Idiopathic Pulmonary Fibrosis
Conditions
Brief summary
This Phase IIb, randomized, placebo-controlled, multicenter, international study will evaluate the efficacy, safety, and tolerability of sildenafil or placebo added to pirfenidone (Esbriet) treatment in participants with advanced IPF and intermediate or high probability of Group 3 pulmonary hypertension (PH) who are on a stable dose of pirfenidone with demonstrated tolerability. Participants will be randomized to receive 1 year of treatment with either oral sildenafil or matching placebo while continuing to take pirfenidone.
Interventions
DRUGPirfenidone
Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.
DRUGPlacebo
Placebo matched with sildenafil.
DRUGSildenafil
Sildenafil will be given as 20 mg, TID.
Sponsors
Hoffmann-La Roche
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
* Diagnosis of IPF for at least 3 months prior to Screening * Confirmation of IPF diagnosis by the investigator in accordance with the 2011 international consensus guidelines at screening * Advanced IPF (defined as a measurable carbon monoxide diffusing capacity \[DLCO\] less than or equal to (\<=)40% of predicted value at Screening) and intermediate or high probability of group 3 pulmonary hypertension (PH) * Participants receiving pirfenidone for at least 12 weeks, at a dose in the range of 1602 to 2403 mg/day for at least 4 weeks prior to Screening and must not have experienced either a new or ongoing adverse event of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 4.03) Grade 2 or higher and considered by the investigator to be related to pirfenidone, or an interruption of pirfenidone treatment of greater than (\>)7 days for any reason * WHO Functional Class II or III at Screening * 6MWD of 100 to 450 meters at screening * Women of childbearing potential and for men who are not surgically sterile agreement to remain abstinent or use of contraceptive measures
Exclusion criteria
* History of any of the following types of PH: Group 1 (PAH); Group 1 (pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis); Group 2 (left-heart disease); Group 3 (due to conditions other than interstitial lung disease, including chronic obstructive pulmonary disease \[COPD\], sleep-disordered breathing, alveolar hypoventilation, high altitude, or developmental abnormalities); Group 4 (chronic thromboembolic pulmonary hypertension); Group 5 (other disorders) * History of clinically significant cardiac disease * History of coexistent and clinically significant COPD, bronchiectasis, asthma, inadequately treated sleep-disordered breathing, or any clinically significant pulmonary diseases or disorders other than IPF or PH secondary to IPF * History of use of drugs and toxins known to cause PAH, including aminorex, fenfluramine, dexenfluramine, and amphetamines * FEV1/FVC ratio less than (\<) 0.70 post bronchodilator; SpO2 saturation at rest \<92% with \>= 6 liters (L) of supplemental oxygen at Screening * Extent of emphysema greater than the extent of fibrotic changes (honeycombing and reticular changes) on any previous high-resolution computed tomography (HRCT) scan, in the opinion of the Investigator * Smoked tobacco within 3 months prior to screening or is unwilling to avoid tobacco products (cigarettes, pipe, cigars) throughout the study * Illicit drug or significant alcohol abuse * Electrocardiogram (ECG) with a heart-rate corrected QT interval (corrected using Fridericia's formula \[QTcF\]) \>=500 milliseconds (ms) at screening, or a family or personal history of long QT syndrome *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause | Baseline up to Week 52 | Disease Progression defined as relative decline in 6-minute walking distance (6MWD) from baseline (defined as \>25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death From Any Cause | Baseline up to Week 52 | — |
| Time to First Occurrence of Disease Progression | Baseline up to Week 52 | Disease Progression defined as relative decline in 6MWD from baseline (defined as \>25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. |
| Time to Multiple Occurrence of Disease Progression Events | Baseline up to Week 52 | Disease Progression defined as relative decline in 6MWD from baseline (defined as \>25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. In case participant had more than one event as described in the endpoint definition the second, third etc event was counted as well for the calculation of the endpoint. |
| Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15% | Baseline up to Week 52 | — |
| Time to First Occurrence of Relevant ≥15% Decline From Baseline in 6-minute Walking Distance (6MWD) | Baseline up to Week 52 | — |
| Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52 | Baseline up to Week 52 | N.A. = non-calculable |
| Percentage of Participants With Lung Transplantation | Baseline up to Week 52 | — |
| Time to Respiratory-Related Death | Baseline up to Week 52 | — |
| Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity | Baseline, Week 52 | — |
| Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs) | Baseline, Week 52 | — |
| Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE) | Baseline, Week 52 | — |
| Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter | Baseline, Week 52 | — |
