Idiopathic Pulmonary Fibrosis, Pulmonary Hypertension
Conditions
Keywords
Idiopathic Pulmonary Fibrosis, Pulmonary Hypertension, PH, IPF, Ambrisentan, ERA, Endothelin Receptor Antagonist, Cardiovascular
Brief summary
Ambrisentan is an endothelin receptor antagonist used for the treatment of pulmonary hypertension (PH). Based on research suggesting a role for endothelin-1 in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the poor prognosis for patients with IPF who are also diagnosed with PH, this study was designed to evaluate the effectiveness and safety of ambrisentan in that patient population.
Interventions
DRUGAmbrisentan
Ambrisentan (5 mg or 10 mg tablet) administered orally once daily.
DRUGPlacebo
Placebo to match ambrisentan administered orally once daily.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Selected Inclusion Criteria: * Weight ≥ 40 kg at screening * Diagnosis of IPF based on modified American Thoracic Society-European Respiratory Society guidelines * Diagnosis of PH based on the following hemodynamic requirements: mean pulmonary artery pressure (mPAP ≥ 25 mm Hg; pulmonary vascular resistance \> 240 dyne.sec/cm\^5; pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤ 15 mm Hg * Forced vital capacity (FVC) ≥ 40% * Able to walk at least 50 meters during two 6-minute walk tests * If receiving calcium channel blockers, low-dose oral corticosteroids, immunosuppressive, cytoxic, or antifibrotic drugs dose must have been stable. Selected
Exclusion criteria
* Diagnosis of PH primarily due to an etiology other than IPF * Surgical lung biopsy diagnosis other than Usual Interstitial Pneumonia * Other known cause of interstitial lung disease * Evidence of significant obstructive lung disease * Recent hospitalization for an acute exacerbation of IPF * Recent active pulmonary or upper respiratory tract infection * Left ventricular ejection fraction \< 40% * Serum creatinine ≥ 2.5 mg/dL * Required hemodialysis, peritoneal dialysis, or hemofiltration * Female subject who was pregnant or breastfeeding * Recent treatment for PH with an endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor, or prostacyclin derivative * Recent treatment with high dose oral corticosteroids * Recent treatment (within 4 weeks prior to screening) with imatinib mesylate (Gleevec) * Alanine aminotransferase or aspartate aminotransferase lab value that was greater than 1.5 x the upper limit of the normal range * Discontinued other ERA treatment for any adverse reaction other than those associated with liver function test abnormalities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Six-minute Walk Distance (6MWD). | Baseline to Week 16 | The change from baseline in 6MWD at Week 16 (end of blinded treatment) was evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transition Dyspnea Index (TDI) | Baseline to Week 16 | The change in TDI at Week 16 (end of blinded treatment) was evaluated. TDI measures the change from the baseline characteristic Baseline Dyspnea Index. The TDI range is -9 to +9 (worst to best; 0 = no change). |
| Change From Baseline in WHO Functional Class | Baseline to Week 16 | WHO functional class rates severity of pulmonary hypertension, with 4 categories on a scale of 1 to 4 with the worst category being 4. Change is represented as an increase (+1: Improved), decrease (-1: Deteriorated), or no change (0: No change) on the scale. |
| Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted | Baseline to Week 16 | FVC is a pulmonary function test, and is defined as the volume of air that can forcibly be blown out after taking a full breath. FVC% predicted is defined as FVC% of the patient divided by the average FVC% in the population for any person of similar age, sex and body composition. |
| Change From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) | Baseline to Week 16 | Assessment of the the level of the amino acid fragment NT-proBNP is used to establish prognosis in cardiovascular disease. |
| Long-term Survival | Week 48 | Long-term survival was assessed as a Kaplan-Meier (KM) estimate of the percent probability of survival, with censoring at Week 48. |
| Hemoglobin-corrected Diffusing Capacity for Carbon Monoxide (DLCO) Percent Predicted | Baseline to Week 16 | DLCO is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide. DLCO% predicted is defined as DLCO% of the patient divided by the average DLCO% in the population for any person of similar age, sex and body composition. |
| Change in Quality of Life (QOL) Score as Assessed by the Short-Form 36® (SF-36) | Baseline to Week 16 | Each SF-36 score is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. An increase in score indicates an improvement in health state. |
| Change in QOL Score as Assessed by the St. George's Respiratory Questionnaire (SRGQ) | Baseline to Week 16 | The SRGQ is designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency & severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations. |
| Change From Baseline in the Borg Dyspnea Index (BORG) Immediately Following Exercise | Baseline to Week 16 | Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). |
Countries
Australia, Austria, Canada, Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled in a total of 29 study sites in Australia, Europe, and North America. The first participant was screened on 21 October 2009. The last participant observation was on 22 February 2011.
