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Clinical Trial Results:
Multi-center non-drug-interventional extension study to assess long-term safety and effects on growth in patients who received bosentan or placebo as adjunctive therapy to inhaled nitric oxide for persistent pulmonary hypertension of the newborn in FUTURE 4 (AC-052-391)

Summary
EudraCT number	2012-001829-27
Trial protocol	BE CZ PL FR
Global end of trial date	05 Dec 2014

Results information
Results version number	v1(current)
This version publication date	27 Apr 2016
First version publication date	18 Jun 2015
Other versions

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

AC-052-392

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Actelion Pharmaceuticals Ltd

Sponsor organisation address

Gewerbestrasse 16, Allschwil,, Switzerland, 4123

Public contact

clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com

Scientific contact

clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000425-PIP02-10

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

16 Jan 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

05 Dec 2014

Global end of trial reached?

Yes

Global end of trial date

05 Dec 2014

Was the trial ended prematurely?

Main objective of the trial

The main objective of this extension observational study (AC-052-392) was to assess long-term safety and effects on growth in patients who received bosentan or placebo as adjunctive therapy to inhaled nitric oxide (iNO) for persistent pulmonary hypertension of the newborn (PPHN) in the short-term interventional FUTURE 4 study (AC-052-391).

Protection of trial subjects

This clinical study was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21, and with the ethical principles laid down in the Declaration of Helsinki. Parent(s) or the legal representative(s) were asked if they agreed that their baby took part in the FUTURE 4 extension (AC-052-392) study.

Background therapy

Not applicable

Evidence for comparator

Actual start date of recruitment

14 Dec 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Czech Republic: 2

Country: Number of subjects enrolled

Korea, Republic of: 1

Country: Number of subjects enrolled

United States: 3

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

Patients who received at least one dose of study drug (bosentan or placebo) in FUTURE 4 study (AC-052-391 / 2011-000203-41) were allowed to be enrolled in the FUTURE 4 extension study (AC-052-392).

Screening details

21 patients were randomized and received at least one dose of study drug in the FUTURE 4 study (AC-052-391), among whom 15 entered the FUTURE 4 extension study. 6 patients did not enter the extension study (3 parents could not be reached, 1 parent refused, 1 parent was lost to follow-up, 1 moved to another country)

Period 1 title

Core study baseline

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

Bosentan 2 mg/kg

Arm description

Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here.

Arm type

Experimental

Investigational medicinal product name

bosentan

Investigational medicinal product code

ACT-050088

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Nasogastric use

Dosage and administration details

Bosentan as add-on to iNO was administered twice daily by nasogastric or orogastric tube at a dose of 2 mg/kg of weight at birth for a maximum duration of 10 days during the FUTURE 4 study (AC-052-391).

Placebo

Arm description

Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here.

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet

Routes of administration

Nasogastric use

Dosage and administration details

Placebo as add-on to iNO was administered by nasogastric or orogastric tube for a maximum duration of 6.5 days during the FUTURE 4 study (AC-052-391).

Number of subjects in period 1	Bosentan 2 mg/kg	Placebo
Started	7	8
Completed	7	8

Period 2 title

Observational period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ex-bosentan

Arm description

This arm includes patients who received bosentan at least once to a maximum of 10 days during neonatal age in the FUTURE 4 (AC-052-391) study and were followed for growth and adverse events during the first year of life (i.e., 12 months after the core FUTURE 4 end of study). They did not receive any study treatments during this observational period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Ex-placebo

Arm description

This arm includes patients who received placebo at least once to a maximum of 6.5 days during neonatal age in the FUTURE 4 (AC-052-391) study and were followed-up for growth and adverse events during the first year of life (i.e., 12 months after the core FUTURE 4 end of study). They did not receive any study treatments during this observational period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Ex-bosentan	Ex-placebo
Started	7	8
Completed	7	8

Baseline characteristics

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Reporting group title

Bosentan 2 mg/kg

Reporting group description

Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here.

Reporting group title

Placebo

Reporting group description

Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here.

Reporting group values	Bosentan 2 mg/kg	Placebo	Total
Number of subjects	7	8	15
Age categorical
Age at baseline during the core FUTURE 4 study
Units: Subjects
Newborns (0-27 days)	7	8	15
Age continuous
Age at baseline in FUTURE 4 (AC-052-391) study
Units: days
median (full range (min-max))	1.1 (0.6 to 2.6)	1.7 (0.6 to 5.9)	-
Gender categorical
Units: Subjects
Female	4	6	10
Male	3	2	5
PPHN etiology
Among the 6 patients reported to have neonatal aspiration in the Bosentan group, 1 also had respiratory distress syndrome. So, data reported in the table below for the Bosentan arm must be read as follows: neonatal aspiration: n = 6, neonatal respiratory distress syndrome: n = 2 since the conditions related to parenchymal lung disease are not mutually exclusive.
Units: Subjects
Idiopathic	0	3	3
Neonatal aspiration	6	3	9
Neonatal respiratory distress syndrome	1	0	1
Pneumonia / Sepsis	0	2	2

End points

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Reporting group title

Bosentan 2 mg/kg

Reporting group description

Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here.

