Pulmonary Arterial Hypertension
Conditions
Keywords
bosentan, pulmonary arterial hypertension, children, FUTURE 1
Brief summary
The main objective of the FUTURE 2 study was to assess the long-term safety and tolerability of the pediatric formulation of bosentan in children with idiopathic pulmonary arterial hypertension or familial pulmonary arterial hypertension who completed FUTURE 1 study.
Interventions
DRUGBosentan
32-mg dispersible and breakable tablet. The body weight-adjusted dose of the dispersible tablet was dispersed in a teaspoon of water (not mixed with food) before being administered orally
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent by the parents or the legal representatives. * Patients who completed the FUTURE 1 study. * Patients who tolerated bosentan pediatric formulation and for whom bosentan is considered beneficial at the end of FUTURE 1. * Males or females \>= 2 and \< 12 years of age at enrollment in FUTURE 2 (this study). Females who are menstruating must have a negative pregnancy test. A reliable method of contraception must be considered, if appropriate.
Exclusion criteria
* Intolerance to bosentan despite dose reductions. * Any clinically significant laboratory abnormality that precludes continuation of bosentan therapy. * Pregnancy or breast-feeding. * Known hypersensitivity to bosentan or any of the excipients. * Premature and permanent study drug discontinuation during FUTURE 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Study (EOS) in Height for Age. | From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average | In order to compare the growth data with those of healthy children, growth curves are calculated from height data collected throughout the follow-up period. For each patient, height measured at each study visit was converted to a z-score and expressed in standard deviations (SD) from WHO growth standards. The Z-score was calculated according to the following formula: Z-score = (observed value of the study participant - median value of the reference population) / SD value of the reference population |
| Change From Baseline to End of Study (EOS) in Body Weight | From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average | The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including growth as measured by changes from baseline in body weight and height. |
| Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP) | From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average | The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in blood pressure. |
| Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP) | From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average | The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in blood pressure. |
| Change From Baseline to End of Study (EOS) in Pulse Rate | From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average | The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in pulse rate. |
| Proportion of Patients With Treatment-emergent Liver Function Abnormalities | After baseline, up to 1 calendar day after study treatment discontinuation in FUTURE 1 or FUTURE 2, i.e. 31 months in average | The main study objective was to assess the long-term safety and tolerability 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 times upper limit of normal (ULN) is reported here. |
| Proportion of Patients With Treatment-emergent Hemoglobin Abnormalities | After baseline, up to 1 calendar day after study treatment discontinuation in FUTURE 1 or FUTURE 2, i.e. 31 months in average | The main study objective was to assess the long-term safety and tolerability 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. |
| Number of Subjects With Adverse Events Leading to Premature Discontinuation of Study Treatment | From the first study drug administration in FUTURE 1, for an average of 31 months | — |
Participant flow
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.
Pre-assignment details
The actual number of patients enrolled in FUTURE 2 (F-2) was 33 because 2 patients did not complete FUTURE 1 (F-1) and one patient completed F-1 but was not enrolled in F-2.
Participants by arm
| Arm | Count |
|---|---|
| Patients With Previous Bosentan This group included patients who already received bosentan (film-coated tablets) before enrollment in FUTURE 1, and then received the pediatric formulation of bosentan (dispersible tablets) during FUTURE 1 and FUTURE 2 (initiation at 2 mg/kg b.i.d. for 4 weeks, then up-titrated 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). | 15 |
| Bosentan-naive Patients This group included patients who were not treated with bosentan before enrollment in FUTURE 1, and received the pediatric formulation of bosentan (dispersible tablets) during FUTURE 1 and FUTURE 2 according to the same dosing regimen as described for Patients with previous bosentan.