Pre-assignment details
96 participants were screened; 40 participants were randomized and treated, and comprise the Safety Analysis Set and the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Ambrisentan Participants were randomized to receive ambrisentan treatment for 56 weeks | 25 |
| Placebo Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks. | 15 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Clinical status did not improve | 1 | 0 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Study terminated by Sponsor | 13 | 12 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ambrisentan | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 68 years STANDARD_DEVIATION 7.7 | 68 years STANDARD_DEVIATION 5.2 | 68 years STANDARD_DEVIATION 6.8 |
| Baseline Dyspnea Index (BDI) | 5.0 units on a scale STANDARD_DEVIATION 2.15 | 4.4 units on a scale STANDARD_DEVIATION 2.1 | 4.8 units on a scale STANDARD_DEVIATION 2.13 |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 25 participants | 14 participants | 39 participants |
| Region of Enrollment Australia | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Canada | 3 participants | 1 participants | 4 participants |
| Region of Enrollment Germany | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Italy | 4 participants | 1 participants | 5 participants |
| Region of Enrollment United States | 14 participants | 9 participants | 23 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 20 Participants | 10 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 25 | 12 / 15 |
| serious Total, serious adverse events | 12 / 25 | 3 / 15 |
Outcome results
Primary
Change From Baseline in Six-minute Walk Distance (6MWD).
The change from baseline in 6MWD at Week 16 (end of blinded treatment) was evaluated.
Time frame: Baseline to Week 16
Population: Participants in the Full Analysis Set (randomized and received at least one dose of study medication) with evaluable data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change From Baseline in Six-minute Walk Distance (6MWD). | -96 meters | Standard Error 38 |
| Placebo | Change From Baseline in Six-minute Walk Distance (6MWD). | -67 meters | Standard Error 51 |
p-value: 0.69695% CI: [-54, 17]Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted
FVC is a pulmonary function test, and is defined as the volume of air that can forcibly be blown out after taking a full breath. FVC% predicted is defined as FVC% of the patient divided by the average FVC% in the population for any person of similar age, sex and body composition.
Time frame: Baseline to Week 16
Population: Insufficient data due to study termination
Secondary
Change From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)
Assessment of the the level of the amino acid fragment NT-proBNP is used to establish prognosis in cardiovascular disease.
Time frame: Baseline to Week 16
Population: Insufficient data due to study termination
Secondary
Change From Baseline in the Borg Dyspnea Index (BORG) Immediately Following Exercise
Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time frame: Baseline to Week 16
Population: Insufficient data due to study termination
Secondary
Change From Baseline in WHO Functional Class
WHO functional class rates severity of pulmonary hypertension, with 4 categories on a scale of 1 to 4 with the worst category being 4. Change is represented as an increase (+1: Improved), decrease (-1: Deteriorated), or no change (0: No change) on the scale.
Time frame: Baseline to Week 16
Population: Participants in the Full Analysis Set with evaluable data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan | Change From Baseline in WHO Functional Class | -1: Deteriorated | 0 units on a scale |
| Ambrisentan | Change From Baseline in WHO Functional Class | 0: No change | 11 units on a scale |
| Ambrisentan | Change From Baseline in WHO Functional Class | +1: Improved | 3 units on a scale |
| Placebo | Change From Baseline in WHO Functional Class | -1: Deteriorated | 1 units on a scale |
| Placebo | Change From Baseline in WHO Functional Class | 0: No change | 5 units on a scale |
| Placebo | Change From Baseline in WHO Functional Class | +1: Improved | 2 units on a scale |
Secondary
Change in QOL Score as Assessed by the St. George's Respiratory Questionnaire (SRGQ)
The SRGQ is designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency & severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations.
Time frame: Baseline to Week 16
Population: Insufficient data due to study termination
Secondary
Change in Quality of Life (QOL) Score as Assessed by the Short-Form 36® (SF-36)
Each SF-36 score is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. An increase in score indicates an improvement in health state.
Time frame: Baseline to Week 16
Population: Insufficient data due to study termination
Secondary
Hemoglobin-corrected Diffusing Capacity for Carbon Monoxide (DLCO) Percent Predicted
DLCO is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide. DLCO% predicted is defined as DLCO% of the patient divided by the average DLCO% in the population for any person of similar age, sex and body composition.
Time frame: Baseline to Week 16
Population: Insufficient data due to study termination
Secondary
Long-term Survival
Long-term survival was assessed as a Kaplan-Meier (KM) estimate of the percent probability of survival, with censoring at Week 48.
Time frame: Week 48
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Long-term Survival | 22 percent probability (KM% estimate) |
| Placebo | Long-term Survival | 23 percent probability (KM% estimate) |
Secondary
Transition Dyspnea Index (TDI)
The change in TDI at Week 16 (end of blinded treatment) was evaluated. TDI measures the change from the baseline characteristic Baseline Dyspnea Index. The TDI range is -9 to +9 (worst to best; 0 = no change).
Time frame: Baseline to Week 16
Population: Participants in the Full Analysis Set with evaluable data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Transition Dyspnea Index (TDI) | -1.5 units on a scale | Standard Deviation 3.08 |
| Placebo | Transition Dyspnea Index (TDI) | -1.4 units on a scale | Standard Deviation 3.78 |