Clinical Trial Results:
An open label, prospective multicenter study to assess the pharmacokinetics, tolerability, safety and efficacy of the pediatric formulation of bosentan two versus three times a day in children with pulmonary arterial hypertension
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Summary
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EudraCT number |
2010-021825-11 |
Trial protocol |
NL HU DE ES CZ FR IT BG Outside EU/EEA |
Global end of trial date |
26 Aug 2013
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Results information
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Results version number |
v3(current) |
This version publication date |
14 Jun 2017
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First version publication date |
06 Aug 2015
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Other versions |
v1 , v2 |
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-052-373
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01223352 | ||
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) |
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 |
25 Sep 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Aug 2013
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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 investigate the pharmacokinetics (PK) of the dispersible tablet formulation of bosentan at doses of 2 mg/kg b.i.d. and 2 mg/kg t.i.d. in children with pulmonary arterial hypertension (PAH) from ≥ 3 months to < 12 years of age.
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Protection of trial subjects |
This clinical study was designed and conducted in accordance with the ICH Harmonized Tripartite
Guidelines for GCPs, with the ethical principles laid down in the ‘Declaration of Helsinki’ and with the laws and regulations of the countries in which the research was conducted.
Child’s parents or legal representatives were asked if they agreed that their child took part in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study.
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Background therapy |
The following medications were allowed to be taken along with the study drug: anticoagulants, diuretics, digoxin, calcium channel blockers, prostanoids and phosphodiesterase-5 inhibitors. All background PAH therapies were required to be maintained at a stable dose during the study. Intiation or dose increase of ongoing PAH-specific therapy (prostanoids and / or phosphodiesterase-5 inhibitors) was required to be associated with PAH progression, and this led to study discontinuation. Patients receiving the commercial formulation of bosentan (adult tablet formulation) before entering the FUTURE 3 study had to stop it and instead take the study drug (dispersible tablet formulation). | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Mar 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
South Africa: 6
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Ukraine: 1
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Country: Number of subjects enrolled |
United States: 2
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Country: Number of subjects enrolled |
Australia: 2
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Country: Number of subjects enrolled |
Belarus: 3
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Country: Number of subjects enrolled |
China: 6
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Country: Number of subjects enrolled |
Czech Republic: 2
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Hungary: 3
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Country: Number of subjects enrolled |
India: 3
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Country: Number of subjects enrolled |
Israel: 2
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Mexico: 1
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Country: Number of subjects enrolled |
Poland: 5
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Country: Number of subjects enrolled |
Russian Federation: 10
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Country: Number of subjects enrolled |
Serbia: 5
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Worldwide total number of subjects |
64
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EEA total number of subjects |
23
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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) |
21
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Children (2-11 years) |
43
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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 were recruited from 45 expert pediatric centers in 20 countries worldwide. | |||||||||
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Pre-assignment
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Screening details |
The screening period took place within 4 weeks prior to enrollment into the study. | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Bosentan 2 mg/kg t.i.d. | |||||||||
Arm description |
2 mg/kg bosentan was administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks | |||||||||
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 |
32 mg quadrisected dispersible tablet. The dosage of bosentan was adjusted according to the patient’s body weight at initiation of the study treatment and adminsitered after dispersion in a teaspoon of water. Dosage readjustment, by steps of 8 mg, was permitted after 12 weeks of treatment.
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Arm title
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Bosentan 2 mg/kg b.i.d. | |||||||||
Arm description |
2 mg/kg bosentan was administered twice daily (morning and evening) for a planned duration of 24 weeks | |||||||||
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 |
32 mg quadrisected dispersible tablet. The dosage of bosentan was adjusted according to the patient’s body weight at initiation of the study treatment and adminsitered after dispersion in a teaspoon of water. Dosage readjustment, by steps of 8 mg, was permitted after 12 weeks of treatment.
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Baseline characteristics reporting groups
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Reporting group title |
Bosentan 2 mg/kg t.i.d.
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Reporting group description |
2 mg/kg bosentan was administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bosentan 2 mg/kg b.i.d.
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Reporting group description |
2 mg/kg bosentan was administered twice daily (morning and evening) for a planned duration of 24 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
All-treated set
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set includes all randomized patients who received at least one dose of study drug. Because all randomized patients received study drug at least once, the all-randomized set and the all-treated set are identical. Baseline characteristics,safety data and exploratory endpoints were analyzed using this analysis set.
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Subject analysis set title |
Pharmacokinetic (PK) set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set includes patients in the all-treated set without any major protocol violation and for whom at least 5 of the 6 blood samples requested for PK assessments were available. This set was used for the analysis of the pharmacokinetic data.
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End points reporting groups
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Reporting group title |
Bosentan 2 mg/kg t.i.d.
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Reporting group description |
2 mg/kg bosentan was administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks | ||
Reporting group title |
Bosentan 2 mg/kg b.i.d.
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Reporting group description |
2 mg/kg bosentan was administered twice daily (morning and evening) for a planned duration of 24 weeks | ||
Subject analysis set title |
All-treated set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set includes all randomized patients who received at least one dose of study drug. Because all randomized patients received study drug at least once, the all-randomized set and the all-treated set are identical. Baseline characteristics,safety data and exploratory endpoints were analyzed using this analysis set.
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Subject analysis set title |
Pharmacokinetic (PK) set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
This analysis set includes patients in the all-treated set without any major protocol violation and for whom at least 5 of the 6 blood samples requested for PK assessments were available. This set was used for the analysis of the pharmacokinetic data.
