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

Phase 2

Completed

Conditions: Idiopathic Pulmonary Fibrosis

Interventions: Drug: Pirfenidone
Drug: Placebo
Drug: Sildenafil

Registration Number: NCT02951429

Lead Sponsor: Hoffmann-La Roche

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 177

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pirfenidone + Placebo	Placebo	Participants will receive pirfenidone along with placebo matched to sildenafil, orally, three times a day (TID) for 52 weeks.
Pirfenidone + Placebo	Pirfenidone	Participants will receive pirfenidone along with placebo matched to sildenafil, orally, three times a day (TID) for 52 weeks.
Pirfenidone + Sildenafil	Pirfenidone	Participants will receive pirfenidone along with sildenafil, orally, TID for 52 weeks.
Pirfenidone + Sildenafil	Sildenafil	Participants will receive pirfenidone along with sildenafil, orally, TID for 52 weeks.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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
Time to All-Cause Non-Elective Hospitalization	Baseline up to Week 52	N.A. = non-calculable
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: 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
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.
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter	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
Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter	Baseline, Week 52
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.

Trial Locations

Locations (56): ULB Hôpital Erasme
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Brussels, Belgium
Cliniques Universitaires St-Luc
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Bruxelles, Belgium
UZ Antwerpen
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Edegem, Belgium
UZ Leuven Gasthuisberg
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Leuven, Belgium
CHU Sart-Tilman
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Liège, Belgium
CHU UCL Mont-Godinne
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Mont-godinne, Belgium
Hotel Dieu Hospital
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Kingston, Ontario, Canada
CHUM Hôpital Notre-Dame
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Montreal, Quebec, Canada
Institut universitaire de cardiologie et de pneumologie de Québec (Hôpital Laval)
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Ste. Foy, Quebec, Canada
Thomayerova nemocnice; Pneumologicka klinika 1.LF UK TN
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Praha 4 - Krc, Czechia
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ULB Hôpital Erasme
🇧🇪Brussels, Belgium