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. | 21 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative reason | 0 | 5 |
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Disease progression | 0 | 2 |
| Overall Study | F-1 completed but not enrolled in F-2 | 1 | 0 |
| Overall Study | Transplant | 0 | 1 |
| Overall Study | Treatment failure | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | Patients With Previous Bosentan | Bosentan-naive Patients | Total |
|---|---|---|---|
| Age, Continuous | 7 Years | 7 Years | 7 Years |
| Age, Customized 2-3 years old | 1 Participants | 3 Participants | 4 Participants |
| Age, Customized 4-5 years old | 3 Participants | 6 Participants | 9 Participants |
| Age, Customized 6-11 years old | 11 Participants | 12 Participants | 23 Participants |
| Duration of pulmonary arterial hypertension (PAH) | 37.6 Months | 14 Months | 25.8 Months |
| Etiology of pulmonary arterial hypertension (PAH) Familial PAH | 3 Participants | 2 Participants | 5 Participants |
| Etiology of pulmonary arterial hypertension (PAH) Idiopathic PAH | 12 Participants | 19 Participants | 31 Participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 15 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 15 | 16 / 21 | 26 / 36 |
| serious Total, serious adverse events | 9 / 15 | 9 / 21 | 18 / 36 |
Outcome results
Primary
Change From Baseline to End of Study (EOS) in Body Weight
The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including growth as measured by changes from baseline in body weight and height.
Time frame: From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average
Population: All-treated analysis set (all patients who received at least one dose of study drug in the combined FUTURE 1 / FUTURE 2 trial periods). Missing or incomplete data were treated as missing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Body Weight | Weight at baseline | 19.6 kg |
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Body Weight | Weight change from baseline to EOS | 8.2 kg |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Body Weight | Weight at baseline | 21.6 kg |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Body Weight | Weight change from baseline to EOS | 8.5 kg |
| Total | Change From Baseline to End of Study (EOS) in Body Weight | Weight at baseline | 19.6 kg |
| Total | Change From Baseline to End of Study (EOS) in Body Weight | Weight change from baseline to EOS | 8.3 kg |
Primary
Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP)
The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in blood pressure.
Time frame: From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average
Population: All-treated analysis set (all patients who received at least one dose of study drug in the combined FUTURE 1 / FUTURE 2 trial periods). Missing or incomplete data were treated as missing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP) | DBP at baseline | 54.5 mmHg |
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP) | DBP change from baseline to EOS | -5 mmHg |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP) | DBP at baseline | 60 mmHg |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP) | DBP change from baseline to EOS | -2 mmHg |
| Total | Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP) | DBP at baseline | 59 mmHg |
| Total | Change From Baseline to End of Study (EOS) in Diastolic Blood Pressure (DBP) | DBP change from baseline to EOS | -3 mmHg |
Primary
Change From Baseline to End of Study (EOS) in Height for Age.
In order to compare the growth data with those of healthy children, growth curves are calculated from height data collected throughout the follow-up period. For each patient, height measured at each study visit was converted to a z-score and expressed in standard deviations (SD) from WHO growth standards. The Z-score was calculated according to the following formula: Z-score = (observed value of the study participant - median value of the reference population) / SD value of the reference population
Time frame: From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average
Population: All-treated analysis set (all patients who received at least one dose of study drug in the combined FUTURE 1 / FUTURE 2 trial periods). Missing or incomplete data were treated as missing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score at EOS | -0.74 Z-score |
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score at baseline | -0.8 Z-score |
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score change from baseline to EOS | -0.05 Z-score |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score at EOS | -0.08 Z-score |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score at baseline | 0.32 Z-score |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score change from baseline to EOS | -0.01 Z-score |
| Total | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score at baseline | -0.64 Z-score |
| Total | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score change from baseline to EOS | -0.01 Z-score |
| Total | Change From Baseline to End of Study (EOS) in Height for Age. | Z-score at EOS | -0.36 Z-score |
Primary
Change From Baseline to End of Study (EOS) in Pulse Rate
The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in pulse rate.
Time frame: From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average
Population: All-treated analysis set (all patients who received at least one dose of study drug in the combined FUTURE 1 / FUTURE 2 trial periods). Missing or incomplete data were treated as missing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Pulse Rate | Pulse rate at baseline | 87 Beats per minutes |
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Pulse Rate | Pulse rate change from baseline to EOS | -11 Beats per minutes |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Pulse Rate | Pulse rate at baseline | 94.5 Beats per minutes |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Pulse Rate | Pulse rate change from baseline to EOS | -10 Beats per minutes |
| Total | Change From Baseline to End of Study (EOS) in Pulse Rate | Pulse rate at baseline | 88 Beats per minutes |
| Total | Change From Baseline to End of Study (EOS) in Pulse Rate | Pulse rate change from baseline to EOS | -11 Beats per minutes |
Primary
Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP)
The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in blood pressure.
