Idiopathic Pulmonary Fibrosis
Conditions
Keywords
idiopathic pulmonary fibrosis, interstitial lung disease, ambrisentan
Brief summary
The ARTEMIS-IPF study was conducted to determine if ambrisentan was effective in delaying disease progression and death in participants with idiopathic pulmonary fibrosis (IPF), to evaluate its safety, and to evaluate its effect on development of pulmonary hypertension, quality of life, and dyspnea (shortness of breath) symptoms in this participant population. Participants were randomized in a 2:1 ratio to receive ambrisentan or placebo, respectively. Participation in the study was to be up to 4 years, depending on how long it would take to enroll participants and observe study events. After randomization, visits to the clinic took place every 3 months, and laboratory procedures were performed every month.
Interventions
DRUGAmbrisentan
Ambrisentan (5mg or 10 mg tablet) was administered orally once daily.
DRUGPlacebo
Placebo to match ambrisentan was administered orally once daily.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or females from 40 to 80 years of age * Diagnosis of IPF * Honeycombing (fibrosis in the lung) on high-resolution computerised tomography (HRCT) scan of less than or equal to 5% * Willing and able to have 2 right heart catheterizations performed * Willing to have monthly lab tests to monitor liver function * Able to perform the 6 minute walk test (indicated adequate physical function) * Must have meet lung function requirements * Normal liver function tests * Negative serum pregnancy test * Willing to use at least 2 reliable methods of contraception * Able to understand and willing to sign informed consent form
Exclusion criteria
* No restrictive lung disease (other than usual interstitial pneumonia or IPF) * No obstructive lung disease * No recent or active respiratory exacerbations * No recent hospitalization for an IPF exacerbation * No recent history of alcohol abuse * Chronic sildenafil (or same drug class) use for pulmonary hypertension * Chronic treatment with certain medications for IPF within 30 days of randomization * No other serious medical conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death or Disease (IPF) Progression. | Up to 48 months | The median time to death or disease progression was based on Kaplan-Meier (KM) estimates of pooling over strata, and was defined as the first occurrence of any of the following: * Either 1) a decrease of ≥ 10% in FVC (L) and a decrease of ≥ 5% in diffuse lung capacity for carbon monoxide (DLCO) (ml/min/mmHg), or 2) a decrease of ≥ 5% in FVC (L) and a decrease of ≥ 15% in DLCO (ml/min/mmHg); deterioration in FVC and DLCO must be confirmed at the subsequent visit within 28 (± 14) days * Respiratory hospitalization (hospitalization involving worsening of, or deterioration in respiratory symptoms, gas exchange/hypoxemia, or radiographic findings on chest x-ray or high-resolution computerised tomography (HRCT) scan * All-cause mortality |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in FVC % Predicted at Week 48 | Baseline and Week 48 | FVC is defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted is defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition. |
| Change in DLCO % Predicted at Week 48 | Baseline and Week 48 | DLCO is the extent to which oxygen passes from the air sacs of the lungs into the blood. DLCO % predicted is defined as DLCO % of the participant divided by the average DLCO % in the population for any person of similar age, sex and body composition. |
| Change in 6MWT at Week 48 | Baseline and Week 48 | The 6MWT is a measure of exercise tolerance, and measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. |
| Proportion of Participants With No Disease Progression or Death at 48 Weeks | Baseline and Week 48 | The proportion of participants with no disease progression or death is presented as a percentage using a Kaplan-Meier (KM) estimate of survival or not experiencing disease progression. |
| Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Baseline and Week 48 | The SGRQ is designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airways disease. The range of each score is 0-100, with 0 indicating fewer limitations and 100 indicating more limitations; an increase in score indicates an increase in limitations. |
| Change in Dyspnea Score at Week 48 as Assessed by the Transitional Dyspnea Index (TDI) | Baseline and Week 48 | The transitional focal score (-9 to 9) is the sum of relative change from baseline for the Functional Impairment, Magnitude of Task, and Magnitude of Effort scores (each -3 to 3 scale). A TDI score of -9 represents a maximum degradation of all three tests; a score of 9 represents a maximum improvement of all three tests. |
| Percentage of Participants Who Developed PH on Study | Up to 48 weeks | The percentage of participants known to have developed pulmonary hypertension on study documented by right heart catheterization (RHC) was analyzed. RHC was done at baseline and 48 weeks, or at the early termination visit. |
| Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) | Baseline and Week 48 | The range of each health domain score is 0-100, with 0 indicating a poorer health state and 100 indicating a better health state. An increase in score indicates an improvement in health state. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Czechia, France, Germany, Ireland, Israel, Italy, Mexico, Netherlands, Peru, Poland, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in a total of 136 study sites in North and South America, Europe, and Australia. The first participant was screened on 10 December 2008. The last participant observation was on 28 February 2011.
