Clinical trial NCT03099187: A Study of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing Interstitial Lung Disease
Official title: Multicenter, International, Double-blind, Two-Arm, Randomized, Placebo-controlled Phase II Trial of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing ILD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Diseases, Interstitial
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-04-04
Enrollment: 253
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of pirfenidone in participants with fibrosing interstitial lung disease (ILD) who cannot be classified with moderate or high confidence into any other category of fibrosing ILD by multidisciplinary team (MDT) review ("unclassifiable" ILD).

Detailed description: Study participants will be randomised to receive 801 mg pirfenidone or placebo three times daily for 24 weeks. The efficacy of pirfenidone versus placebo will be assessed by daily measurement of forced vital capacity using a handheld spirometer over the treatment period. Additionally, the study will assess the efficacy and safety of pirfenidone with and without concomitant mycophenolate mofetil treatment and in study participants with or without interstitial pneumonia with autoimmune features (IPAF). All study participants who attend the follow-up visit at Week 28 will be offered the opportunity to receive open-label pirfenidone within the trial protocol. In order to maintain blinding of the controlled period of the study, all study participants will discontinue treatment by Week 24 and return for a follow-up visit 4 weeks later. Study participants eligible to participate in the single-arm 12-month extension will be initiated on open-label pirfenidone during this visit (re-starting the dose titration from one capsule three times daily \[TID\]). During the long-term extension period, study participants will be monitored for safety, initially at monthly visits during the first 6 months and thereafter approximately every 3 months. A final follow-up visit will take place 4 weeks after the last dose of pirfenidone is taken.

Eligibility criteria: Inclusion Criteria:

* Age \>= 18-85 years
* Confirmed fibrosing ILD which, following multidisciplinary team review, cannot be classified with either high or moderate confidence as a specific idiopathic interstitial pneumonia or other defined ILD
* Progressive disease as considered by the investigator as participants deterioration within the last 6 months, which is defined as a rate of decline in forced vital capacity (FVC) \>5% or a significant symptomatic worsening not due to cardiac, pulmonary vascular or other causes
* Extent of fibrosis \>10% on high-resolution computed tomography
* Forced vital capacity \>= 45% of predicted value
* Diffusing capacity of the lung for carbon monoxide (DLco) \>= 30% of predicted value
* Forced expiratory volume in 1 second/FVC ratio \>= 0.7
* Able to do 6-minute walk distance (6MWD) \>= 150 meters
* For women of childbearing potential: agreement to remain abstinent or use a non-hormonal or hormonal contraceptive method with a failure rate of \< 1% per year during the treatment period and for at least 90 days after the last dose of pirfenidone
* For men, agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria:

* Diagnosis with moderate or high confidence of nonspecific interstitial pneumonia and any ILD with an identifiable cause such as connective tissue disease-ILD, chronic hypersensitivity pneumonitis, or others
* Diagnosis of idiopathic pulmonary fibrosis independent of the confidence level
* History of unstable angina or myocardial infarction during the previous 6 months
* Treatment with high dose systemic corticosteroids, or any immunosuppressant other than mycophenolate mofetil/acid (MMF), at any time within the 4 weeks of the screening period. Participants being treated with MMF should be on a stable dose that is expected to remain stable throughout the trial and was started at least 3 months prior to screening
* Participants previously treated with pirfenidone or nintedanib
* Participants treated with N-acetyl-cysteine for fibrotic lung disease, at any time within the 4 weeks of the screening period
* Drug treatment for any type of pulmonary hypertension
* Participation in a trial of an investigational medicinal product within the last 4 weeks
* Significant other organ co-morbidity including hepatic or renal impairment
* Predicted life expectancy \< 12 months or on an active transplant waiting list
* Use of any tobacco product in the 12 weeks prior to the start of screening, or any unwillingness to abstain from their use through to the Follow-up Visit
* Illicit drug or alcohol abuse within 12 months prior to screening
* Planned major surgery during the trial
* Hypersensitivity to the active substance or to any of the excipients of pirfenidone
* History of angioedema
* Concomitant use of fluvoxamine
* Clinical evidence of any active infection
* Any history of hepatic impairment, elevation of transaminase enzymes, or liver function test results as: Total bilirubin above the upper limit of normal (ULN), Aspartate aminotransferase or alanine aminotransferase \>1.5 × ULN, and Alkaline phosphatase \>2.0 × ULN
* Creatinine clearance \< 30 milliliter (mL) per minute, calculated using the Cockcroft-Gault formula
* Any serious medical condition, clinically significant abnormality on an Electrocardiogram (ECG) at screening, or laboratory test results
* An ECG with a heart rate corrected QT interval using Fridericia's formula as \>= 500 milliseconds at screening, or a family or personal history of long QT syndrome