| Time to All-Cause Non-Elective Hospitalization | Baseline up to Week 52 | N.A. = non-calculable |
| Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF) | Baseline, Week 52 | — |
| Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO) | Baseline, Week 52 | — |
| Change From Baseline to Week 52 in Forced Vital Capacity (FVC) | Baseline, Week 52 | — |
| Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Week 52 | The World Health Organisation (WHO) functional class system defines the severity of an participant's symptoms. Class II - Participants with Pulmonary Hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class III - Participants with Pulmonary Hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class IV - participants with pulmonary hypertension with inability to carry out any physical activity without symptoms. These participants manifest signs of right heart failure, breathlessness and /or fatigue, which may even be present at rest. Discomfort is increased by any physical activity. |
| Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52 | Baseline, Week 52 | — |
| St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Baseline, Week 52 | The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in participants with diseases of airways obstruction. Three component scores are calculated, where the higher the component result the worse the condition: Symptoms concerned with the effect of respiratory symptoms, their frequency and severity (range: 0-16.61) Activity concerned with activities that cause or are limited by breathlessness (range: 0-30.31) Impacts covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease (range: 0- 53.08) Total score summaries the impact of disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. |
| University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Changes From Baseline at Week 52 | Baseline, Week 52 | The UCSD-SOBQ is a respiratory questionnaire and it assesses dyspnea associated with activities of daily living (ADL). Participants indicate severity of SOB on a 6-point scale in 21 ADL. Three additional questions ask about fear of harm from overexertion, limitations and fear caused by SOB. A total score ranges from 0 to 120, with higher scores indicating greater impairment. |
| Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52 | Baseline up to Week 52 | — |
| Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52 | Baseline up to Week 52 | — |
| Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 | Baseline up to Week 52 | — |
| Percentage of Participants With Adverse Events | Baseline up to Week 52 + 28 days | — |
| Borg Scale Result at the End of the Test at Week 52 | Week 52 | The Borg Scale rates participant's level of perceived exertion during any activity from 0-10, with 0 being no effort at all and 10 being maximal exertion. |
| Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter | Baseline, Week 52 | — |
Countries
Belgium, Canada, Czechia, Egypt, Germany, Greece, Hungary, Israel, Italy, Netherlands, South Africa, Spain, Turkey (Türkiye)
Participant flow
Pre-assignment details
Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.
Participants by arm
| Arm | Count |
|---|---|
| Pirfenidone+Sildenafil Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks. | 88 |
| Pirfenidone+Placebo Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks. | 89 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 |
| Overall Study | Death | 28 | 36 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Lung Transplantation | 9 | 6 |
| Overall Study | Other | 1 | 3 |
| Overall Study | Participant ongoing in the study | 23 | 17 |
| Overall Study | Progressive Disease | 1 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 11 |
Baseline characteristics
| Characteristic | Pirfenidone+Placebo | Total | Pirfenidone+Sildenafil |
|---|---|---|---|
| Age, Continuous | 68.9 Years STANDARD_DEVIATION 7.1 | 68.6 Years STANDARD_DEVIATION 7.4 | 68.2 Years STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 79 Participants | 157 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 88 Participants | 173 Participants | 85 Participants |
| Sex: Female, Male Female | 24 Participants | 43 Participants | 19 Participants |
| Sex: Female, Male Male | 65 Participants | 134 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 88 | 36 / 89 |
| other Total, other adverse events | 53 / 88 | 58 / 89 |
| serious Total, serious adverse events | 54 / 88 | 55 / 89 |
Outcome results
Primary
Percentage of Participants With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause
Disease Progression defined as relative decline in 6-minute walking distance (6MWD) from baseline (defined as \>25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality.
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pirfenidone+Sildenafil | Percentage of Participants With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause | 72.7 Percentage of Participants |
| Pirfenidone+Placebo | Percentage of Participants With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause | 69.7 Percentage of Participants |
p-value: 0.652795% CI: [-11.3, 17.97]Chi-squared
Secondary
Borg Scale Result at the End of the Test at Week 52
The Borg Scale rates participant's level of perceived exertion during any activity from 0-10, with 0 being no effort at all and 10 being maximal exertion.
