Pulmonary Hypertension
Conditions
Keywords
pulmonary hypertension, bosentan, BENEFIT, CTEPH, inoperable chronic thromboembolic pulmonary hypertension (CTEPH)
Brief summary
The present trial investigates the long-term safety, tolerability and efficacy of bosentan in patients with inoperable CTEPH.
Interventions
DRUGbosentan
Oral bosentan * Initial dose: 62.5 mg twice a day (b.i.d.) for 4 weeks for all patients * Maintenance dose: 125 mg b.i.d. (62.5 mg b.i.d. if weight \< 40 kg)
Sponsors
Actelion
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients having completed the 16-week treatment period of protocol AC-052-366 (NCT00313222) * Signed informed consent
Exclusion criteria
* Any major violation of protocol AC-052-366 (NCT00313222) * Pregnancy or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to All Assessed Time Points in 6-minute Walk Test (6MWT) Distance | Until discontinuation of study drug, up to 3.3 years | Exercise capacity was assessed using the 6MWT. Area used for testing had to be a minimum of 30m in length and 2-3m in width, with 3m gradations. Areas were well ventilated with air temperature controlled. The test was administered at the same time of day and by the same tester throughout the study. The tester measured the distance walked by non-encouraged patients during the timed 6min period. If the test was stopped before 6 minutes, the main reason for stopping the test was recorded. The tester measured the distance walked by patients during the timed 6min period. |
| Change From Baseline to All Assessed Time Points in Borg Dyspnea Index | Until discontinuation of study drug, up to 3.3 years | Maximal dyspnea during the walk test was assessed by the patient using the Borg dyspnea index. Immediately following each walk test, patients rated perceived maximal breathlessness during the walk test on a 12-point scale (0 \[nothing at all\], 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 \[maximum ever experienced\]). |
| Disease Severity - Number of Patients Showing Improvement by One Class or More in World Health Organisation (WHO) Functional Classification of Pulmonary Hypertension (PH) | Until discontinuation of study drug, up to 3.3 years | Disease severity was assessed by WHO classification of PH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. |
| Time to Clinical Worsening up to End-of-study | Until discontinuation of study drug, up to 3.3 years | An event of clinical worsening was defined as death during the treatment period, a treatment-emergent adverse event that led to permanent discontinuation of study treatment and with outcome death, hospitalization due to worsening pulmonary hypertension, or lung transplantation. Patients are censored at 1 day after the end of treatment or at day of pulmonary endarterectomy if earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing a Serious Adverse Event(s) up to 28 Days After Study Medication Discontinuation | 28 days after discontinuation of study drug, up to 3.3 years | — |
| Occurrence of Liver Function Test and Hemoglobin Abnormality | Until discontinuation of study drug, up to 3.3 years | Number of patients with an increase in liver aminotransferases to \>3 times upper limit of normal (ULN) or a decrease in hemoglobin concentration to ≤10 g/dL |
| Number of Patients With an Adverse Event(s) Leading to Premature Discontinuation of Study Medication | Until discontinuation of study drug, up to 3.3 years | — |
Participant flow
Recruitment details
Patients were enrolled at 26 centers in 13 countries (Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Italy, The Netherlands, Poland, Spain, UK, and USA. The first patient started treatment on 26 January 2006 and the last patient received their last dose of study treatment on 23 February 2009.
