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

Multicenter, International, Double-blind, Two-Arm, Randomized, Placebo-controlled Phase II Trial of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing ILD

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).

Study Overview

• Status: Completed
• Conditions: Lung Diseases, Interstitial
• Intervention / Treatment: Drug: Pirfenidone; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 253
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • New Lambton Heights, New South Wales, Australia, 2305
      • John Hunter Hospital; Respiratory Department; Respiratory Department
  • Queensland
    • Nundah, Queensland, Australia, 4101
      • Lung Research Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital, Department of Respiratory and Sleep Medicine
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital; Respiratory Clinical Trials Unit, Thoracic Medicine
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Respiratory Department
    • Prahan, Victoria, Australia, 3181
      • The Alfred Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital; Advanced Lung Disease Unit
• Belgium
  • Brussels, Belgium, 1070
    • ULB Hôpital Erasme
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires St-Luc
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Pacifica Lung Research Center/St. Paul's Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8N4A6
      • St. Joseph's Healthcare Hamilton
• Czechia
  • Brno, Czechia, 639 00
    • Fakultni Nemocnice Brno-Bohunice; Klinika Tuberkulozy A Respiracnich Chorob
  • Jihlava, Czechia, 58633
    • