Pulmonary Arterial Hypertension
Conditions
Keywords
pediatric, pulmonary arterial hypertension, bosentan, Tracleer
Brief summary
The objectives of the FUTURE 3 Study Extension are to evaluate the long-term safety, tolerability and efficacy of the pediatric formulation of bosentan two versus three times a day in children with Pulmonary Arterial Hypertension (PAH).
Interventions
DRUGBosentan
Oral dispersible tablet administered as 2mg/kg two (b.i.d.) or three (t.i.d.) times per day
Sponsors
Actelion
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Patients who completed the FUTURE 3 core study (AC-052-373) or prematurely discontinued due to PAH-progression, if bosentan was not permanently discontinued 2. Patients who tolerated bosentan pediatric formulation and for whom bosentan is considered beneficial at the end of the FUTURE 3 core study (AC-052-373) 3. Signed informed consent by the parents or the legal representatives prior to any study-mandated procedure.
Exclusion criteria
1. Known intolerance or hypersensitivity to bosentan or any of the excipients of the dispersible bosentan tablet 2. Any clinically significant laboratory abnormality that precludes continuation of bosentan therapy 3. Pregnancy 4. AST and/or ALT values \> 3 times the upper limit of normal range (ULN) 5. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C 6. Premature and permanent study drug discontinuation during the FUTURE 3 core study (AC-052-373) 7. Any major violation of the FUTURE 3 core study (AC-052-373) protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation | Up to 62 weeks in average | This is the total number of subjects with at least one adverse event (serious or not serious) whether or not causally related to the study drug and presented cumulatively in the FUTURE 3 and FUTURE 3 Extension study. NOTE: FUTURE 3 extension study was exploratory and no primary efficacy and safety endpoints were defined in the protocol. So, this safety outcome measure was selected and reported as primary endpoint here. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | At Month 18 | The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study. |
| Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | At Month 12 | The GCIS is a scale used to rate the patient's current overall clinical condition (Very Good, Good, Neither Good or Bad, Bad, and Very Bad). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study. |
| Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | At Month 18 | The GCIS is a scale used to rate the patient's current overall clinical condition (Very Good, Good, Neither Good or Bad, Bad, and Very Bad). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study. |
| Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days | Up to 62 weeks in average | Number of patients with at least one PAH-worsening component (death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH, new/worsening right heart failure) reported cumulatively over FUTURE 3 core and extension study. |
| Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days | From baseline to Month 18 | PAH progression was defined by time elapsed from the first study drug administration in the FUTURE core study to the day of the first occurrence of any of the following PAH worsening events: death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH or new / worsening right heart failure. Subjects without a PAH worsening event were censored at EOT + 7 days. PAH progression was estimated by Kaplan-Meier methodology and expressed by the percentage of participants free of events at different time points. |
| Overall Survival | From baseline to month 18 | Overall survival was defined as the time elapsed between the first study drug administration and death (any cause) up to end of study (Month 18 survival follow-up), regardless of whether the patient was on study treatment. Patients who died, regardless of the cause of death, were considered to have had an event. Patients last known to have been alive were censored on their date of last contact. Percentage of participants without death at different time points was estimated using Kaplan-Meier methodology. |
| Exceptional Use Treatment Period (EUTP): Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) up to 7 Days After Permanent Discontinuation of Study Drug | Up to 7 days after discontinuation of study drug (up to 3 years and 4 months) | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. |
| Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | At Month 12 | The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study. |
| EUTP: Percentage of Participants With AEs Leading to Premature Discontinuation of Study Drug | Up to 3 years and 4 months | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Percentage of participants with AEs leading to premature discontinuation of study drug were reported. |
| EUTP: Percentage of Participants With SAEs From 7 up to 60 Days After Permanent Discontinuation of Study Drug | From 7 up to 60 days after permanent discontinuation of study drug (up to 3 years and 4 months) | A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
| EUTP: Percentage of Participants With Deaths | Up to 7 days after discontinuation of study drug (up to 3 years and 4 months) | Percentage of participants with deaths were reported. |
| EUTP: Percentage of Participants With Adverse Events of Special Interest (AESI) | Up to 7 days after discontinuation of study drug (up to 3 years and 4 months) | Percentage of participants with AESI including liver abnormalities and anemia were reported. |