Pre-assignment details
494 participants were randomized; 492 participants were treated, and comprise the Safety Analysis Set and the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Ambrisentan Ambrisentan (5 mg or 10 mg tablet) administered orally once daily | 329 |
| Placebo Placebo to match ambrisentan administered orally once daily | 163 |
| Total | 492 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 2 |
| Overall Study | Began prohibited concomitant medication | 0 | 1 |
| Overall Study | Death | 21 | 5 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Missing data | 1 | 0 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Protocol Violation | 6 | 1 |
| Overall Study | Randomized but not treated | 1 | 1 |
| Overall Study | Received lung transplant | 1 | 1 |
| Overall Study | Screen failure following randomization | 1 | 0 |
| Overall Study | Study discontinued by Sponsor | 271 | 140 |
| Overall Study | Subject moved to pursue lung transplant | 1 | 1 |
| Overall Study | Treated but never dosed with Study drug | 1 | 0 |
| Overall Study | Withdrawal by Subject | 13 | 7 |
Baseline characteristics
| Characteristic | Ambrisentan | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 65.8 years STANDARD_DEVIATION 7.4 | 65.9 years STANDARD_DEVIATION 7.3 | 66.1 years STANDARD_DEVIATION 7.1 |
| Baseline Pulmonary Hypertension (PH) per interactive voice response system (IVRS) No | 293 participants | 438 participants | 145 participants |
| Baseline Pulmonary Hypertension (PH) per interactive voice response system (IVRS) Yes | 36 participants | 54 participants | 18 participants |
| Disease duration | 1.13 years STANDARD_DEVIATION 1.39 | 1.06 years STANDARD_DEVIATION 1.33 | 0.91 years STANDARD_DEVIATION 1.19 |
| Forced vital capacity (FVC) percent predicted | 68.74 percentage of FVC % predicted STANDARD_DEVIATION 13.12 | 69.11 percentage of FVC % predicted STANDARD_DEVIATION 13.33 | 69.86 percentage of FVC % predicted STANDARD_DEVIATION 13.75 |
| Hemoglobin Adjusted Diffusing lung capacity for carbon monoxide (DLCO) percent predicted | 42.04 percentage of DLCO % predicted STANDARD_DEVIATION 13.77 | 43.20 percentage of DLCO % predicted STANDARD_DEVIATION 13.69 | 45.57 percentage of DLCO % predicted STANDARD_DEVIATION 13.25 |
| N-acetylcysteine (NAC) Use No | 310 participants | 463 participants | 153 participants |
| N-acetylcysteine (NAC) Use Yes | 19 participants | 27 participants | 8 participants |
| Prior IPF Medications No | 205 participants | 302 participants | 97 participants |
| Prior IPF Medications Yes | 124 participants | 189 participants | 65 participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 4 participants | 5 participants | 1 participants |
| Race/Ethnicity, Customized Black or African Heritage | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Not Permitted | 3 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized Other | 27 participants | 43 participants | 16 participants |
| Race/Ethnicity, Customized White | 293 participants | 438 participants | 145 participants |
| Region of Enrollment Argentina | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Australia | 22 participants | 34 participants | 12 participants |
| Region of Enrollment Austria | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Belgium | 7 participants | 13 participants | 6 participants |
| Region of Enrollment Brazil | 18 participants | 24 participants | 6 participants |
| Region of Enrollment Canada | 25 participants | 39 participants | 14 participants |
| Region of Enrollment Chile | 3 participants | 4 participants | 1 participants |
| Region of Enrollment Colombia | 8 participants | 11 participants | 3 participants |
| Region of Enrollment Czech Republic | 10 participants | 16 participants | 6 participants |
| Region of Enrollment France | 21 participants | 31 participants | 10 participants |
| Region of Enrollment Germany | 17 participants | 26 participants | 9 participants |
| Region of Enrollment Ireland | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Israel | 8 participants | 15 participants | 7 participants |
| Region of Enrollment Italy | 11 participants | 14 participants | 3 participants |
| Region of Enrollment Mexico | 5 participants | 9 participants | 4 participants |