Primary outcomes:
measure: Rate of Decline in Forced Vital Capacity (FVC) Over the 24-week Double-blind Treatment Period
timeFrame: Up to Week 24
Secondary outcomes:
measure: Change in Percent Predicted FVC
timeFrame: Baseline (Day 1) to Week 24
measure: Change in FVC
timeFrame: Baseline (Day 1) to Week 24
measure: Categorical Change in FVC of >5%
timeFrame: Baseline (Day 1) to Week 24
measure: Categorical Change in FVC of >10%
timeFrame: Baseline (Day 1) to Week 24
measure: Change in Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLco)
timeFrame: Baseline (Day 1) to Week 24
measure: Change in 6-minute Walk Distance (6MWD)
timeFrame: Baseline (Day 1) to Week 24
measure: Change in University of California, San Diego-Shortness of Breath Questionnaire Score
timeFrame: Baseline (Day 1) to Week 24
measure: Change in Score in Leicester Cough Questionnaire Score
timeFrame: Baseline (Day 1) to Week 24
measure: Change in Cough Visual Analog Scale (VAS) Score
timeFrame: Baseline (Day 1) to Week 24
measure: Change in Total and Sub-scores of the Saint George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline (Day 1) to Week 24
measure: Number of Participants With Non-elective Hospitalization, Both Respiratory and All Cause
timeFrame: Baseline (Day 1) to Week 24
measure: Percentage of Participants With Investigator-reported Acute Exacerbations
timeFrame: Baseline (Day 1) to Week 24
measure: Time to First Investigator-reported Acute Exacerbations
timeFrame: Baseline (Day 1) to Week 24
measure: Progression-free Survival (PFS)
timeFrame: Baseline (Day 1) to Week 24
measure: Progression-free Survival (PFS)
timeFrame: Baseline (Day 1) to Week 24
measure: Time to Death From Any Cause
timeFrame: Baseline (Day 1) to Week 24
measure: Time to Death From Respiratory Diseases
timeFrame: Baseline (Day 1) to Week 24
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Baseline (Day 1) to Week 28
measure: Number of Participants With Dose Reductions and Treatment Interruptions During the Double-Blind Period
timeFrame: From administration of the first dose of study drug to Week 24
measure: Number of Participants With Dose Reductions and Treatment Interruptions During the 12-month Safety Follow-up
timeFrame: From the Follow-up Visit at Week 28 through the follow-up period of 12 Months
measure: Number of Participants Withdrawn From Trial Treatment or Trial Discontinuations During the Double-Blind Period
timeFrame: Baseline (Day 1) to Week 24
measure: Number of Participants Withdrawn From Trial Treatment or Trial Discontinuations During the 12-month Safety Follow-up
timeFrame: From the Follow-up Visit at Week 28 through the follow-up period of 12 Months
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital; Respiratory Department; Respiratory Department
state: New South Wales
city: Nundah
country: Australia
facility: Lung Research Queensland
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital, Department of Respiratory and Sleep Medicine
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital; Respiratory Clinical Trials Unit, Thoracic Medicine
state: South Australia
city: Heidelberg
country: Australia
facility: Respiratory Department
state: Victoria
city: Prahan
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital; Advanced Lung Disease Unit
state: Western Australia
city: Brussels
country: Belgium
facility: ULB Hôpital Erasme
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Vancouver
country: Canada
facility: Pacifica Lung Research Center/St. Paul's Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Brno
country: Czechia
facility: Fakultni Nemocnice Brno-Bohunice; Klinika Tuberkulozy A Respiracnich Chorob
city: Jihlava
country: Czechia
facility: Nemocnice Jihlava
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc; Pneumologicka klinika
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze; I. klinika tuberkulozy a respiracnich nemoci
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital; Lungesygdomme, Forskning
city: Hellerup
country: Denmark
facility: Gentofte Hospital, Lungemedicinsk Afdeling
city: Odense C
country: Denmark
facility: Odense Universitetshospital, Lungemedicinsk Afdeling J
city: Bad Berka
country: Germany
facility: Zentralklinik Bad Berka GmbH; Pneumologie
city: Berlin
country: Germany