Pre-assignment details
In total, 148 of the patients who received randomized treatment in BENEFIT (NCT00313222) rolled over into the BENEFIT OL extension. In addition, 3 patients on bosentan who were prematurely discontinued from BENEFIT (NCT00313222) were also included in the analysis, providing a total of 151 patients
Participants by arm
| Arm | Count |
|---|---|
| Bosentan Oral bosentan
* Initial dose: 62.5 mg twice a day (b.i.d.) for 4 weeks for all patients
* Maintenance dose: 125 mg b.i.d. (62.5 mg b.i.d. if weight \< 40 kg) | 151 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative | 2 |
| Overall Study | Adverse Event | 20 |
| Overall Study | Death | 9 |
| Overall Study | Lack of clinical improvement | 4 |
| Overall Study | Treatment failure | 1 |
| Overall Study | Withdrawal of consent | 11 |
Baseline characteristics
| Characteristic | Bosentan |
|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 11.7 |
| Age, Customized 25-81 years | 151 participants |
| Borg dyspnea index | 4.2 points on a scale STANDARD_DEVIATION 2.2 |
| Region of Enrollment Australia | 17 participants |
| Region of Enrollment Austria | 10 participants |
| Region of Enrollment Belgium | 8 participants |
| Region of Enrollment Canada | 6 participants |
| Region of Enrollment Czech Republic | 20 participants |
| Region of Enrollment France | 18 participants |
| Region of Enrollment Germany | 14 participants |
| Region of Enrollment Italy | 28 participants |
| Region of Enrollment Netherlands | 11 participants |
| Region of Enrollment Poland | 9 participants |
| Region of Enrollment Spain | 3 participants |
| Region of Enrollment United Kingdom | 2 participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 100 Participants |
| Sex: Female, Male Male | 51 Participants |
| Six-minute walk test (6MWT) | 345.2 walk distance (m) STANDARD_DEVIATION 93.4 |
| World Health Organisation (WHO) functional class Class I | 3 participants |
| World Health Organisation (WHO) functional class Class II | 41 participants |
| World Health Organisation (WHO) functional class Class III | 91 participants |
| World Health Organisation (WHO) functional class Class IV | 4 participants |
| World Health Organisation (WHO) functional class Unassessed | 12 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 151 |
| serious Total, serious adverse events | 51 / 151 |
Outcome results
Primary
Change From Baseline to All Assessed Time Points in 6-minute Walk Test (6MWT) Distance
Exercise capacity was assessed using the 6MWT. Area used for testing had to be a minimum of 30m in length and 2-3m in width, with 3m gradations. Areas were well ventilated with air temperature controlled. The test was administered at the same time of day and by the same tester throughout the study. The tester measured the distance walked by non-encouraged patients during the timed 6min period. If the test was stopped before 6 minutes, the main reason for stopping the test was recorded. The tester measured the distance walked by patients during the timed 6min period.
Time frame: Until discontinuation of study drug, up to 3.3 years
Population: Numbers of patients assessed at 6 month, month 12, month 18, month 24 and end of the treatment period were 137, 128, 121, 106, and 137 respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Change From Baseline to All Assessed Time Points in 6-minute Walk Test (6MWT) Distance | month 6 | 8.4 walk distance change from baseline (m) | Standard Deviation 66.4 |
| Bosentan | Change From Baseline to All Assessed Time Points in 6-minute Walk Test (6MWT) Distance | month 12 | 18.2 walk distance change from baseline (m) | Standard Deviation 64 |
| Bosentan | Change From Baseline to All Assessed Time Points in 6-minute Walk Test (6MWT) Distance | month 18 | 17.7 walk distance change from baseline (m) | Standard Deviation 63.1 |
| Bosentan | Change From Baseline to All Assessed Time Points in 6-minute Walk Test (6MWT) Distance | month 24 | 20.2 walk distance change from baseline (m) | Standard Deviation 64.8 |
| Bosentan | Change From Baseline to All Assessed Time Points in 6-minute Walk Test (6MWT) Distance | end of the treatment period | 16.9 walk distance change from baseline (m) | Standard Deviation 69.4 |
Primary
Change From Baseline to All Assessed Time Points in Borg Dyspnea Index
Maximal dyspnea during the walk test was assessed by the patient using the Borg dyspnea index. Immediately following each walk test, patients rated perceived maximal breathlessness during the walk test on a 12-point scale (0 \[nothing at all\], 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 \[maximum ever experienced\]).
