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

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

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.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: Pirfenidone; Drug: Placebo; Drug: Sildenafil

• Study Type: Interventional
• Enrollment (Actual): 177
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • ULB Hôpital Erasme
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires St-Luc
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
  • Liège, Belgium, 4000
    • CHU Sart-Tilman
  • Mont-godinne, Belgium, 5530
    • CHU UCL Mont-Godinne
• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Hotel Dieu Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM Hopital Notre-Dame
    • Ste. Foy, Quebec, Canada, G1V 4G5
      • Institut universitaire de cardiologie et de pneumologie de Québec (Hôpital Laval)
• Czechia
  • Praha 4 - Krc, Czechia, 140 59
    • Thomayerova nemocnice; Pneumologicka klinika 1.LF UK TN
• Egypt
  • Alexandria, Egypt, 21131
    • Clinical Research Center (CRC), Faculty of Medicine, Alexandria University
  • Cairo, Egypt, 11562
    • Kasr El-Aini-Chest Unit; Department 3-Chest Unit
  • Cairo, Egypt, 11566
    • Ain Shams University Hospital-Chest unit; Chest unit
• Germany
  • Coswig, Germany, 01640
    • Fachkrankenhaus Coswig GmbH Zentrum f.Pneumologie Beatmungsmedizin Thorax-u.Gefäßchirurgie
  • Donaustauf, Germany, 93093
    • Klinik Donaustauf Zentrum für Pneumologie
  • Essen, Germany, 45239
    • Ruhrlandklinik Lungenzentrum der UNI Essen Abt.Pneumologie-Allergologie
  • Fulda, Germany, 36043
    • Klinikum Fulda gAG; Universitätsmedizin Marburg, Campus Fulda
  • Gießen, Germany, 35392
    • Universitätsklinikum Standort Gießen Medizinische Klinik II u. Poliklinik Innere Med./Pneumologie
  • Heidelberg, Germany, 69126
    • Thoraxklinik Heidelberg gGmbH
  • Immenhausen, Germany, 34376
    • Fachklinik für Lungenerkrankungen
  • München, Germany, 81377
    • Klinikum der Universität München; Campus Großhadern; Med. Klinik und Poliklinik V
• Greece
  • Athens, Greece, 115 27
    • Sotiria Hospital for Diseases of the Chest, Academic Department of Pneumonology
  • Chaidari, Greece, 124 62
    • University General Hospital of Athens "Attikon", B' University Pulmonary Clinic
  • Heraklio, Greece, 711 10
    • University General Hospital of Heraklio, Pulmonary Clinic
• Hungary
  • Budapest, Hungary, 1121
    • Orszagos Koranyi TBC es Pulmonologiai Intezet
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem X; Pulmonologiai Klinika
• Israel
  • Beer Sheba, Israel, 8410101
    • Soroka; Pulmonary Clinic
  • Haifa, Israel, 3436212
    • Carmel Medical Center; Pulmonary Institute
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center; Pulmonary Inst.
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center; Pulmonary Institute
  • Kfar Saba, Israel, 4428164
    • Meir Medical Center; Pulmonary Dept
  • Petach Tikva, Israel, 4941492
    • Beilinson Medical Center; Pulmonary Inst.
  • Rehovot, Israel, 7610001
    • Kaplan Medical Center
• Italy
  • Emilia-Romagna
    • Forlì, Emilia-Romagna, Italy, 47121
      • Ospedale Morgagni-Pierantoni; U.O. Pneumologia
    • Modena, Emilia-Romagna, Italy, 41124
      • A.O. Universitaria Policlinico Di Modena; DIP. Malattie Dell'apparato Respiratorio
  • Lombardia
    • Milano, Lombardia, Italy, 20123
      • Ospedale San Giuseppe; U.O. di Pneumologia
    • Monza, Lombardia, Italy, 20900
      • ASST DI MONZA; U O Clinica Pneumologica
  • Puglia
    • Foggia, Puglia, Italy, 71100
      • A.O.U. Ospedali Riuniti Di Foggia-Ospedale D'avanzo; Malattie Dell'apparato Respiratorio IV
  • Sicilia
    • Catania, Sicilia, Italy, 95123
      • A.O.U. Policlinico Vittorio Emanuele; Centro per la cura delle Malattie Rare del Polmone
  • Toscana
    • Siena, Toscana, Italy, 53100
      • A.O. Univ. Senese Policlinico S. Maria alle Scotte; UOC Malattie Resepiratorie e Trapianto Polmonare
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Azienda Ospedaliera di Padova; Dip. Scienze Cardiologiche Toraciche Vascolari-UOC Pneumologia
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Vu Medisch Centrum; Afdeling Longziekten
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
• South Africa
  • Cape Town, South Africa, 7700
    • University of Cape Town Lung Institute; Lung Clinical Research
  • Parktown West, South Africa, 2196
    • Milpark Hospital
  • Parow, South Africa, 7505
    • University of Stellenbosch; Respiratory Research
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic I provincial; Servicio de Neumologia
  • Valencia, Spain, 46009
    • Hospital Universitario la Fe; Servicio de Neumologia
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08097
      • Hospital Universitari de Bellvitge ; Servicio de Neumologia
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital Universitario Marques de Valdecilla; Servicio de neumologia
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro Majadahonda; Servicio de Neumología
• Turkey
  • Ankara, Turkey, 06100
    • Ankara Uni Faculty of Medicine; Chest Diseases
  • Bursa, Turkey, 16059
    • Uludag University; Pulmonology and Allergy Department
  • Istanbul, Turkey, 34020
    • Yedikule Gogus Hastaliklari ve Gogus Cerrahisi EAH;Gogus Hastaliklari
  • Istanbul, Turkey, 34093
    • Istanbul Universitesi Capa Tıp Fakültesi; Gogus Hastalıkları Anabilim dalı
  • İzmir, Turkey, 35040
    • Ege Universitesi Tıp Fakültesi; Gögüs Hastalıkları Bilim Dalı

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Behr J, Nathan SD, Wuyts WA, Mogulkoc Bishop N, Bouros DE, Antoniou K, Guiot J, Kramer MR, Kirchgaessler KU, Bengus M, Gilberg F, Perjesi A, Harari S, Wells AU. Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021 Jan;9(1):85-95. doi: 10.1016/S2213-2600(20)30356-8. Epub 2020 Aug 18. Erratum In: Lancet Respir Med. 2021 Apr;9(4):e38.

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2016
• Primary Completion (Actual): September 26, 2019
• Study Completion (Actual): August 22, 2020

Study Registration Dates

• First Submitted: October 28, 2016
• First Submitted That Met QC Criteria: October 28, 2016
• First Posted (Estimate): November 1, 2016

Study Record Updates

• Last Update Posted (Actual): November 12, 2020
• Last Update Submitted That Met QC Criteria: October 20, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Hypertension; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Hypertension, Pulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Peripheral Nervous System Agents; Urological Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Pirfenidone; Sildenafil Citrate
• Other Study ID Numbers: MA29957; 2015-005131-40 (EudraCT Number)