facility: Evang. Lungenklinik Berlin Klinik für Pneumologie
city: Gießen
country: Germany
facility: Klinik der Justus-Liebig-Universität; Innere Medizin
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg gGmbH
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: Dublin
country: Ireland
facility: Mater Misericordiae University hospital
city: Dublin
country: Ireland
facility: St Vincents University Hospital
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: Milano
country: Italy
facility: Ospedale San Giuseppe; U.O. di Pneumologia
state: Lombardia
city: Torrette Di Ancona
country: Italy
facility: A.O.U. Ospedali Riuniti Umberto I -G.M. Lancisi-G. Salesi Ancona; SOD Pneumologia
state: Marche
city: Orbassano (TO)
country: Italy
facility: A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone
state: Piemonte
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi; SOD Pneumologia e Fisiopatologia Toracico Polmonare
state: Toscana
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne;Klinika Alergologii i Pneumonologii
city: Lodz
country: Poland
facility: Uniwersytecki Szpital Kliniczny Nr 1 im.N.Barlickiego Oddzial Kliniczny Pneumonologii i Alergologii
city: Warszawa
country: Poland
facility: Instytut Gruźlicy i Chorób Płuc, I Klinika Chorób Płuc
city: Aveiro
country: Portugal
facility: Hospital Infante D. Pedro; Servico de Pneumologia
city: Coimbra
country: Portugal
facility: HUC; Servico de Pneumologia A
city: Porto
country: Portugal
facility: Hospital de Sao Joao; Servico de Pneumologia
city: Vila Nova De Gaia
country: Portugal
facility: CHVNG/E_Unidade 1; Servico de Pneumologia
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: Madrid
country: Spain
facility: Hospital Universitario La Princesa; Servicio de Neumologia
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos - Servicio de Neumologia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Neumologia
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: Southmead Hospital; Respiratory Department
city: Cambridge
country: United Kingdom
facility: Papworth Hospital NHS Foundation Trust; Respiratory Department
city: Edinburgh
country: United Kingdom
facility: Edinburgh Royal Infirmary; Respiratory Department
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital (Wonford)
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
city: London
country: United Kingdom
facility: University College London Hospital; Respiratory Medicine
city: London
country: United Kingdom
facility: Royal Brompton Hospital; Respiratory Department
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital; North West Lung Research Centre
city: Sheffield
country: United Kingdom
facility: Northern General Hospital
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
city: Stoke on Trent
country: United Kingdom
facility: Royal Stoke University Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Molina-Molina M, Kreuter M, Cottin V, Corte TJ, Gilberg F, Kirchgaessler KU, Axmann J, Maher TM. Efficacy of Pirfenidone vs. Placebo in Unclassifiable Interstitial Lung Disease, by Surgical Lung Biopsy Status: Data From a post-hoc Analysis. Front Med (Lausanne). 2022 Jun 17;9:897102. doi: 10.3389/fmed.2022.897102. eCollection 2022.
citation: Kreuter M, Maher TM, Corte TJ, Molina-Molina M, Axmann J, Gilberg F, Kirchgaessler KU, Cottin V. Pirfenidone in Unclassifiable Interstitial Lung Disease: A Subgroup Analysis by Concomitant Mycophenolate Mofetil and/or Previous Corticosteroid Use. Adv Ther. 2022 Feb;39(2):1081-1095. doi: 10.1007/s12325-021-02009-w. Epub 2021 Dec 22.
citation: Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, Axmann J, Kirchgaessler KU, Samara K, Gilberg F, Cottin V. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020 Feb;8(2):147-157. doi: 10.1016/S2213-2600(19)30341-8. Epub 2019 Sep 29.
citation: Graney BA, Fischer A. Interstitial Pneumonia with Autoimmune Features. Ann Am Thorac Soc. 2019 May;16(5):525-533. doi: 10.1513/AnnalsATS.201808-565CME.
citation: Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, Axmann J, Kirchgaessler KU, Cottin V. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: design of a double-blind, randomised, placebo-controlled phase II trial. BMJ Open Respir Res. 2018 Sep 4;5(1):e000289. doi: 10.1136/bmjresp-2018-000289. eCollection 2018.