Time frame: Until discontinuation of study drug, up to 3.3 years
Population: Numbers of patients assessed at 6 month, month 12, month 18, month 24 and end of the treatment period were 136, 127, 120, 105, and 136 respectively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosentan | Change From Baseline to All Assessed Time Points in Borg Dyspnea Index | month 6 | -0.5 Scores on a scale | Standard Deviation 1.7 |
| Bosentan | Change From Baseline to All Assessed Time Points in Borg Dyspnea Index | month 12 | -0.4 Scores on a scale | Standard Deviation 1.8 |
| Bosentan | Change From Baseline to All Assessed Time Points in Borg Dyspnea Index | month 18 | -0.1 Scores on a scale | Standard Deviation 1.9 |
| Bosentan | Change From Baseline to All Assessed Time Points in Borg Dyspnea Index | month 24 | -0.1 Scores on a scale | Standard Deviation 1.9 |
| Bosentan | Change From Baseline to All Assessed Time Points in Borg Dyspnea Index | end of the treatment period | -0.2 Scores on a scale | Standard Deviation 2.1 |
Primary
Disease Severity - Number of Patients Showing Improvement by One Class or More in World Health Organisation (WHO) Functional Classification of Pulmonary Hypertension (PH)
Disease severity was assessed by WHO classification of PH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA.
Time frame: Until discontinuation of study drug, up to 3.3 years
Population: Numbers of patients assessed at 6 month, month 12, month 18, month 24 and end of the treatment period were 138, 129, 123, 109, and 139 respectively
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan | Disease Severity - Number of Patients Showing Improvement by One Class or More in World Health Organisation (WHO) Functional Classification of Pulmonary Hypertension (PH) | month 6 | 26 participants with improved WHO class |
| Bosentan | Disease Severity - Number of Patients Showing Improvement by One Class or More in World Health Organisation (WHO) Functional Classification of Pulmonary Hypertension (PH) | month 12 | 30 participants with improved WHO class |
| Bosentan | Disease Severity - Number of Patients Showing Improvement by One Class or More in World Health Organisation (WHO) Functional Classification of Pulmonary Hypertension (PH) | month 18 | 33 participants with improved WHO class |
| Bosentan | Disease Severity - Number of Patients Showing Improvement by One Class or More in World Health Organisation (WHO) Functional Classification of Pulmonary Hypertension (PH) | month 24 | 33 participants with improved WHO class |
| Bosentan | Disease Severity - Number of Patients Showing Improvement by One Class or More in World Health Organisation (WHO) Functional Classification of Pulmonary Hypertension (PH) | end of treatment period | 30 participants with improved WHO class |
Primary
Time to Clinical Worsening up to End-of-study
An event of clinical worsening was defined as death during the treatment period, a treatment-emergent adverse event that led to permanent discontinuation of study treatment and with outcome death, hospitalization due to worsening pulmonary hypertension, or lung transplantation. Patients are censored at 1 day after the end of treatment or at day of pulmonary endarterectomy if earlier.
Time frame: Until discontinuation of study drug, up to 3.3 years
Population: Study population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan | Time to Clinical Worsening up to End-of-study | month 12 (events) | 11 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 18 (censored) | 25 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 18 (events) | 15 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 24 (censored) | 34 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 24 (events)) | 19 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 30 (censored) | 78 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 30 (events) | 20 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 36 (censored) | 122 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 36 (events) | 21 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | end of study (censored) | 130 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | end of study (events) | 21 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 6 (events) | 8 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 6 (censored) | 11 participants |
| Bosentan | Time to Clinical Worsening up to End-of-study | month 12 (censored) | 18 participants |
Secondary
Number of Patients Experiencing a Serious Adverse Event(s) up to 28 Days After Study Medication Discontinuation
Time frame: 28 days after discontinuation of study drug, up to 3.3 years
Population: Study population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Number of Patients Experiencing a Serious Adverse Event(s) up to 28 Days After Study Medication Discontinuation | 51 participants |
Secondary
Number of Patients With an Adverse Event(s) Leading to Premature Discontinuation of Study Medication
Time frame: Until discontinuation of study drug, up to 3.3 years
Population: Study population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Number of Patients With an Adverse Event(s) Leading to Premature Discontinuation of Study Medication | 28 participants |
Secondary
Occurrence of Liver Function Test and Hemoglobin Abnormality
Number of patients with an increase in liver aminotransferases to \>3 times upper limit of normal (ULN) or a decrease in hemoglobin concentration to ≤10 g/dL
Time frame: Until discontinuation of study drug, up to 3.3 years
Population: study population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan | Occurrence of Liver Function Test and Hemoglobin Abnormality | Increase in liver function test | 27 participants |
| Bosentan | Occurrence of Liver Function Test and Hemoglobin Abnormality | Decrease in hemoglobin | 9 participants |