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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

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    Trial identification
    Sponsor protocol code
    AC-052-392
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    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
    Paediatric regulatory details
    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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    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?
    No
    General information about the trial
    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
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    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
    15
    EEA total number of subjects
    11
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    15
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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).

    Pre-assignment
    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
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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).

    Arm title
    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
    Period 2 title
    Observational period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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
    Arm title
    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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    Baseline characteristics reporting groups
    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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    End points reporting groups
    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
    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.

    Reporting group title
    Ex-placebo
    Reporting group 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.

    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
    0
    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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    Adverse events information
    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 used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    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
    Respiratory, thoracic and mediastinal disorders
    Wheezing
         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
    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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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    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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