| EUTP: Percentage of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 7 Days After Permanent Discontinuation of Study Drug | Up to 7 days after discontinuation of study drug (up to 3 years and 4 months) | Percentage of participants with treatment-emergent marked laboratory abnormalities were reported. |
| EUTP: Percentage of Participants With Liver Function Abnormalities | Up to 7 days after discontinuation of study drug (up to 3 years and 4 months) | Percentage of participants with liver function abnormalities: Alanine aminotransferase (ALT) greater than (\>)3\*upper limit of normal (ULN), ALT/aspartate aminotransferase (AST) \>3\*ULN, ALT /AST \>3\*ULN and less than or equal to (\<=) 5\*ULN, ALT/AST \>5\*ULN and \<=8\*ULN, ALT/AST \>8\*ULN and ALT/AST \>3\*ULN, total bilirubin \>2\*ULN and alkaline phosphatase (ALP) \<=2\*ULN were reported. |
| EUTP: Percentage of Participants With Any Time Occurrence of Hemoglobin <=10 Gram Per Deciliter (g/dL) and <=8g/dL Between Baseline and up to 7 Days After End of Treatment (EOT) | Baseline, up to 7 days after end of treatment (up to 3 years and 4 months) | Percentage of participants with any time occurrence of hemoglobin (Hgb) less than or equal to (\<=) 10 g/dL and 8 g/dL between baseline and up to the last day of treatment + 7 days during EUTP were reported. Here N (number of subjects analyzed) signifies subjects who were evaluable for this outcome measure. |
| EUTP: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 7 Days After Permanent Discontinuation of Study Drug | Up to 7 days after discontinuation of study drug (up to 3 years and 4 months) | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
Countries
Australia, Belarus, China, Czechia, France, Germany, Hungary, India, Israel, Italy, Mexico, Poland, Russia, Serbia, South Africa, Spain, Ukraine, United States
Participant flow
Recruitment details
Participants in this 1-year extension study were pediatric patients who completed the 6-month randomized open-label core study AC-052-373. In addition, patients were required to have tolerated study treatment during the FUTURE 3 core study and were considered by the investigator to benefit from continued bosentan treatment.
Pre-assignment details
64 patients were randomized in the FUTURE 3 core study, among whom 58 were enrolled in the FUTURE 3 extension study. Of the 58 participants in the FUTURE 3 extension study, a total of 10 participants entered the exceptional use treatment period (EUTP). Data for 3 participants in China after 19 Nov 2019 was not included in the report to meet the Human Genetic Resources Administration Office (HGRAO) requirements.
Participants by arm
| Arm | Count |
|---|---|
| Bosentan 2mg/kg b.i.d. Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study. | 33 |
| Bosentan 2mg/kg t.i.d. Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study. | 31 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core + Extension | Adverse Event | 8 | 6 | 0 |
| Core + Extension | Other (administrative reason) | 1 | 0 | 0 |
| Core + Extension | Other (PAH not the main etiology of PH) | 0 | 2 | 0 |
| Core + Extension | Withdrawal by Subject | 1 | 1 | 0 |
| Exceptional Use Treatment Period | Administrative decision | 0 | 0 | 1 |
| Exceptional Use Treatment Period | Death | 0 | 0 | 1 |
| Exceptional Use Treatment Period | Ongoing at the cut-off date of 19 Nov 2019 | 0 | 0 | 3 |
| Exceptional Use Treatment Period | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Bosentan 2mg/kg b.i.d. | Total | Bosentan 2mg/kg t.i.d. |
|---|---|---|---|
| Age, Continuous | 4.5 years STANDARD_DEVIATION 3.35 | 4.8 years STANDARD_DEVIATION 3.57 | 5.2 years STANDARD_DEVIATION 3.81 |
| Age, Customized Age Categories as per protocol Children (2-11 years) | 23 Participants | 43 Participants | 20 Participants |
| Age, Customized Age Categories as per protocol Infants and toddlers (28 days-23 months) | 10 Participants | 21 Participants | 11 Participants |
| Pulmonary Arterial Hypertension (PAH) etiology Associated PAH (i.e.,PAH after surgery for CHD) | 11 Participants | 24 Participants | 13 Participants |
| Pulmonary Arterial Hypertension (PAH) etiology Congenital heart disease | 6 Participants | 8 Participants | 2 Participants |
| Pulmonary Arterial Hypertension (PAH) etiology Heritable | 2 Participants | 2 Participants | 0 Participants |
| Pulmonary Arterial Hypertension (PAH) etiology Idiopathic | 14 Participants | 29 Participants | 15 Participants |
| Pulmonary Arterial Hypertension (PAH) etiology Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race as per protocol Asian | 6 Participants | 10 Participants | 4 Participants |
| Race/Ethnicity, Customized Race as per protocol Black | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race as per protocol Caucasian/White | 25 Participants | 48 Participants | 23 Participants |
| Race/Ethnicity, Customized Race as per protocol Hispanic | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race as per protocol Other | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Female | 18 Participants | 28 Participants | 10 Participants |
| Sex: Female, Male Male | 15 Participants | 36 Participants | 21 Participants |
| World Health Organization functional class (WHO FC) FC I | 9 Participants | 19 Participants | 10 Participants |
| World Health Organization functional class (WHO FC) FC II | 12 Participants | 27 Participants | 15 Participants |
| World Health Organization functional class (WHO FC) FC III | 12 Participants | 18 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 33 | 4 / 31 | 1 / 10 |
| other Total, other adverse events | 24 / 33 | 23 / 31 | 8 / 10 |
| serious Total, serious adverse events | 15 / 33 | 13 / 31 | 4 / 10 |