| Region of Enrollment Peru | 12 participants | 18 participants | 6 participants |
| Region of Enrollment Poland | 3 participants | 6 participants | 3 participants |
| Region of Enrollment Spain | 7 participants | 8 participants | 1 participants |
| Region of Enrollment Switzerland | 5 participants | 6 participants | 1 participants |
| Region of Enrollment United Kingdom | 3 participants | 9 participants | 6 participants |
| Region of Enrollment United States | 141 participants | 203 participants | 62 participants |
| Sex: Female, Male Female | 85 Participants | 137 Participants | 52 Participants |
| Sex: Female, Male Male | 244 Participants | 355 Participants | 111 Participants |
| Six mile walk test (6MWT) | 410.4 meters STANDARD_DEVIATION 118.7 | 413.7 meters STANDARD_DEVIATION 119.6 | 420.5 meters STANDARD_DEVIATION 121.4 |
| Smoking status Current | 7 participants | 12 participants | 5 participants |
| Smoking status Former | 217 participants | 321 participants | 104 participants |
| Smoking status Never | 105 participants | 158 participants | 53 participants |
| Surgical lung biopsy (SLB) to Confirm Diagnosis of IPF (per IVRS) No | 175 participants | 262 participants | 87 participants |
| Surgical lung biopsy (SLB) to Confirm Diagnosis of IPF (per IVRS) Yes | 154 participants | 230 participants | 76 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 227 / 329 | 104 / 163 |
| serious Total, serious adverse events | 73 / 329 | 25 / 163 |
Outcome results
Primary
Time to Death or Disease (IPF) Progression.
The median time to death or disease progression was based on Kaplan-Meier (KM) estimates of pooling over strata, and was defined as the first occurrence of any of the following: * Either 1) a decrease of ≥ 10% in FVC (L) and a decrease of ≥ 5% in diffuse lung capacity for carbon monoxide (DLCO) (ml/min/mmHg), or 2) a decrease of ≥ 5% in FVC (L) and a decrease of ≥ 15% in DLCO (ml/min/mmHg); deterioration in FVC and DLCO must be confirmed at the subsequent visit within 28 (± 14) days * Respiratory hospitalization (hospitalization involving worsening of, or deterioration in respiratory symptoms, gas exchange/hypoxemia, or radiographic findings on chest x-ray or high-resolution computerised tomography (HRCT) scan * All-cause mortality
Time frame: Up to 48 months
Population: Full Analysis Set: participants who were randomized and treated
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ambrisentan | Time to Death or Disease (IPF) Progression. | 84.14 weeks |
| Placebo | Time to Death or Disease (IPF) Progression. | NA weeks |
p-value: 0.0195% CI: [1.14, 2.66]Log Rank
Secondary
Change in 6MWT at Week 48
The 6MWT is a measure of exercise tolerance, and measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface.
Time frame: Baseline and Week 48
Population: Participants in the Full Analysis Set with evaluable change data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change in 6MWT at Week 48 | -52.5 meters | Standard Deviation 148.7 |
| Placebo | Change in 6MWT at Week 48 | -10.6 meters | Standard Deviation 89.8 |
p-value: 0.1595% CI: [-5, 37]Van Elteren test
Secondary
Change in DLCO % Predicted at Week 48
DLCO is the extent to which oxygen passes from the air sacs of the lungs into the blood. DLCO % predicted is defined as DLCO % of the participant divided by the average DLCO % in the population for any person of similar age, sex and body composition.
Time frame: Baseline and Week 48
Population: Participants in the Full Analysis Set with evaluable change data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change in DLCO % Predicted at Week 48 | -2.68 percent change in DLCO % predicted | Standard Deviation 27.6 |
| Placebo | Change in DLCO % Predicted at Week 48 | -11.28 percent change in DLCO % predicted | Standard Deviation 32.06 |
p-value: 0.2595% CI: [-2.2, 7.9]Van Elteren test
Secondary
Change in Dyspnea Score at Week 48 as Assessed by the Transitional Dyspnea Index (TDI)
The transitional focal score (-9 to 9) is the sum of relative change from baseline for the Functional Impairment, Magnitude of Task, and Magnitude of Effort scores (each -3 to 3 scale). A TDI score of -9 represents a maximum degradation of all three tests; a score of 9 represents a maximum improvement of all three tests.