Time frame: Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Borg Scale Result at the End of the Test at Week 52 | 0.9 Points on Scale | Standard Deviation 3 |
| Pirfenidone+Placebo | Borg Scale Result at the End of the Test at Week 52 | 0.7 Points on Scale | Standard Deviation 3.24 |
Secondary
Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52 | -52.9 meters | Standard Deviation 121.07 |
| Pirfenidone+Placebo | Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52 | -40.8 meters | Standard Deviation 91.26 |
Secondary
Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52 | 110.1 pg/mL) | Standard Deviation 612.98 |
| Pirfenidone+Placebo | Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52 | 605.9 pg/mL) | Standard Deviation 1273.19 |
p-value: 0.564695% CI: [-920.03, 506.85]Linear Mixed Effects Model
Secondary
Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 | SpO2 before the test (at rest) | -0.5 Percentage | Standard Deviation 4.63 |
| Pirfenidone+Sildenafil | Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 | SpO2 lowest during the test | -3.4 Percentage | Standard Deviation 8.93 |
| Pirfenidone+Sildenafil | Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 | SpO2 after the test | 0.5 Percentage | Standard Deviation 9.97 |
| Pirfenidone+Placebo | Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 | SpO2 before the test (at rest) | -0.8 Percentage | Standard Deviation 3.77 |
| Pirfenidone+Placebo | Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 | SpO2 lowest during the test | 0.3 Percentage | Standard Deviation 5.27 |
| Pirfenidone+Placebo | Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 | SpO2 after the test | -2.3 Percentage | Standard Deviation 6.67 |
Secondary
Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52
Time frame: Baseline up to Week 52
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52 | 0.6 L | Standard Deviation 1.27 |
| Pirfenidone+Placebo | Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52 | 0.6 L | Standard Deviation 1.43 |
Secondary
Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO)
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO) | -2.918 Percentage Predicted | Standard Deviation 6.2296 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO) | -2.440 Percentage Predicted | Standard Deviation 8.282 |
Secondary
Change From Baseline to Week 52 in Forced Vital Capacity (FVC)
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Forced Vital Capacity (FVC) | -2.761 Percentage Predicted | Standard Deviation 7.8044 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Forced Vital Capacity (FVC) | -1.616 Percentage Predicted | Standard Deviation 11.1158 |
Secondary
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter | -0.05 cm | Standard Deviation 0.595 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter | -0.09 cm | Standard Deviation 0.54 |
Secondary
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF)
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF) | 1.22 Percentage | Standard Deviation 9.166 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF) | -0.85 Percentage | Standard Deviation 5.767 |
Secondary
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity | -0.014 m/s | Standard Deviation 0.6326 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity | 0.103 m/s | Standard Deviation 0.6699 |
Secondary
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs)
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs) | 2.0 mmHg | Standard Deviation 15.65 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs) | 3.6 mmHg | Standard Deviation 22.38 |
Secondary
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter | 0.462 cm | Standard Deviation 1.2305 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter | 0.095 cm | Standard Deviation 1.2875 |
Secondary
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE)
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE) | -0.204 cm | Standard Deviation 0.417 |
| Pirfenidone+Placebo | Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE) | -0.146 cm | Standard Deviation 0.4453 |
Secondary
Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52
The World Health Organisation (WHO) functional class system defines the severity of an participant's symptoms. Class II - Participants with Pulmonary Hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class III - Participants with Pulmonary Hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class IV - participants with pulmonary hypertension with inability to carry out any physical activity without symptoms. These participants manifest signs of right heart failure, breathlessness and /or fatigue, which may even be present at rest. Discomfort is increased by any physical activity.
Time frame: Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirfenidone+Sildenafil | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Class II | 19.3 Percentage |
| Pirfenidone+Sildenafil | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Class III | 33.0 Percentage |
| Pirfenidone+Sildenafil | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Class IV | 3.4 Percentage |
| Pirfenidone+Sildenafil | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Missing | 0 Percentage |
| Pirfenidone+Placebo | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Missing | 1.1 Percentage |
| Pirfenidone+Placebo | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Class II | 13.5 Percentage |
| Pirfenidone+Placebo | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Class IV | 1.1 Percentage |
| Pirfenidone+Placebo | Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 | Class III | 24.7 Percentage |
Secondary
Percentage of Participants With Adverse Events
Time frame: Baseline up to Week 52 + 28 days
Population: Participants with AEs that started or worsened on or after first intake of randomized treatment until last positive dose + 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pirfenidone+Sildenafil | Percentage of Participants With Adverse Events | 98.9 Percentage |
| Pirfenidone+Placebo | Percentage of Participants With Adverse Events | 93.3 Percentage |
Secondary
Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15%
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pirfenidone+Sildenafil | Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15% | 53.4 Percentage |