Outcome results
Primary
Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation
This is the total number of subjects with at least one adverse event (serious or not serious) whether or not causally related to the study drug and presented cumulatively in the FUTURE 3 and FUTURE 3 Extension study. NOTE: FUTURE 3 extension study was exploratory and no primary efficacy and safety endpoints were defined in the protocol. So, this safety outcome measure was selected and reported as primary endpoint here.
Time frame: Up to 62 weeks in average
Population: The analysis was performed on the Safety population analysis set, including all patients who received at least one dose of study treatment and evaluated according to the study treatment that they received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation | 29 Participants |
| Bosentan 2mg/kg t.i.d. | Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation | 26 Participants |
Other Pre-specified
Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS)
The GCIS is a scale used to rate the patient's current overall clinical condition (Very Good, Good, Neither Good or Bad, Bad, and Very Bad). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time frame: At Month 12
Population: The intent to treat population was used for these analyses. No imputation method was used. Only patients with available results at the corresponding time point are included in the analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Stable | 16 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Worsened | 2 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Improved | 9 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Improved | 10 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Worsened | 3 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Stable | 16 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Worsened | 0 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Stable | 16 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Worsened | 1 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Stable | 12 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Improved | 11 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Improved | 6 Participants |
Other Pre-specified
Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC)
The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time frame: At Month 12
Population: The intent to treat population was used. Where a missing visit score exists between two visits with scores, the missing score was imputed with the worse score of the non-missing scores; if the missing score was not between 2 visits with scores, it was replaced by the last non-missing score.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Improved WHO FC | 7 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Stable WHO FC | 22 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Worsened WHO FC | 4 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Worsened WHO FC | 3 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Stable WHO FC | 25 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Improved WHO FC | 3 Participants |
Other Pre-specified
Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS)
The GCIS is a scale used to rate the patient's current overall clinical condition (Very Good, Good, Neither Good or Bad, Bad, and Very Bad). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time frame: At Month 18
Population: The intent to treat population was used. No imputation method was used. Only patients with available results at the corresponding time point are including in the analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Worsened | 4 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Stable | 8 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Improved | 6 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Stable | 9 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Improved | 6 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Worsened | 5 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Worsened | 1 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Improved | 5 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Physician | Stable | 12 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Stable | 7 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Worsened | 1 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) | Assessment by Parents/Legal representative | Improved | 10 Participants |
Other Pre-specified
Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC)
The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time frame: At Month 18
Population: The intent to treat population was used. Where a missing visit score exists between two visits with scores, the missing score was imputed with the worse score of the non-missing scores; if the missing score was not between 2 visits with scores, it was replaced by the last non-missing score.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Stable WHO FC | 25 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Improved WHO FC | 3 Participants |
| Bosentan 2mg/kg b.i.d. | Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Worsened WHO FC | 5 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Stable WHO FC | 25 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Improved WHO FC | 3 Participants |
| Bosentan 2mg/kg t.i.d. | Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) | Worsened WHO FC | 3 Participants |
Other Pre-specified
EUTP: Percentage of Participants With Adverse Events of Special Interest (AESI)
Percentage of participants with AESI including liver abnormalities and anemia were reported.
