Clinical Trial Results:
An open-label, long-term, safety, and tolerability extension study using the pediatric formulation of bosentan in the treatment of children with idiopathic or familial pulmonary arterial hypertension who completed FUTURE 1
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Summary
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EudraCT number |
2005-001967-70 |
Trial protocol |
GB DE IT |
Global end of trial date |
28 Oct 2011
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Results information
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Results version number |
v2(current) |
This version publication date |
17 Jun 2016
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First version publication date |
06 Aug 2015
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Other versions |
v1 |
Version creation reason |
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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-052-367
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00319020 | ||
WHO universal trial number (UTN) |
- | ||
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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) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 Sep 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Oct 2011
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Oct 2011
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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 |
To assess the long-term safety and tolerability of the pediatric formulation of bosentan in children with idiopathic or familial pulmonary arterial hypertension (iPAH or fPAH)
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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 of the countries where the study was conducted, and with the ethical principles laid down in the Declaration of Helsinki.
Only patients who completed the FUTURE 1 study, who tolerated bosentan 32 mg dispersible tablets (pediatric formulation) during FUTURE 1 and for whom continuation of bosentan treatment was considered beneficial by the investigator, were offered the oppurtunity to participate in the FUTURE 1 Extension trial.
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Background therapy |
The following concomitant medications were allowed at inclusion and during the study: calcium channel blockers, intravenous epoprostenol, intravenous or inhaled iloprost, anticoagulants, diuretics, digoxin | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Aug 2005
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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 |
France: 15
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Netherlands: 6
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
United States: 7
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Worldwide total number of subjects |
36
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EEA total number of subjects |
28
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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) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
36
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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 |
36 Children (≥ 2 years and < 12 years) with idiopathic or familial pulmonary arterial hypertension were recruited from 11 centers across Europe and USA and enrolled in the FUTURE 1 trial (baseline). Only patients who completed FUTURE 1 (n=34) could be enrolled in FUTURE 2. Enrollment in FUTURE 2 started August 23, 2005. | |||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
The actual number of patients enrolled in FUTURE 2 was 33 because 2 patients did not complete FUTURE 1 and one patient completed FUTURE 1 but was not enrolled in FUTURE 2. | |||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (FUTURE 1 + FUTURE 2) (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
In this open-label extension trial, all subjects received the pediatric formulation of bosentan according to the core (FUTURE 1) study drug regimen, with the aim to determine its long term safety.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Patients with previous bosentan | |||||||||||||||||||||||||||||||||||||||
Arm description |
This group included patients who already received bosentan (film-coated tablets) before enrollment in FUTURE 1, and then received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen. | |||||||||||||||||||||||||||||||||||||||
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 |
Oral use
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Dosage and administration details |
The pediatric formulation of bosentan was initiated at a dose of 2 mg/kg b.i.d. for 4 weeks, then uptitrated to the maintenance dose of 4 mg/kg b.i.d. for the next 8 weeks of the FUTURE 1 trial (AC-052- 365) and to be continued in FUTURE 2. The dose could be down-titrated to 2 mg/kg b.i.d. if not tolerated. The body weight-adjusted dose of the dispersible tablet was dispersed in a teaspoon of water (not mixed with food) before being administered orally.
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Arm title
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Bosentan-naive Patients | |||||||||||||||||||||||||||||||||||||||
Arm description |
This group included patients who were not treated with bosentan before enrollment in FUTURE 1, and received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen. | |||||||||||||||||||||||||||||||||||||||
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 |
Oral use
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Dosage and administration details |
The pediatric formulation of bosentan was initiated at a dose of 2 mg/kg b.i.d. for 4 weeks, then uptitrated to the maintenance dose of 4 mg/kg b.i.d. for the next 8 weeks of the FUTURE 1 trial (AC-052- 365) and to be continued in FUTURE 2. The dose could be down-titrated to 2 mg/kg b.i.d. if not tolerated. The body weight-adjusted dose of the dispersible tablet was dispersed in a teaspoon of water (not mixed with food) before being administered orally.
