / 72 (33.33%)
occurrences all number	18	26	24
Tachycardia
subjects affected / exposed	6 / 70 (8.57%)	2 / 71 (2.82%)	6 / 72 (8.33%)
occurrences all number	6	2	9
Pregnancy, puerperium and perinatal conditions
Agitation neonatal
subjects affected / exposed	7 / 70 (10.00%)	3 / 71 (4.23%)	9 / 72 (12.50%)
occurrences all number	8	3	10
Bradycardia neonatal
subjects affected / exposed	6 / 70 (8.57%)	3 / 71 (4.23%)	8 / 72 (11.11%)
occurrences all number	7	3	8
Intraventricular haemorrhage neonatal
subjects affected / exposed	7 / 70 (10.00%)	12 / 71 (16.90%)	10 / 72 (13.89%)
occurrences all number	8	15	11
Jaundice neonatal
subjects affected / exposed	41 / 70 (58.57%)	41 / 71 (57.75%)	49 / 72 (68.06%)
occurrences all number	47	46	50
Neonatal respiratory distress syndrome
subjects affected / exposed	10 / 70 (14.29%)	13 / 71 (18.31%)	8 / 72 (11.11%)
occurrences all number	12	13	8
Retinopathy of prematurity
subjects affected / exposed	3 / 70 (4.29%)	3 / 71 (4.23%)	6 / 72 (8.33%)
occurrences all number	3	3	6
Weight decrease neonatal
subjects affected / exposed	2 / 70 (2.86%)	2 / 71 (2.82%)	4 / 72 (5.56%)
occurrences all number	2	2	4
Blood and lymphatic system disorders
Anaemia neonatal
subjects affected / exposed	22 / 70 (31.43%)	31 / 71 (43.66%)	31 / 72 (43.06%)
occurrences all number	26	52	37
Coagulation disorder neonatal
subjects affected / exposed	2 / 70 (2.86%)	1 / 71 (1.41%)	5 / 72 (6.94%)
occurrences all number	2	1	5
Thrombocytopenia
subjects affected / exposed	4 / 70 (5.71%)	5 / 71 (7.04%)	6 / 72 (8.33%)
occurrences all number	5	5	6
General disorders and administration site conditions
Oedema
subjects affected / exposed	7 / 70 (10.00%)	7 / 71 (9.86%)	5 / 72 (6.94%)
occurrences all number	7	7	7
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	6 / 70 (8.57%)	6 / 71 (8.45%)	5 / 72 (6.94%)
occurrences all number	7	8	8
Constipation
subjects affected / exposed	6 / 70 (8.57%)	6 / 71 (8.45%)	9 / 72 (12.50%)
occurrences all number	7	7	9
Gastric haemorrhage
subjects affected / exposed	3 / 70 (4.29%)	6 / 71 (8.45%)	2 / 72 (2.78%)
occurrences all number	3	6	2
Necrotising enterocolitis neonatal
subjects affected / exposed	3 / 70 (4.29%)	6 / 71 (8.45%)	2 / 72 (2.78%)
occurrences all number	3	6	2
Regurgitation
subjects affected / exposed	10 / 70 (14.29%)	1 / 71 (1.41%)	12 / 72 (16.67%)
occurrences all number	10	1	13
Vomiting
subjects affected / exposed	9 / 70 (12.86%)	8 / 71 (11.27%)	9 / 72 (12.50%)
occurrences all number	9	9	10
Respiratory, thoracic and mediastinal disorders
apnoea neonatal
subjects affected / exposed	31 / 70 (44.29%)	27 / 71 (38.03%)	26 / 72 (36.11%)
occurrences all number	39	31	29
Bronchopulmonary dysplasia
subjects affected / exposed	6 / 70 (8.57%)	9 / 71 (12.68%)	6 / 72 (8.33%)
occurrences all number	6	9	6
Hypercapnia
subjects affected / exposed	3 / 70 (4.29%)	1 / 71 (1.41%)	4 / 72 (5.56%)
occurrences all number	3	1	5
Nasal inflammation
subjects affected / exposed	7 / 70 (10.00%)	7 / 71 (9.86%)	10 / 72 (13.89%)
occurrences all number	7	7	10
Neonatal tachypnoea
subjects affected / exposed	12 / 70 (17.14%)	8 / 71 (11.27%)	10 / 72 (13.89%)
occurrences all number	14	9	11
Pneumothorax
subjects affected / exposed	4 / 70 (5.71%)	2 / 71 (2.82%)	3 / 72 (4.17%)
occurrences all number	4	2	3
Skin and subcutaneous tissue disorders
Dermatitis diaper
subjects affected / exposed	7 / 70 (10.00%)	2 / 71 (2.82%)	6 / 72 (8.33%)
occurrences all number	7	2	7
Renal and urinary disorders
Atelectasis neonatal
subjects affected / exposed	0 / 70 (0.00%)	4 / 71 (5.63%)	4 / 72 (5.56%)
occurrences all number	0	5	4
Metabolism and nutrition disorders
Feeding intolerance
subjects affected / exposed	11 / 70 (15.71%)	10 / 71 (14.08%)	17 / 72 (23.61%)
occurrences all number	11	11	17
Hyperglycaemia
subjects affected / exposed	2 / 70 (2.86%)	3 / 71 (4.23%)	5 / 72 (6.94%)
occurrences all number	2	3	5
Hypermagnesaemia
subjects affected / exposed	3 / 70 (4.29%)	4 / 71 (5.63%)	4 / 72 (5.56%)
occurrences all number	3	4	4
Hypocalcaemia
subjects affected / exposed	3 / 70 (4.29%)	3 / 71 (4.23%)	7 / 72 (9.72%)
occurrences all number	4	3	7
Hypoglycaemia
subjects affected / exposed	4 / 70 (5.71%)	3 / 71 (4.23%)	1 / 72 (1.39%)
occurrences all number	6	5	1
Hyponatraemia
subjects affected / exposed	5 / 70 (7.14%)	5 / 71 (7.04%)	6 / 72 (8.33%)
occurrences all number	7	6	6
Metabolic acidosis
subjects affected / exposed	4 / 70 (5.71%)	9 / 71 (12.68%)	5 / 72 (6.94%)
occurrences all number	4	11	5