Time frame: Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With Adverse Events of Special Interest (AESI) | 20 percentage of participants |
Other Pre-specified
EUTP: Percentage of Participants With AEs Leading to Premature Discontinuation of Study Drug
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Percentage of participants with AEs leading to premature discontinuation of study drug were reported.
Time frame: Up to 3 years and 4 months
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With AEs Leading to Premature Discontinuation of Study Drug | 0 percentage of participants |
Other Pre-specified
EUTP: Percentage of Participants With Any Time Occurrence of Hemoglobin <=10 Gram Per Deciliter (g/dL) and <=8g/dL Between Baseline and up to 7 Days After End of Treatment (EOT)
Percentage of participants with any time occurrence of hemoglobin (Hgb) less than or equal to (\<=) 10 g/dL and 8 g/dL between baseline and up to the last day of treatment + 7 days during EUTP were reported. Here N (number of subjects analyzed) signifies subjects who were evaluable for this outcome measure.
Time frame: Baseline, up to 7 days after end of treatment (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With Any Time Occurrence of Hemoglobin <=10 Gram Per Deciliter (g/dL) and <=8g/dL Between Baseline and up to 7 Days After End of Treatment (EOT) | Hgb <=8 g/dL | 0 percentage of participants |
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With Any Time Occurrence of Hemoglobin <=10 Gram Per Deciliter (g/dL) and <=8g/dL Between Baseline and up to 7 Days After End of Treatment (EOT) | Hgb <=10 g/dL | 22.2 percentage of participants |
Other Pre-specified
EUTP: Percentage of Participants With Deaths
Percentage of participants with deaths were reported.
Time frame: Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With Deaths | 10 percentage of participants |
Other Pre-specified
EUTP: Percentage of Participants With Liver Function Abnormalities
Percentage of participants with liver function abnormalities: Alanine aminotransferase (ALT) greater than (\>)3\*upper limit of normal (ULN), ALT/aspartate aminotransferase (AST) \>3\*ULN, ALT /AST \>3\*ULN and less than or equal to (\<=) 5\*ULN, ALT/AST \>5\*ULN and \<=8\*ULN, ALT/AST \>8\*ULN and ALT/AST \>3\*ULN, total bilirubin \>2\*ULN and alkaline phosphatase (ALP) \<=2\*ULN were reported.
Time frame: Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With Liver Function Abnormalities | 0 percentage of participants |
Other Pre-specified
EUTP: Percentage of Participants With SAEs From 7 up to 60 Days After Permanent Discontinuation of Study Drug
A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: From 7 up to 60 days after permanent discontinuation of study drug (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With SAEs From 7 up to 60 Days After Permanent Discontinuation of Study Drug | 0 percentage of participants |
Other Pre-specified
EUTP: Percentage of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 7 Days After Permanent Discontinuation of Study Drug
Percentage of participants with treatment-emergent marked laboratory abnormalities were reported.
Time frame: Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 7 Days After Permanent Discontinuation of Study Drug | 0 percentage of participants |
Other Pre-specified
EUTP: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 7 Days After Permanent Discontinuation of Study Drug
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | EUTP: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 7 Days After Permanent Discontinuation of Study Drug | 40 percentage of participants |
Other Pre-specified
Exceptional Use Treatment Period (EUTP): Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) up to 7 Days After Permanent Discontinuation of Study Drug
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline.
Time frame: Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Population: Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan 2mg/kg b.i.d. | Exceptional Use Treatment Period (EUTP): Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) up to 7 Days After Permanent Discontinuation of Study Drug | 80 percentage of participants |
Other Pre-specified
Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days
Number of patients with at least one PAH-worsening component (death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH, new/worsening right heart failure) reported cumulatively over FUTURE 3 core and extension study.
