A Study of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing Interstitial Lung Disease

NCT ID: NCT03099187

Last Updated: 2021-01-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 253 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-15
• Study Completion Date: 2020-01-10

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.

Conditions

Lung Diseases, Interstitial

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Pirfenidone

Participants will receive pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

Group Type: EXPERIMENTAL

Pirfenidone

Intervention Type: DRUG

Pirfenidone 267 mg capsules three times in a day.

Placebo

Participants will receive matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching placebo capsules three times in a day.

Interventions

Pirfenidone

Pirfenidone 267 mg capsules three times in a day.

Intervention Type: DRUG

Placebo

Matching placebo capsules three times in a day.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia

John Hunter Hospital; Respiratory Department; Respiratory Department

New Lambton Heights, New South Wales, Australia

Lung Research Queensland

Nundah, Queensland, Australia

Princess Alexandra Hospital, Department of Respiratory and Sleep Medicine

Woolloongabba, Queensland, Australia

Royal Adelaide Hospital; Respiratory Clinical Trials Unit, Thoracic Medicine

Adelaide, South Australia, Australia

Respiratory Department

Heidelberg, Victoria, Australia

The Alfred Hospital

Prahan, Victoria, Australia

Fiona Stanley Hospital; Advanced Lung Disease Unit

Murdoch, Western Australia, Australia

ULB Hôpital Erasme

Brussels, , Belgium

Cliniques Universitaires St-Luc

Brussels, , Belgium

UZ Leuven Gasthuisberg

Leuven, , Belgium

Pacifica Lung Research Center/St. Paul's Hospital

Vancouver, British Columbia, Canada

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada

Fakultni Nemocnice Brno-Bohunice; Klinika Tuberkulozy A Respiracnich Chorob

Brno, , Czechia

Nemocnice Jihlava

Jihlava, , Czechia

Fakultni nemocnice Olomouc; Pneumologicka klinika

Olomouc, , Czechia

Vseobecna fakultni nemocnice v Praze; I. klinika tuberkulozy a respiracnich nemoci

Prague, , Czechia

Aarhus Universitetshospital; Lungesygdomme, Forskning

Aarhus N, , Denmark

Gentofte Hospital, Lungemedicinsk Afdeling

Hellerup, , Denmark

Odense Universitetshospital, Lungemedicinsk Afdeling J

Odense C, , Denmark

Zentralklinik Bad Berka GmbH; Pneumologie

Bad Berka, , Germany

Evang. Lungenklinik Berlin Klinik für Pneumologie

Berlin, , Germany

Klinik der Justus-Liebig-Universität; Innere Medizin

Giessen, , Germany

Thoraxklinik Heidelberg gGmbH

Heidelberg, , Germany

Klinikum der Universität München; Campus Großhadern; Med. Klinik und Poliklinik V

München, , Germany

Sotiria Hospital for Diseases of the Chest, Academic Department of Pneumonology

Athens, , Greece

University General Hospital of Athens "Attikon", B' University Pulmonary Clinic

Chaïdári, , Greece

University General Hospital of Heraklio, Pulmonary Clinic

Heraklio, , Greece

Mater Misericordiae University hospital

Dublin, , Ireland

St Vincents University Hospital

Dublin, , Ireland

Soroka; Pulmonary Clinic

Beersheba, , Israel

Carmel Medical Center; Pulmonary Institute

Haifa, , Israel

Shaare Zedek Medical Center; Pulmonary Inst.

Jerusalem, , Israel

Hadassah Medical Center; Pulmonary Institute

Jerusalem, , Israel

Meir Medical Center; Pulmonary Dept

Kfar Saba, , Israel

Beilinson Medical Center; Pulmonary Inst.

Petah Tikva, , Israel

Kaplan Medical Center

Rehovot, , Israel

Ospedale Morgagni-Pierantoni; U.O. Pneumologia

Forlì, Emilia-Romagna, Italy

Ospedale San Giuseppe; U.O. di Pneumologia

Milan, Lombardy, Italy

A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone

Orbassano (TO), Piedmont, Italy

A.O.U. Ospedali Riuniti Umberto I -G.M. Lancisi-G. Salesi Ancona; SOD Pneumologia

Torrette Di Ancona, The Marches, Italy

Azienda Ospedaliero-Universitaria Careggi; SOD Pneumologia e Fisiopatologia Toracico Polmonare

Florence, Tuscany, Italy

Uniwersyteckie Centrum Kliniczne;Klinika Alergologii i Pneumonologii

Gdansk, , Poland

Uniwersytecki Szpital Kliniczny Nr 1 im.N.Barlickiego Oddzial Kliniczny Pneumonologii i Alergologii

Lodz, , Poland

Instytut Gruźlicy i Chorób Płuc, I Klinika Chorób Płuc

Warsaw, , Poland

Hospital Infante D. Pedro; Servico de Pneumologia

Aveiro, , Portugal

HUC; Servico de Pneumologia A

Coimbra, , Portugal

Hospital de Sao Joao; Servico de Pneumologia

Porto, , Portugal

CHVNG/E_Unidade 1; Servico de Pneumologia

Vila Nova de Gaia, , Portugal

Hospital Universitari de Bellvitge ; Servicio de Neumologia

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital Universitario Marques de Valdecilla; Servicio de neumologia

Santander, Cantabria, Spain

Hospital Universitario La Princesa; Servicio de Neumologia

Madrid, , Spain

Hospital Clínico San Carlos - Servicio de Neumologia

Madrid, , Spain

Hospital Universitario 12 de Octubre; Servicio de Neumologia

Madrid, , Spain

University Hospital Birmingham Queen Elizabeth Hospital

Birmingham, , United Kingdom

Southmead Hospital; Respiratory Department

Bristol, , United Kingdom

Papworth Hospital NHS Foundation Trust; Respiratory Department

Cambridge, , United Kingdom

Edinburgh Royal Infirmary; Respiratory Department

Edinburgh, , United Kingdom

Royal Devon and Exeter Hospital (Wonford)

Exeter, , United Kingdom

Glenfield Hospital

Leicester, , United Kingdom

University College London Hospital; Respiratory Medicine

London, , United Kingdom

Royal Brompton Hospital; Respiratory Department

London, , United Kingdom

Wythenshawe Hospital; North West Lung Research Centre

Manchester, , United Kingdom

Northern General Hospital

Sheffield, , United Kingdom

Southampton University Hospitals NHS Trust

Southampton, , United Kingdom

Royal Stoke University Hospital

Stoke-on-Trent, , United Kingdom

Countries

Australia; Belgium; Canada; Czechia; Denmark; Germany; Greece; Ireland; Israel; Italy; Poland; Portugal; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 35783648 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34936057 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31578169 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30695649 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30233802 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-002744-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MA39189

Identifier Type: -

Identifier Source: org_study_id