Idiopathic Pulmonary Fibrosis
Conditions
Keywords
idiopathic pulmonary fibrosis, MUSIC
Brief summary
The AC-055B201/MUSIC study is a Phase II study, comparing one dose of ACT-064922 (macitentan) 10 mg with placebo in patients with idiopathic pulmonary fibrosis (IPF). The main study objective is to demonstrate that macitentan positively affects the forced vital capacity (FVC) in comparison with placebo in patients with idiopathic pulmonary fibrosis (IPF). The secondary objectives are to evaluate the effect of macitentan on the time to disease worsening or death in patients with IPF, and to evaluate the benefit/risk profile of macitentan in the treatment of patients with IPF.
Detailed description
The study included two treatment periods: Period 1 (fixed duration) from randomization up to the primary endpoint evaluation (Month 12 or earlier in case of premature discontinuation of study drug) and Period 2 (variable duration) from the primary endpoint evaluation visit up to the end of study (EOS). EOS occurred when the last patient randomized and not prematurely discontinued completed Period 1.
Interventions
DRUGACT-064992 (macitentan)
ACT-064992 (macitentan) tablet, 10 mg, once daily
DRUGPlacebo
matching placebo, once daily
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent. 2. Male or female patients of at least 18 years of age (females of child-bearing potential must use a reliable method of contraception). 3. IPF diagnosis within 3 years prior to randomization, proven according to the American Thoracic Society/European Respiratory Society consensus conference criteria, with surgical lung biopsy.
Exclusion criteria
1. Interstitial lung disease due to conditions other than IPF. 2. Presence of extensive honeycombing on Baseline high-resolution computed tomography (HRCT) scan performed within 3 months prior to randomization. 3. Severe concomitant illness limiting life expectancy (\< 1 year). 4. Severe restrictive lung disease: forced vital capacity (FVC) \< 50% predicted, or FVC \< 1.2 liter. 5. Diffusing capacity of the lung for carbon monoxide (DLCO) \< 30% predicted. 6. Residual volume ≥ 120% predicted. 7. Obstructive lung disease: forced expiratory volume in 1 second (FEV1)/FVC) \< 0.70. 8. Documented sustained improvement of the patient's IPF condition up to 12 months prior to randomization with or without IPF-specific therapy. 9. Recent pulmonary or upper respiratory tract infection (up to 4 weeks prior to randomization). 10. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests). 11. Chronic heart failure with New York Heart Association class III/IV or known left ventricular ejection fraction \< 25%. 12. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C. 13. Estimated creatinine clearance \< 30 mL/min. 14. Aspartate aminotransferase (AST) and/or alanine aminotransferase \> 1.5 x upper limit of normal. 15. Hemoglobin \< 75% of the lower limit of the normal range. 16. Systolic blood pressure \< 100 mmHg. 17. Pregnant or breast-feeding. 18. Current drug or alcohol dependence. 19. Chronic treatment with the following drugs (within 4 weeks of randomization): * Oral corticosteroids (\> 20 mg/day of prednisone or equivalent), * Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine, * Antifibrotic drugs including pirfenidone, D penicillamine, colchicine, tumor necrosis factor α blockers, imatinib and interferon γ, * Chronic use of N-acetylcysteine prescribed for IPF (\> 600 mg/day). * Oral anticoagulants prescribed for IPF. 20. Treatment with endothelin receptor antagonists within 4 weeks prior to randomization. 21. Systemic treatment within 4 weeks prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors). 22. Treatment with Cytochrome P450 3A inducers within 4 weeks prior to randomization. 23. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients. 24. Planned treatment, or treatment with another investigational drug within 4 weeks prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Vital Capacity (FVC) at Baseline and End of Period 1 | 12 months | FVC was measured at baseline and at the end of Period 1. The same equipment and tester were used during the course of the study. The equipment was calibrated and the calibration documented prior to each patient's measurement. The person responsible for conducting the pulmonary function tests was required to comply with the study guidelines and the American Thoracic Society/European Respiratory Society joint criteria on lung function testing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Up to end of study (Up to 24 months) | Disease worsening was indicated by pulmonary function test/idiopathic pulmonary fibrosis worsening (PFT/IPF) or acute respiratory decompensation of IPF. PFT/IPF worsening was indicated by the occurrence of both of the following: confirmed by two tests at least 4 weeks apart, as defined by the occurrence of both of the following: decrease from baseline ≥ 10% in forced vital capacity and decrease from baseline ≥ 15% in corrected diffusing capacity of the lung for carbon monoxide. Acute respiratory decompensation of IPF was defined as an unexplained rapid deterioration (over a period of less than 4 weeks) of the patient's condition with increasing shortness of breath requiring oxygen supplementation ≥ 5 L/min to maintain a resting oxygen saturation ≥ 90% or arterial oxygen pressure ≥ 55 mmHg (sea level) or 50 mmHg (high altitude). |
Countries
Australia, Canada, France, Germany, Israel, Italy, Slovenia, South Africa, Spain, Sweden, Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was conducted at 48 centers in Australia, Canada, France, Germany, Israel, Italy, Slovenia, South Africa, Spain, Sweden, Turkey, and the USA.
Pre-assignment details
The study included a screening period of up to 28 days followed by a double-blind treatment phase that was further divided into two periods. 300 patients were screened and 178 randomized in a 2:1 ratio to study treatment with ACT-064922 or placebo
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo, once daily
Placebo : matching placebo, once daily | 59 |
| ACT-064922 ACT-064922 tablet, 10 mg, once daily
ACT-064992 (macitentan) : tablet, 10 mg, once daily | 119 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 8 |
| Overall Study | Lung transplant | 0 | 2 |
| Overall Study | Withdrawal of consent | 1 | 8 |
Baseline characteristics
| Characteristic | Placebo | Total | ACT-064922 |
|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 6.32 | 64.9 years STANDARD_DEVIATION 7.37 | 65.1 years STANDARD_DEVIATION 7.85 |
| Region of Enrollment Australia | 9 participants | 27 participants | 18 participants |
| Region of Enrollment Canada | 5 participants | 15 participants | 10 participants |
| Region of Enrollment France | 10 participants | 26 participants | 16 participants |
| Region of Enrollment Germany | 5 participants | 13 participants | 8 participants |
| Region of Enrollment Israel | 2 participants | 7 participants | 5 participants |
| Region of Enrollment Italy | 1 participants | 8 participants | 7 participants |
| Region of Enrollment Slovenia | 1 participants | 2 participants | 1 participants |
| Region of Enrollment South Africa | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Spain | 4 participants | 11 participants | 7 participants |
| Region of Enrollment Sweden | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Turkey | 3 participants | 11 participants | 8 participants |
| Region of Enrollment United States | 18 participants | 55 participants | 37 participants |
| Sex: Female, Male Female | 22 Participants | 57 Participants | 35 Participants |
| Sex: Female, Male Male | 37 Participants | 121 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 57 / 59 | 114 / 119 |
| serious Total, serious adverse events | 20 / 59 | 37 / 119 |
Outcome results
Primary
Forced Vital Capacity (FVC) at Baseline and End of Period 1
FVC was measured at baseline and at the end of Period 1. The same equipment and tester were used during the course of the study. The equipment was calibrated and the calibration documented prior to each patient's measurement. The person responsible for conducting the pulmonary function tests was required to comply with the study guidelines and the American Thoracic Society/European Respiratory Society joint criteria on lung function testing.
Time frame: 12 months
Population: All randomized patients
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) at Baseline and End of Period 1 | Baseline | 2.74 litres | 95% Confidence Interval 0.776 |
| Placebo | Forced Vital Capacity (FVC) at Baseline and End of Period 1 | End of Period 1 | 2.40 litres | 95% Confidence Interval 0.918 |
| ACT-064922 | Forced Vital Capacity (FVC) at Baseline and End of Period 1 | Baseline | 2.83 litres | 95% Confidence Interval 0.834 |
| ACT-064922 | Forced Vital Capacity (FVC) at Baseline and End of Period 1 | End of Period 1 | 2.57 litres | 95% Confidence Interval 1.012 |
Comparison: The null hypothesis was that there was no difference between ACT-064922 and placebo for the change in FVC from baseline to the end of Period 1. The aim was to detect a placebo-corrected change in FVC of ≥ 0.1 L (Standard Deviation = 0.2 L) at a two-sided 0.05 type 1 error level and 80% power.p-value: 0.963195% CI: [-0.09, 0.08]Wilcoxon Rank Sum
Secondary
Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study
Disease worsening was indicated by pulmonary function test/idiopathic pulmonary fibrosis worsening (PFT/IPF) or acute respiratory decompensation of IPF. PFT/IPF worsening was indicated by the occurrence of both of the following: confirmed by two tests at least 4 weeks apart, as defined by the occurrence of both of the following: decrease from baseline ≥ 10% in forced vital capacity and decrease from baseline ≥ 15% in corrected diffusing capacity of the lung for carbon monoxide. Acute respiratory decompensation of IPF was defined as an unexplained rapid deterioration (over a period of less than 4 weeks) of the patient's condition with increasing shortness of breath requiring oxygen supplementation ≥ 5 L/min to maintain a resting oxygen saturation ≥ 90% or arterial oxygen pressure ≥ 55 mmHg (sea level) or 50 mmHg (high altitude).
Time frame: Up to end of study (Up to 24 months)
Population: All randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 4 | 59 participants |
| Placebo | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 8 | 57 participants |
| Placebo | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 12 | 44 participants |
| Placebo | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 16 | 22 participants |
| Placebo | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 20 | 8 participants |
| Placebo | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 24 | 2 participants |
| ACT-064922 | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 20 | 14 participants |
| ACT-064922 | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 4 | 112 participants |
| ACT-064922 | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 16 | 43 participants |
| ACT-064922 | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 8 | 103 participants |
| ACT-064922 | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 24 | 1 participants |
| ACT-064922 | Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study | Patients at Risk of Event at Month 12 | 81 participants |
p-value: 0.705695% CI: [0.626, 1.996]Log Rank