Time frame: Up to 62 weeks in average
Population: The intent to treat population was used
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days | No PAH-worsening event | 23 Participants |
| Bosentan 2mg/kg b.i.d. | Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days | At least one PAH-worsening event | 10 Participants |
| Bosentan 2mg/kg t.i.d. | Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days | No PAH-worsening event | 26 Participants |
| Bosentan 2mg/kg t.i.d. | Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days | At least one PAH-worsening event | 5 Participants |
Other Pre-specified
Overall Survival
Overall survival was defined as the time elapsed between the first study drug administration and death (any cause) up to end of study (Month 18 survival follow-up), regardless of whether the patient was on study treatment. Patients who died, regardless of the cause of death, were considered to have had an event. Patients last known to have been alive were censored on their date of last contact. Percentage of participants without death at different time points was estimated using Kaplan-Meier methodology.
Time frame: From baseline to month 18
Population: These are the numbers of patients at risk at the time of study treatment initiation in the FUTURE 3 core study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | Overall Survival | Kaplan-Meier estimate at Month 12 | 81.8 Percentage of participants |
| Bosentan 2mg/kg b.i.d. | Overall Survival | Kaplan-Meier estimate at Month 18 | 75.8 Percentage of participants |
| Bosentan 2mg/kg t.i.d. | Overall Survival | Kaplan-Meier estimate at Month 12 | 90.0 Percentage of participants |
| Bosentan 2mg/kg t.i.d. | Overall Survival | Kaplan-Meier estimate at Month 18 | 86.5 Percentage of participants |
Comparison: Post-hoc analysis: Cox proportional hazard regression univariate model with treatment as covariate (treatment-only univariate model)95% CI: [0.582, 6.428]Regression, Cox
Comparison: Post-hoc analysis: Cox proportional hazard regression univariate model with WHO FC at baseline (FC III vs FC I/II) as covariatep-value: 0.0085Regression, Cox
Comparison: Post-hoc analysis: Treatment Hazard Ratio (HR) in the multivariate model with treatment and WHO FC at baseline as covariates95% CI: [0.437, 5.052]Regression, Cox
Comparison: Test of the improvement in model fit from the univariate to the multivariate model with WHO FC at baseline as covariatep-value: 0.014log(e) likelihood ratio
Other Pre-specified
Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days
PAH progression was defined by time elapsed from the first study drug administration in the FUTURE core study to the day of the first occurrence of any of the following PAH worsening events: death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH or new / worsening right heart failure. Subjects without a PAH worsening event were censored at EOT + 7 days. PAH progression was estimated by Kaplan-Meier methodology and expressed by the percentage of participants free of events at different time points.
Time frame: From baseline to Month 18
Population: These are the numbers of patients at risk at the time of study treatment initiation in the FUTURE 3 core study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan 2mg/kg b.i.d. | Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days | Kaplan-Meier estimate at Month 12 | 74.9 Percentage of patients free of events |
| Bosentan 2mg/kg b.i.d. | Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days | Kaplan-Meier estimate at Month 18 | 68.2 Percentage of patients free of events |
| Bosentan 2mg/kg t.i.d. | Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days | Kaplan-Meier estimate at Month 12 | 88.9 Percentage of patients free of events |
| Bosentan 2mg/kg t.i.d. | Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days | Kaplan-Meier estimate at Month 18 | 81.0 Percentage of patients free of events |
Comparison: Post-hoc analysis: Cox proportional hazard regression univariate model with treatment as covariate (treatment-only univariate model)95% CI: [0.47, 4.399]Regression, Cox
Comparison: Post-hoc analysis: Cox proportional hazard regression univariate model with WHO FC at baseline (FC III vs FC I/II) as covariatep-value: 0.0526Regression, Cox
Comparison: Post-hoc analysis: Treatment Hazard Ratio (HR) in the multivariate model with treatment and WHO FC at baseline as covariates95% CI: [0.371, 3.681]Regression, Cox
Comparison: Test of improvement in model fit from the univariate to the multivariate model with WHO FC at baseline as covariatep-value: 0.076log(e) likelihood ratio