Efficacy, Safety, and Tolerability Study of Pirfenidone in Combination With Sildenafil in Participants With Advanced Idiopathic Pulmonary Fibrosis (IPF) and Intermediate or High Probability of Group 3 Pulmonary Hypertension

Study Overview
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Brief Summary
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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.

Official Title
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A Phase IIb, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Sildenafil Added to Pirfenidone in Patients With Advanced Idiopathic Pulmonary Fibrosis and Intermediate or High Probability of Group 3 Pulmonary Hypertension

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: Pirfenidone
* Drug: Placebo
* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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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 Exclusion criteria based on pirfenidone reference safety information: 1. participants with a history of angioedema due to pirfenidone; 2. concomitant use of fluvoxamine Exclusion criteria based on sildenafil reference safety information: 1. co-administration with nitric oxide donors or organic nitrates, phosphodiesterase-5 (PDE5) inhibitors, guanylate cyclase stimulators, and most potent of the Cytochrome P450 3A4 (CYP3A4) inhibitors; 2. loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION); 3. use of an alpha-blocker; 4. participants with bleeding disorders or active peptic ulceration; 5. known hereditary degenerative retinal disorders such as retinitis pigmentosa; 6. galactose intolerance

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Pirfenidone + Placebo<br>Participants will receive pirfenidone along with placebo matched to sildenafil, orally, three times a day (TID) for 52 weeks. | Drug: Pirfenidone<br>* Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.<br>* Other names: Esbriet, RO0220912;Drug: Placebo<br>* Placebo matched with sildenafil.<br>|
| Experimental: Pirfenidone + Sildenafil<br>Participants will receive pirfenidone along with sildenafil, orally, TID for 52 weeks. | Drug: Pirfenidone<br>* Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.<br>* Other names: Esbriet, RO0220912;Drug: Sildenafil<br>* Sildenafil will be given as 20 mg, TID.<br>* Other names: RO0280296;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Week 52 | 
| 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. | Baseline up to Week 52 | 
| 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 | N.A. = non-calculable | Baseline up to Week 52 | 
| Time to All-Cause Non-Elective Hospitalization | N.A. = non-calculable | Baseline up to Week 52 | 
| Time to Death From Any Cause |  | Baseline up to Week 52 | 
| 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 | 
| Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter |  | Baseline, Week 52 | 
| 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 | 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. | Week 52 | 
| 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 | 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. | Baseline, Week 52 | 
| 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. | Baseline, Week 52 | 
| 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 | 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. | Week 52 |