Time frame: From baseline (FUTURE 1) up to 28 days after study treatment discontinuation (EOS or premature study treatment discontinuation), i.e. 32 months in average
Population: All-treated analysis set (all patients who received at least one dose of study drug in the combined FUTURE 1 / FUTURE 2 trial periods). Missing or incomplete data were treated as missing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP) | SBP at baseline | 101.5 mmHg |
| Patients With Previous Bosentan | Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP) | SBP change from baseline to EOS | -10.5 mmHg |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP) | SBP at baseline | 104 mmHg |
| Bosentan-naive Patients | Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP) | SBP change from baseline to EOS | 4 mmHg |
| Total | Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP) | SBP at baseline | 102.5 mmHg |
| Total | Change From Baseline to End of Study (EOS) in Systolic Blood Pressure (SBP) | SBP change from baseline to EOS | -4.5 mmHg |
Primary
Number of Subjects With Adverse Events Leading to Premature Discontinuation of Study Treatment
Time frame: From the first study drug administration in FUTURE 1, for an average of 31 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With Previous Bosentan | Number of Subjects With Adverse Events Leading to Premature Discontinuation of Study Treatment | 1 Participants |
| Bosentan-naive Patients | Number of Subjects With Adverse Events Leading to Premature Discontinuation of Study Treatment | 5 Participants |
| Total | Number of Subjects With Adverse Events Leading to Premature Discontinuation of Study Treatment | 6 Participants |
Primary
Proportion of Patients With Treatment-emergent Hemoglobin Abnormalities
The main study objective was to assess the long-term safety and tolerability 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.
Time frame: After baseline, up to 1 calendar day after study treatment discontinuation in FUTURE 1 or FUTURE 2, i.e. 31 months in average
Population: All-treated analysis set (all patients who received at least one dose of study drug in the combined FUTURE 1 / FUTURE 2 trial periods). Missing or incomplete data were treated as missing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With Previous Bosentan | Proportion of Patients With Treatment-emergent Hemoglobin Abnormalities | 13.3 Percentage of participants |
| Bosentan-naive Patients | Proportion of Patients With Treatment-emergent Hemoglobin Abnormalities | 9.5 Percentage of participants |
| Total | Proportion of Patients With Treatment-emergent Hemoglobin Abnormalities | 11.1 Percentage of participants |
Primary
Proportion of Patients With Treatment-emergent Liver Function Abnormalities
The main study objective was to assess the long-term safety and tolerability 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 times upper limit of normal (ULN) is reported here.
Time frame: After baseline, up to 1 calendar day after study treatment discontinuation in FUTURE 1 or FUTURE 2, i.e. 31 months in average
Population: All-treated analysis set (all patients who received at least one dose of study drug in the combined FUTURE 1 / FUTURE 2 trial periods). Missing or incomplete data were treated as missing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients With Previous Bosentan | Proportion of Patients With Treatment-emergent Liver Function Abnormalities | ALT > 3 x ULN | 0 Percentage of participants |
| Patients With Previous Bosentan | Proportion of Patients With Treatment-emergent Liver Function Abnormalities | AST > 3 x ULN | 0 Percentage of participants |
| Bosentan-naive Patients | Proportion of Patients With Treatment-emergent Liver Function Abnormalities | ALT > 3 x ULN | 4.8 Percentage of participants |
| Bosentan-naive Patients | Proportion of Patients With Treatment-emergent Liver Function Abnormalities | AST > 3 x ULN | 4.8 Percentage of participants |
| Total | Proportion of Patients With Treatment-emergent Liver Function Abnormalities | AST > 3 x ULN | 2.8 Percentage of participants |
| Total | Proportion of Patients With Treatment-emergent Liver Function Abnormalities | ALT > 3 x ULN | 2.8 Percentage of participants |