| Pirfenidone+Placebo | Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15% | 50.6 Percentage |
p-value: 0.704695% CI: [-12.13, 17.84]Chi-squared
Secondary
Percentage of Participants With Lung Transplantation
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pirfenidone+Sildenafil | Percentage of Participants With Lung Transplantation | 10.2 Percentage |
| Pirfenidone+Placebo | Percentage of Participants With Lung Transplantation | 6.7 Percentage |
Secondary
St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52
The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in participants with diseases of airways obstruction. Three component scores are calculated, where the higher the component result the worse the condition: Symptoms concerned with the effect of respiratory symptoms, their frequency and severity (range: 0-16.61) Activity concerned with activities that cause or are limited by breathlessness (range: 0-30.31) Impacts covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease (range: 0- 53.08) Total score summaries the impact of disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone+Sildenafil | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Total score | 6.149 Units on a scale | Standard Deviation 12.3407 |
| Pirfenidone+Sildenafil | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Symptoms component score | 2.498 Units on a scale | Standard Deviation 19.6074 |
| Pirfenidone+Sildenafil | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Activities component score | 3.997 Units on a scale | Standard Deviation 15.4341 |
| Pirfenidone+Sildenafil | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Impacts component score | 8.417 Units on a scale | Standard Deviation 15.004 |
| Pirfenidone+Placebo | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Impacts component score | 12.118 Units on a scale | Standard Deviation 15.3487 |
| Pirfenidone+Placebo | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Total score | 11.437 Units on a scale | Standard Deviation 12.5187 |
| Pirfenidone+Placebo | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Activities component score | 10.871 Units on a scale | Standard Deviation 14.5246 |
| Pirfenidone+Placebo | St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 | Symptoms component score | 8.261 Units on a scale | Standard Deviation 19.5558 |
p-value: 0.525595% CI: [-9.98, 2.36]ANCOVA
Secondary
Time to All-Cause Non-Elective Hospitalization
N.A. = non-calculable
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone+Sildenafil | Time to All-Cause Non-Elective Hospitalization | 47.57 Weeks |
| Pirfenidone+Placebo | Time to All-Cause Non-Elective Hospitalization | 49.86 Weeks |
p-value: 0.774895% CI: [0.7, 1.62]Log Rank
Secondary
Time to Death From Any Cause
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone+Sildenafil | Time to Death From Any Cause | NA Weeks |
| Pirfenidone+Placebo | Time to Death From Any Cause | NA Weeks |
p-value: 0.425895% CI: [0.38, 1.5]Log Rank
Secondary
Time to First Occurrence of Disease Progression
Disease Progression defined as relative decline in 6MWD from baseline (defined as \>25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality.
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone+Sildenafil | Time to First Occurrence of Disease Progression | 26.00 Weeks |
| Pirfenidone+Placebo | Time to First Occurrence of Disease Progression | 25.43 Weeks |
p-value: 0.756895% CI: [0.67, 1.34]Log Rank
Secondary
Time to First Occurrence of Relevant ≥15% Decline From Baseline in 6-minute Walking Distance (6MWD)
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone+Sildenafil | Time to First Occurrence of Relevant ≥15% Decline From Baseline in 6-minute Walking Distance (6MWD) | 39.00 Weeks |
| Pirfenidone+Placebo | Time to First Occurrence of Relevant ≥15% Decline From Baseline in 6-minute Walking Distance (6MWD) | 38.71 Weeks |
p-value: 0.75595% CI: [0.62, 1.41]Log Rank
Secondary
Time to Multiple Occurrence of Disease Progression Events
Disease Progression defined as relative decline in 6MWD from baseline (defined as \>25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. In case participant had more than one event as described in the endpoint definition the second, third etc event was counted as well for the calculation of the endpoint.
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone+Sildenafil | Time to Multiple Occurrence of Disease Progression Events | 20.57 Weeks |
| Pirfenidone+Placebo | Time to Multiple Occurrence of Disease Progression Events | 13.29 Weeks |
p-value: 0.37695% CI: [0.68, 1.15]Log Rank
Secondary
Time to Respiratory-Related Death
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone+Sildenafil | Time to Respiratory-Related Death | NA Weeks |
| Pirfenidone+Placebo | Time to Respiratory-Related Death | NA Weeks |
p-value: 0.316195% CI: [0.31, 1.47]Log Rank
Secondary
Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52
N.A. = non-calculable
Time frame: Baseline up to Week 52
Population: Participants with data available at week 52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone+Sildenafil | Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52 | 54.29 Weeks |
| Pirfenidone+Placebo | Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52 | NA Weeks |
p-value: 0.917495% CI: [0.65, 1.61]Log Rank
Secondary
University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Changes From Baseline at Week 52
The UCSD-SOBQ is a respiratory questionnaire and it assesses dyspnea associated with activities of daily living (ADL). Participants indicate severity of SOB on a 6-point scale in 21 ADL. Three additional questions ask about fear of harm from overexertion, limitations and fear caused by SOB. A total score ranges from 0 to 120, with higher scores indicating greater impairment.
Time frame: Baseline, Week 52
Population: Participants with data available at week 52 to calculate a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pirfenidone+Sildenafil | University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Changes From Baseline at Week 52 | 12.5 Points on scale | Standard Deviation 20.93 |
| Pirfenidone+Placebo | University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Changes From Baseline at Week 52 | 18.8 Points on scale | Standard Deviation 19.68 |
p-value: 0.426395% CI: [-18, 6]ANCOVA