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End point title |
Daily exposure to bosentan [AUC(0-24c)] | ||||||||||||||||
End point description |
Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively.
The area under the concentration-time curve over a period of 24 hours [AUC(0-24)] was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) [AUC(0-24c)].
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End point type |
Primary
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End point timeframe |
At Week 4, after at least 2 weeks of stable study drug treatment.
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Statistical analysis title |
Treatment comparison of daily exposure | ||||||||||||||||
Statistical analysis description |
Ratio of geometric means between the t.i.d. and b.i.d. dosing regimen (b.i.d. bosentan regimen taken as reference)
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Comparison groups |
Bosentan 2 mg/kg t.i.d. v Bosentan 2 mg/kg b.i.d.
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Number of subjects included in analysis |
58
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||||||
Method |
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Parameter type |
Ratio of geometric means | ||||||||||||||||
Point estimate |
0.85
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.61 | ||||||||||||||||
upper limit |
1.2 | ||||||||||||||||
| Notes [1] - No statistical hypothesis tests were set for this study. The analysis of PK data was carried out descriptively. |
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End point title |
Maximum plasma concentration of bosentan (Cmaxc) | ||||||||||||||||
End point description |
Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. The peak plasma concentration (Cmax) of bosentan was directly obtained from the measured plasma concentrations and was dose-corrected to the target dose of 2 mg/kg (Cmaxc).
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End point type |
Other pre-specified
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End point timeframe |
At Week 4, after at least 2 weeks of stable study drug treatment.
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Statistical analysis title |
Ratio of geometric means for Cmax | ||||||||||||||||
Statistical analysis description |
Ratio of geometric means between the t.i.d. and b.i.d. dosing regimen (b.i.d. bosentan regimen taken as reference), unadjusted
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Comparison groups |
Bosentan 2 mg/kg t.i.d. v Bosentan 2 mg/kg b.i.d.
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Number of subjects included in analysis |
58
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||||||
Method |
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Parameter type |
ratio of geometric means | ||||||||||||||||
Point estimate |
0.71
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.48 | ||||||||||||||||
upper limit |
1.05 | ||||||||||||||||
| Notes [2] - No statistical hypothesis tests were set for this study. The analysis of PK data was carried out descriptively. |
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End point title |
Time to reach Cmax of bosentan (tmax) | ||||||||||||||||
End point description |
Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. tmax was obtained directly from the measured plasma concentrations.
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End point type |
Other pre-specified
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End point timeframe |
At Week 4, after at least 2 weeks of stable study drug treatment
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Daily exposure to bosentan metabolites (Ro 47-8634, Ro 48-5033, Ro 64-1056) | ||||||||||||||||||||||||||||
End point description |
Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. Daily exposure to the metabolites corresponds to the area under the concentration-time curve [AUC(0-24)c] of the corresponding metabolite over a period of 24 hours, and was calculated in the same manner as the primary endpoint.
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End point type |
Other pre-specified
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End point timeframe |
At Week 4, after at least 2 weeks of stable study drug treatment.
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Change from baseline in WHO functional class at end of study | |||||||||||||||||||||
End point description |
Number of patients with improvement, worsening or no change in WHO functional class at end of study compared to baseline.
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End point type |
Other pre-specified
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End point timeframe |
Baseline and end of study
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Change from baseline in Global clincial impression scale (GCIS) at end of study | ||||||||||||||||||||||||||||||
End point description |
The GCIS is an assessment tool to rate the patient’s current overall clinical condition (“Very Good”, “Good”, “Neither Good or Bad”, “Bad” and “Very Bad”). The assessment was performed both by the physician and the parents / legal representatives independently.
Number of patients with clinical condition (as measured by the GCIS) considered as worsened, improved or unchanged are reported here.
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End point type |
Other pre-specified
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End point timeframe |
Baseline and end of study
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Number of patients with treatment-emergent liver function abnormalities | ||||||||||||||||||
End point description |
Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 x ULN (upper limit of normal) The worst post-baseline value was considered.
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End point type |
Other pre-specified
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End point timeframe |
From baseline up to 7 days after end of treatment
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of patients with treatment-emergent hemoglobin abnormalities | ||||||||||||||||||
End point description |
Number of patientsof patients with marked hemoglobin decreases. The worst post-baseline value was considered.
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End point type |
Other pre-specified
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End point timeframe |
From baseline up to 7 days after end of treatment
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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 to 7 days after end of treatment
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Adverse event reporting additional description |
1-SAEs with fatal outcome are not mutually exclusive (One death related to concomitant bronchopneumonia and PAH)
2-One patient (group 2 mg/kg t.i.d). experienced a SAE (adenoviral gastroenteritis) that was reported to the investigator by the parents about 2 months after database closure. This SAE is not displayed below but in the extension study.
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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 |
16.0
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Reporting groups
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Reporting group title |
Bosentan 2 mg/kg t.i.d.
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Reporting group description |
Subjects received 2 mg/kg bosentan 3 times a day for at least 0.4 week to a maximum duration of 28.7 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bosentan 2 mg/kg b.i.d.
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Reporting group description |
Subjects received 2 mg/kg bosentan twice daily for a at least 6 weeks to a maximum duration of 26.4 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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09 May 2012 |
Due to the difficulties in recruitment, inclusion criteria was modified as follows : Reduction of the proportion of patients < 2 years of age and possibility to include patients with pulmonary arterial hypertension associated with unrepaired congenital heart defect |
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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. | |||
| None reported | |||
