Clinical trial NCT02951429: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-11-01
Enrollment: 177
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Baseline up to Week 52
Secondary outcomes:
measure: Time to First Occurrence of Disease Progression
timeFrame: Baseline up to Week 52
measure: Time to Multiple Occurrence of Disease Progression Events
timeFrame: Baseline up to Week 52
measure: Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15%
timeFrame: Baseline up to Week 52
measure: Time to First Occurrence of Relevant ≥15% Decline From Baseline in 6-minute Walking Distance (6MWD)
timeFrame: Baseline up to Week 52
measure: Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52
timeFrame: Baseline up to Week 52
measure: Time to All-Cause Non-Elective Hospitalization
timeFrame: Baseline up to Week 52
measure: Time to Death From Any Cause
timeFrame: Baseline up to Week 52
measure: Percentage of Participants With Lung Transplantation
timeFrame: Baseline up to Week 52
measure: Time to Respiratory-Related Death
timeFrame: Baseline up to Week 52
measure: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs)
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE)
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF)
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO)
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Forced Vital Capacity (FVC)
timeFrame: Baseline, Week 52
measure: Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52
timeFrame: Week 52
measure: Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52
timeFrame: Baseline, Week 52
measure: St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52
timeFrame: Baseline, Week 52
measure: University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Changes From Baseline at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52
timeFrame: Baseline up to Week 52
measure: Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52
timeFrame: Baseline up to Week 52
measure: Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52
timeFrame: Baseline up to Week 52
measure: Percentage of Participants With Adverse Events
timeFrame: Baseline up to Week 52 + 28 days
measure: Borg Scale Result at the End of the Test at Week 52
timeFrame: Week 52
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: ULB Hôpital Erasme
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Liège
country: Belgium
facility: CHU Sart-Tilman
city: Mont-godinne
country: Belgium
facility: CHU UCL Mont-Godinne
city: Kingston
country: Canada
facility: Hotel Dieu Hospital
state: Ontario
city: Montreal
country: Canada
facility: CHUM Hôpital Notre-Dame
state: Quebec
city: Ste. Foy
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec (Hôpital Laval)
state: Quebec
city: Praha 4 - Krc
country: Czechia
facility: Thomayerova nemocnice; Pneumologicka klinika 1.LF UK TN
city: Alexandria
country: Egypt
facility: Clinical Research Center (CRC), Faculty of Medicine, Alexandria University
city: Cairo
country: Egypt
facility: Kasr El-Aini-Chest Unit; Department 3-Chest Unit
city: Cairo
country: Egypt
facility: Ain Shams University Hospital-Chest unit; Chest unit
city: Coswig
country: Germany
facility: Fachkrankenhaus Coswig GmbH Zentrum f.Pneumologie Beatmungsmedizin Thorax-u.Gefäßchirurgie
city: Donaustauf
country: Germany
facility: Klinik Donaustauf Zentrum für Pneumologie
city: Essen
country: Germany
facility: Ruhrlandklinik Lungenzentrum der UNI Essen Abt.Pneumologie-Allergologie
city: Fulda
country: Germany
facility: Klinikum Fulda gAG; Universitätsmedizin Marburg, Campus Fulda
city: Gießen
country: Germany
facility: Universitätsklinikum Standort Gießen Medizinische Klinik II u. Poliklinik Innere Med./Pneumologie
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg gGmbH
city: Immenhausen
country: Germany
facility: Fachklinik für Lungenerkrankungen
city: München
country: Germany
facility: Klinikum der Universität München; Campus Großhadern; Med. Klinik und Poliklinik V
city: Athens
country: Greece
facility: Sotiria Hospital for Diseases of the Chest, Academic Department of Pneumonology
city: Chaidari
country: Greece
facility: University General Hospital of Athens "Attikon", B' University Pulmonary Clinic
city: Heraklio
country: Greece
facility: University General Hospital of Heraklio, Pulmonary Clinic
city: Budapest
country: Hungary
facility: Semmelweis Egyetem X; Pulmonologiai Klinika
city: Budapest
country: Hungary
facility: Orszagos Koranyi TBC es Pulmonologiai Intezet
city: Beer Sheba
country: Israel
facility: Soroka; Pulmonary Clinic
city: Haifa
country: Israel
facility: Carmel Medical Center; Pulmonary Institute
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center; Pulmonary Inst.
city: Jerusalem
country: Israel
facility: Hadassah Medical Center; Pulmonary Institute
city: Kfar Saba
country: Israel
facility: Meir Medical Center; Pulmonary Dept
city: Petach Tikva
country: Israel
facility: Beilinson Medical Center; Pulmonary Inst.
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Forlì
country: Italy
facility: Ospedale Morgagni-Pierantoni; U.O. Pneumologia
state: Emilia-Romagna
city: Modena
country: Italy
facility: A.O. Universitaria Policlinico Di Modena; DIP. Malattie Dell'apparato Respiratorio
state: Emilia-Romagna
city: Milano
country: Italy
facility: Ospedale San Giuseppe; U.O. di Pneumologia
state: Lombardia
city: Monza
country: Italy
facility: ASST DI MONZA; U O Clinica Pneumologica
state: Lombardia
city: Foggia
country: Italy
facility: A.O.U. Ospedali Riuniti Di Foggia-Ospedale D'avanzo; Malattie Dell'apparato Respiratorio IV
state: Puglia
city: Catania
country: Italy
facility: A.O.U. Policlinico Vittorio Emanuele; Centro per la cura delle Malattie Rare del Polmone
state: Sicilia
city: Siena
country: Italy
facility: A.O. Univ. Senese Policlinico S. Maria alle Scotte; UOC Malattie Resepiratorie e Trapianto Polmonare
state: Toscana
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova; Dip. Scienze Cardiologiche Toraciche Vascolari-UOC Pneumologia
state: Veneto
city: Amsterdam
country: Netherlands
facility: Vu Medisch Centrum; Afdeling Longziekten
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute; Lung Clinical Research
city: Parktown West
country: South Africa
facility: Milpark Hospital
city: Parow
country: South Africa
facility: University of Stellenbosch; Respiratory Research
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge ; Servicio de Neumologia
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla; Servicio de neumologia
state: Cantabria
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda; Servicio de Neumología
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Clinic I provincial; Servicio de Neumologia
city: Valencia
country: Spain
facility: Hospital Universitario la Fe; Servicio de Neumologia
city: Ankara
country: Turkey
facility: Ankara Uni Faculty of Medicine; Chest Diseases
city: Bursa
country: Turkey
facility: Uludag University; Pulmonology and Allergy Department
city: Istanbul
country: Turkey
facility: Yedikule Gogus Hastaliklari ve Gogus Cerrahisi EAH;Gogus Hastaliklari
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Capa Tıp Fakültesi; Gogus Hastalıkları Anabilim dalı
city: İzmir
country: Turkey
facility: Ege Universitesi Tıp Fakültesi; Gögüs Hastalıkları Bilim Dalı
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.