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Were there any global substantial amendments to the protocol? Yes

16 Mar 2016

Previous version of the protocol has been revised based upon discussions regarding the design and description of study 03-CL-1202 and based on lessons learned from this study's predecessor, study 03-CL-1201. Key changes: - study treatment - criteria for repeat study treatment dosing changed to encourage repeat dosing and to reflect revision of respiratory support in inclusion criteria -endpoints - definition of primary endpoint revised to be consistent with clinical practice and for clarity -results of Non-Clinical and Clinical Studies - results of study 03-CL-1201 added, data from preliminary studies KL4-CPAP-01 and KL4-ASTH-01 clarified and augmented -inclusion/exclusion criteria - Use of respiratory support in inclusion criteria (3 and 6) revised to be consistent with clinical practice and for clarity; exclusion criterion 7 revised to be consistent with clinical practice; exclusion criterion 11 added due to inadvertent omission from original protocol -statistics - enrollment stratification changed to allow greater enrollment of subjects in higher gestation age stratum -Data safety Monitoring Committee - rules for Data Monitoring Committee reviev had been inadvertently carried over from Study 03-CL-1201 so were changed to reflect the larger study population of Study 03-CL-1202 -Changes for Clarity- extensive revisions made for clarity to introduction and descriptions of study design/rationale, study treatment dosing and administration, study procedures and guidelines, and study evaluations

Were there any global interruptions to the trial? No

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

Clogging of a in-line filter led to a higher number of treatment interruptions than expected. This primarily affected one batch of supplies that were, by chance, predominantly used in European sites.

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Clinical Trial Results:
A MULTINATIONAL, MULTICENTER, MASKED, RANDOMIZED, CONTROLLED STUDY TO ASSESS THE SAFETY AND EFFICACY OF LUCINACTANT FOR INHALATION IN PRETERM NEONATES 26 TO 32 WEEKS GESTATIONAL AGE WITH RESPIRATORY DISTRESS SYNDROME.

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Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS)

Primary: Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS)

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Time to nCPAP Failure

Secondary: Time to nCPAP Failure

Secondary: Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling

Secondary: Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Number of Participants With Bronchopulmonary Dysplasia (BPD)

Secondary: Number of Participants With Bronchopulmonary Dysplasia (BPD)

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Clinical trials

Clinical Trial Results: A MULTINATIONAL, MULTICENTER, MASKED, RANDOMIZED, CONTROLLED STUDY TO ASSESS THE SAFETY AND EFFICACY OF LUCINACTANT FOR INHALATION IN PRETERM NEONATES 26 TO 32 WEEKS GESTATIONAL AGE WITH RESPIRATORY DISTRESS SYNDROME.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS)

Primary: Number of Participants With Respiratory Failure or Death Due to Respiratory Distress Syndrome (RDS)

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Time to nCPAP Failure

Secondary: Time to nCPAP Failure

Secondary: Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling

Secondary: Incidence of Respiratory Failure or Death Due to RDS With Poisson Distribution Modeling

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Incidence of Respiratory Failure or Death Due to RDS

Secondary: Number of Participants With Bronchopulmonary Dysplasia (BPD)

Secondary: Number of Participants With Bronchopulmonary Dysplasia (BPD)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A MULTINATIONAL, MULTICENTER, MASKED, RANDOMIZED, CONTROLLED STUDY TO ASSESS THE SAFETY AND EFFICACY OF LUCINACTANT FOR INHALATION IN PRETERM NEONATES 26 TO 32 WEEKS GESTATIONAL AGE WITH RESPIRATORY DISTRESS SYNDROME.