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
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EudraCT number |
2012-001829-27 |
Trial protocol |
BE CZ PL FR |
Global end of trial date |
05 Dec 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Apr 2016
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First version publication date |
18 Jun 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AC-052-392
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Actelion Pharmaceuticals Ltd
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Sponsor organisation address |
Gewerbestrasse 16, Allschwil,, Switzerland, 4123
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Public contact |
clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com
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Scientific contact |
clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000425-PIP02-10 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Jan 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Dec 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Dec 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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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).
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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.
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Background therapy |
Not applicable | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Dec 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
United States: 3
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Country: Number of subjects enrolled |
Czech Republic: 2
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Country: Number of subjects enrolled |
Korea, Republic of: 1
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Country: Number of subjects enrolled |
Poland: 6
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Worldwide total number of subjects |
15
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EEA total number of subjects |
11
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
15
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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). | |||||||||
Pre-assignment
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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
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Period 1 title |
Core study baseline
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
ACT-050088
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Other name |
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Pharmaceutical forms |
Dispersible tablet
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Routes of administration |
Nasogastric use
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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).
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Dispersible tablet
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Routes of administration |
Nasogastric use
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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).
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Period 2
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Period 2 title |
Observational period
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Is this the baseline period? |
No | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Arm title
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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
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Baseline characteristics reporting groups
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Reporting group title |
Bosentan 2 mg/kg
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Reporting group description |
Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Bosentan 2 mg/kg
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Reporting group description |
Only patients who participated in both the FUTURE 4 and FUTURE 4 extension study are reported here. | ||
Reporting group title |
Placebo
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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
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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
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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
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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).
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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
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End point type |
Primary
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End point timeframe |
0
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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 |
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Notes [2] - Not applicable (no primary endpoint was defined) |
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No statistical analyses for this end point |
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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
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End point type |
Other pre-specified
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End point timeframe |
From birth up to the last available time point of the observational period
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Notes [3] - Due to the low number of subjects, no descriptive analysis was performed |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From baseline up to the end of the observation period in AC-052-392
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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.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Ex-bosentan
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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
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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.
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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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. |