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

Idiopathic Pulmonary Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02951429
• Other study ID #: MA29957
• Secondary ID: 2015-005131-40
• Status: Completed
• Phase: Phase 2
• Start date: December 31, 2016
• Est. completion date: August 22, 2020

Study information

• Verified date: October 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 177
• Est. completion date: August 22, 2020
• Est. primary completion date: September 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Fibrosis
• Hypertension
• Hypertension, Pulmonary
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• Pirfenidone
Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.
• Placebo
Placebo matched with sildenafil.
• Sildenafil
Sildenafil will be given as 20 mg, TID.

Locations

Country	Name	City	State
Belgium	ULB Hôpital Erasme	Brussels
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	CHU Sart-Tilman	Liège
Belgium	CHU UCL Mont-Godinne	Mont-godinne
Canada	Hotel Dieu Hospital	Kingston	Ontario
Canada	CHUM Hôpital Notre-Dame	Montreal	Quebec
Canada	Institut universitaire de cardiologie et de pneumologie de Québec (Hôpital Laval)	Ste. Foy	Quebec
Czechia	Thomayerova nemocnice; Pneumologicka klinika 1.LF UK TN	Praha 4 - Krc
Egypt	Clinical Research Center (CRC), Faculty of Medicine, Alexandria University	Alexandria
Egypt	Ain Shams University Hospital-Chest unit; Chest unit	Cairo
Egypt	Kasr El-Aini-Chest Unit; Department 3-Chest Unit	Cairo
Germany	Fachkrankenhaus Coswig GmbH Zentrum f.Pneumologie Beatmungsmedizin Thorax-u.Gefäßchirurgie	Coswig
Germany	Klinik Donaustauf Zentrum für Pneumologie	Donaustauf
Germany	Ruhrlandklinik Lungenzentrum der UNI Essen Abt.Pneumologie-Allergologie	Essen
Germany	Klinikum Fulda gAG; Universitätsmedizin Marburg, Campus Fulda	Fulda
Germany	Universitätsklinikum Standort Gießen Medizinische Klinik II u. Poliklinik Innere Med./Pneumologie	Gießen
Germany	Thoraxklinik Heidelberg gGmbH	Heidelberg
Germany	Fachklinik für Lungenerkrankungen	Immenhausen
Germany	Klinikum der Universität München; Campus Großhadern; Med. Klinik und Poliklinik V	München
Greece	Sotiria Hospital for Diseases of the Chest, Academic Department of Pneumonology	Athens
Greece	University General Hospital of Athens "Attikon", B' University Pulmonary Clinic	Chaidari
Greece	University General Hospital of Heraklio, Pulmonary Clinic	Heraklio
Hungary	Orszagos Koranyi TBC es Pulmonologiai Intezet	Budapest
Hungary	Semmelweis Egyetem X; Pulmonologiai Klinika	Budapest
Israel	Soroka; Pulmonary Clinic	Beer Sheba
Israel	Carmel Medical Center; Pulmonary Institute	Haifa
Israel	Hadassah Medical Center; Pulmonary Institute	Jerusalem
Israel	Shaare Zedek Medical Center; Pulmonary Inst.	Jerusalem
Israel	Meir Medical Center; Pulmonary Dept	Kfar Saba
Israel	Beilinson Medical Center; Pulmonary Inst.	Petach Tikva
Israel	Kaplan Medical Center	Rehovot
Italy	A.O.U. Policlinico Vittorio Emanuele; Centro per la cura delle Malattie Rare del Polmone	Catania	Sicilia
Italy	A.O.U. Ospedali Riuniti Di Foggia-Ospedale D'avanzo; Malattie Dell'apparato Respiratorio IV	Foggia	Puglia
Italy	Ospedale Morgagni-Pierantoni; U.O. Pneumologia	Forlì	Emilia-Romagna
Italy	Ospedale San Giuseppe; U.O. di Pneumologia	Milano	Lombardia
Italy	A.O. Universitaria Policlinico Di Modena; DIP. Malattie Dell'apparato Respiratorio	Modena	Emilia-Romagna
Italy	ASST DI MONZA; U O Clinica Pneumologica	Monza	Lombardia
Italy	Azienda Ospedaliera di Padova; Dip. Scienze Cardiologiche Toraciche Vascolari-UOC Pneumologia	Padova	Veneto
Italy	A.O. Univ. Senese Policlinico S. Maria alle Scotte; UOC Malattie Resepiratorie e Trapianto Polmonare	Siena	Toscana
Netherlands	Vu Medisch Centrum; Afdeling Longziekten	Amsterdam
Netherlands	Erasmus MC	Rotterdam
South Africa	University of Cape Town Lung Institute; Lung Clinical Research	Cape Town
South Africa	Milpark Hospital	Parktown West
South Africa	University of Stellenbosch; Respiratory Research	Parow
Spain	Hospital Clinic I provincial; Servicio de Neumologia	Barcelona
Spain	Hospital Universitari de Bellvitge ; Servicio de Neumologia	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario Puerta de Hierro Majadahonda; Servicio de Neumología	Majadahonda	Madrid
Spain	Hospital Universitario Marques de Valdecilla; Servicio de neumologia	Santander	Cantabria
Spain	Hospital Universitario la Fe; Servicio de Neumologia	Valencia
Turkey	Ankara Uni Faculty of Medicine; Chest Diseases	Ankara
Turkey	Uludag University; Pulmonology and Allergy Department	Bursa
Turkey	Istanbul Universitesi Capa Tip Fakültesi; Gogus Hastaliklari Anabilim dali	Istanbul
Turkey	Yedikule Gogus Hastaliklari ve Gogus Cerrahisi EAH;Gogus Hastaliklari	Istanbul
Turkey	Ege Universitesi Tip Fakültesi; Gögüs Hastaliklari Bilim Dali	Izmir

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Belgium,  Canada,  Czechia,  Egypt,  Germany,  Greece,  Hungary,  Israel,  Italy,  Netherlands,  South Africa,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline up to Week 52
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.	Baseline up to Week 52
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.	Baseline up to Week 52
Secondary	Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15%		Baseline up to Week 52
Secondary	Time to First Occurrence of Relevant =15% Decline From Baseline in 6-minute Walking Distance (6MWD)		Baseline up to Week 52
Secondary	Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52	N.A. = non-calculable	Baseline up to Week 52
Secondary	Time to All-Cause Non-Elective Hospitalization	N.A. = non-calculable	Baseline up to Week 52
Secondary	Time to Death From Any Cause		Baseline up to Week 52
Secondary	Percentage of Participants With Lung Transplantation		Baseline up to Week 52
Secondary	Time to Respiratory-Related Death		Baseline up to Week 52
Secondary	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity		Baseline, Week 52
Secondary	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs)		Baseline, Week 52
Secondary	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE)		Baseline, Week 52
Secondary	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter		Baseline, Week 52
Secondary	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter		Baseline, Week 52
Secondary	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF)		Baseline, Week 52
Secondary	Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO)		Baseline, Week 52
Secondary	Change From Baseline to Week 52 in Forced Vital Capacity (FVC)		Baseline, Week 52
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.	Week 52
Secondary	Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52		Baseline, Week 52
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.	Baseline, Week 52
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.	Baseline, Week 52
Secondary	Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52		Baseline up to Week 52
Secondary	Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52		Baseline up to Week 52
Secondary	Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52		Baseline up to Week 52
Secondary	Percentage of Participants With Adverse Events		Baseline up to Week 52 + 28 days
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.	Week 52