Time frame: Baseline and Week 48
Population: Participants in the Full Analysis Set with evaluable change data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change in Dyspnea Score at Week 48 as Assessed by the Transitional Dyspnea Index (TDI) | -1.23 units on a scale | Standard Deviation 3.74 |
| Placebo | Change in Dyspnea Score at Week 48 as Assessed by the Transitional Dyspnea Index (TDI) | -0.84 units on a scale | Standard Deviation 2.99 |
p-value: 0.79395% CI: [0, 1]Wilcoxon (Mann-Whitney)
Secondary
Change in FVC % Predicted at Week 48
FVC is defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted is defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition.
Time frame: Baseline and Week 48
Population: Participants in the Full Analysis Set with evaluable change data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change in FVC % Predicted at Week 48 | -10.24 percent change in FVC % predicted | Standard Deviation 25.95 |
| Placebo | Change in FVC % Predicted at Week 48 | -5.28 percent change in FVC % predicted | Standard Deviation 15.68 |
p-value: 0.08695% CI: [-0.805, 9.376]Van Elteren test
Secondary
Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36)
The range of each health domain score is 0-100, with 0 indicating a poorer health state and 100 indicating a better health state. An increase in score indicates an improvement in health state.
Time frame: Baseline and Week 48
Population: Participants in the Full Analysis Set with evaluable change data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ambrisentan | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) | Vitality | -1.67 units on a scale | Standard Deviation 12.67 |
| Ambrisentan | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) | Physical function | -1.65 units on a scale | Standard Deviation 10.86 |
| Ambrisentan | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) | General Health | -2.81 units on a scale | Standard Deviation 9.77 |
| Placebo | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) | Physical function | -2.60 units on a scale | Standard Deviation 7.25 |
| Placebo | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) | General Health | -1.95 units on a scale | Standard Deviation 8.63 |
| Placebo | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) | Vitality | -0.12 units on a scale | Standard Deviation 7.69 |
Secondary
Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ)
The SGRQ is designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airways disease. The range of each score is 0-100, with 0 indicating fewer limitations and 100 indicating more limitations; an increase in score indicates an increase in limitations.
Time frame: Baseline and Week 48
Population: Participants in the Full Analysis Set with evaluable change data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ambrisentan | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Symptoms Score | 3.30 units on a scale | Standard Deviation 22.11 |
| Ambrisentan | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Activity Score | 5.54 units on a scale | Standard Deviation 19.38 |
| Ambrisentan | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Impacts Score | 4.68 units on a scale | Standard Deviation 24.07 |
| Ambrisentan | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Total Score | 4.70 units on a scale | Standard Deviation 19.92 |
| Placebo | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Total Score | 3.04 units on a scale | Standard Deviation 13.8 |
| Placebo | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Symptoms Score | 2.84 units on a scale | Standard Deviation 20.43 |
| Placebo | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Impacts Score | 3.09 units on a scale | Standard Deviation 15.8 |
| Placebo | Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) | Activity Score | 2.05 units on a scale | Standard Deviation 16.47 |
Secondary
Percentage of Participants Who Developed PH on Study
The percentage of participants known to have developed pulmonary hypertension on study documented by right heart catheterization (RHC) was analyzed. RHC was done at baseline and 48 weeks, or at the early termination visit.
Time frame: Up to 48 weeks
Population: Participants in the Full Analysis Set without PH at baseline were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Percentage of Participants Who Developed PH on Study | 0.7 percentage of participants |
| Placebo | Percentage of Participants Who Developed PH on Study | 2.1 percentage of participants |
Secondary
Proportion of Participants With No Disease Progression or Death at 48 Weeks
The proportion of participants with no disease progression or death is presented as a percentage using a Kaplan-Meier (KM) estimate of survival or not experiencing disease progression.
Time frame: Baseline and Week 48
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Proportion of Participants With No Disease Progression or Death at 48 Weeks | 65 percentage of participants |
| Placebo | Proportion of Participants With No Disease Progression or Death at 48 Weeks | 80 percentage of participants |