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Baseline characteristics reporting groups
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Reporting group title |
Patients with previous bosentan
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Reporting group description |
This group included patients who already received bosentan (film-coated tablets) before enrollment in FUTURE 1, and then received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bosentan-naive Patients
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Reporting group description |
This group included patients who were not treated with bosentan before enrollment in FUTURE 1, and received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Patients with previous bosentan
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Reporting group description |
This group included patients who already received bosentan (film-coated tablets) before enrollment in FUTURE 1, and then received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen. | ||
Reporting group title |
Bosentan-naive Patients
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Reporting group description |
This group included patients who were not treated with bosentan before enrollment in FUTURE 1, and received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen. | ||
Subject analysis set title |
All-treated set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients (bosentan-naive patients and patients treated with film-coated bosentan tablets before enrollment) who received at least one dose of study drug (dispersible bosentan tablets) in the combined FUTURE 1 / FUTURE 2 trial periods.
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End point title |
Change from baseline to end of study (EOS) in systolic blood pressure (SBP) [1] | ||||||||||||||||||||||||
End point description |
The main study objective was to assess the long-term safety of bosentan in children with PAH, including changes from baseline in blood pressure.
Only subjects with non missing data at both time points were considered.
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End point type |
Primary
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End point timeframe |
From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
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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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from baseline to end of study (EOS) in diastolic blood pressure (DBP) [2] | ||||||||||||||||||||||||
End point description |
The main study objective was to assess the long-term safety of bosentan in children with PAH, including changes from baseline in blood pressure.
Only subjects with non missing data at both time points were considered.
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End point type |
Primary
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End point timeframe |
From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
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| Notes [2] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from baseline to end of study (EOS) in pulse rate [3] | ||||||||||||||||||||||||
End point description |
The main study objective was to assess the long-term safety of bosentan in children with PAH, including changes from baseline in pulse rate.
Only subjects with non missing data at both time points were considered.
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End point type |
Primary
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End point timeframe |
From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from baseline to end of study (EOS) in body weight [4] | ||||||||||||||||||||||||
End point description |
The main study objective was to assess the long-term safety of bosentan in children with PAH, including growth as measured by changes from baseline in body weight and height.
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End point type |
Primary
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End point timeframe |
From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
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| Notes [4] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from baseline to end of study (EOS) in height for age [5] | ||||||||||||||||||||||||||||
End point description |
The main study objective was to assess the long-term safety of bosentan in children with PAH, including growth as measured by changes from baseline in body weight and height.
For each patient, height was put in the perspective of the height of healthy children of the same age according to the WHO growth standards.
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End point type |
Primary
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End point timeframe |
From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
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| Notes [5] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Proportion of patients with treatment-emergent liver function abnormalities [6] | ||||||||||||||||||||||||
End point description |
The main study objective was to assess the long-term safety of bosentan in children with PAH, including laboratory abnormalities related to liver enzymes.
Proportion of patients with increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above 3 x ULN (upper limit of normal) is reported here.
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End point type |
Primary
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End point timeframe |
After baseline, up to 1 calendar day after study drug discontinuation in FUTURE 1 or FUTURE 2
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| Notes [6] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Proportion of patients with treatment-emergent hemoglobin abnormalities [7] | ||||||||||||||||
End point description |
The main study objective was to assess the long-term safety of bosentan in children with PAH, including hemoglobin abnormalities.
Proportion of patients with marked hemoglobin decreases (i.e., decrease of or above 15% of the lower normal limit (LL)) is reported here.
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End point type |
Primary
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End point timeframe |
After baseline, up to 1 calendar day after study drug discontinuation in FUTURE 1 or FUTURE 2
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| Notes [7] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Number of subjects with adverse events leading to premature discontinuation of study treatment [8] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From the first study drug administration in FUTURE 1
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| Notes [8] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were 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 study drug initiation up to 1 day after study drug discontinuation (up to 28 days after study drug discontinuation for serious adverse events)
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Adverse event reporting additional description |
Four deaths occurred during this time frame and two other deaths (1 due to PAH and cardiac complications and 1 during cardiac catheterization; not listed below) occurred later (38 days and 11 months after study drug discontinuation, respectively).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14.0
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Reporting groups
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Reporting group title |
All treated set
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Reporting group description |
The 36 patients included in this analysis set were exposed to the study drug (pediatric formulation of bosentan), for at least 8.4 weeks up to a maximum of 258 weeks (median: 119.9 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Aug 2008 |
The purpose of this amendment is to adjust the monitoring schedule during this open label extension study. |
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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. | |||
| In 3 patients new therapy was initiated in spite of absence of clinical worsening, reflecting a changing treatment paradigm towards combination therapy. The patients were kept in the time to PAH worsening analyses. | |||