Reporting group title

Placebo

Reporting group description

Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here.

Reporting group title

Ex-bosentan

Reporting group description

Reporting group title

Ex-placebo

Reporting group description

Subject analysis set title

all-enrolled set

Subject analysis set type

Safety analysis

Subject analysis set description

The all-enrolled set in the extension study comprises all patients included in the all-treated set of the FUTURE 4 (AC-052-391) study for whom parent(s) or the legal representative(s) signed the informed consent form for their baby to take part in the FUTURE 4 study extension (AC-052-392).

Primary: Primary EP: none

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End point title

Primary EP: none ^[1]

End point description

This is an exploratory study in a small number of patients and no primary endpoint was defined

End point type

Primary

End point timeframe

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: Not applicable as no primary efficacy endpoint was defined for this observational study designed to explore the long-term safety of bosentan in patients previously treated with bosentan as add-on therapy to iNO in the core FUTURE 4 study

End point values	all-enrolled set
Number of subjects analysed	0 ^[2]
Units: not applicable

Notes
[2] - Not applicable (no primary endpoint was defined)

No statistical analyses for this end point

Other pre-specified: growth: body length and weight

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End point title

growth: body length and weight

End point description

Per protocol, growth variables were to be summarized as changes from baseline to predefined time points. However, because of the small sample size and discrepancies in reporting growth across investigator sites, estimates of changes from baseline by treatment group would have been unreliable. Consequently, only individual absolute values were reported over time based on the standard WHO growth centiles by age. Overall, subjects’ growth curves (length and weight) remained within 5th to 95th WHO growth percentiles

End point type

Other pre-specified

End point timeframe

From birth up to the last available time point of the observational period

End point values	all-enrolled set
Number of subjects analysed	0 ^[3]
Units: number

Notes
[3] - Due to the low number of subjects, no descriptive analysis was performed

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From baseline up to the end of the observation period in AC-052-392

Adverse event reporting additional description

For non-serious adverse events, baseline is defined as end of treatment (EOT) + 7 days in FUTURE 4. For serious adverse event, baseline is defined as EOT + 60 days in FUTURE 4.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Ex-bosentan

Reporting group description

This arm includes patients who received at least one dose of bosentan (2 mg/kg) during the FUTURE 4 (AC-052-391) study and followed-up for adverse events up to 14 months during the FUTURE 4 extension study

Reporting group title

Ex-Placebo

Reporting group description

This arm includes patients who received at least one dose of placebo during the FUTURE 4 (AC-052-391) study and followed-up for adverse events up to 14 months during the FUTURE 4 extension study

Serious adverse events	Ex-bosentan	Ex-Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 7 (0.00%)	0 / 8 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0

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

Non-serious adverse events	Ex-bosentan	Ex-Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 7 (57.14%)	4 / 8 (50.00%)
Injury, poisoning and procedural complications
Scar
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 8 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Vomiting
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Wheezing
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Dermatitis diaper
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Rash
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Seborrhoea
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Positional plagiocephaly
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 7 (14.29%)	1 / 8 (12.50%)
occurrences all number	2	1
Croup infectious
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Ear infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 8 (0.00%)
occurrences all number	1	0
Gastroenteritis viral
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Tonsillitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1
Upper respiratory tract infection
subjects affected / exposed	2 / 7 (28.57%)	0 / 8 (0.00%)
occurrences all number	4	0
Urinary tract infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 8 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

11 Jul 2013

Global amendment includes the following main changes to the protocol: • Data collection was planned to occur via telephone call to a physician taking care of the patient outside of the investigational hospital. Because subjects were not followed by a physician in all countries, the protocol was amended to allow the patients to return for a site visit. • Investigators were informed of the treatment assignment in the FUTURE 4 core study upon release of the study results. Hence, the wording ‘investigator-blinded’ was removed and the absence of drug intervention was added from the study design. • Growth variables were planned to be assessed at the investigational site. The protocol was amended to allow assessment of growth variables by a healthcare professional.

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.

Limitations include: small number of subjects enrolled, lack of standardization of data collection including retrospective data collection.

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Clinical trials

Clinical Trial Results:
Multi-center non-drug-interventional extension study to assess long-term safety and effects on growth in patients who received bosentan or placebo as adjunctive therapy to inhaled nitric oxide for persistent pulmonary hypertension of the newborn in FUTURE 4 (AC-052-391)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary EP: none

Primary: Primary EP: none

Other pre-specified: growth: body length and weight

Other pre-specified: growth: body length and weight

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Multi-center non-drug-interventional extension study to assess long-term safety and effects on growth in patients who received bosentan or placebo as adjunctive therapy to inhaled nitric oxide for persistent pulmonary hypertension of the newborn in FUTURE 4 (AC-052-391)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary EP: none

Primary: Primary EP: none

Other pre-specified: growth: body length and weight

Other pre-specified: growth: body length and weight

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Multi-center non-drug-interventional extension study to assess long-term safety and effects on growth in patients who received bosentan or placebo as adjunctive therapy to inhaled nitric oxide for persistent pulmonary hypertension of the newborn in FUTURE 4 (AC-052-391)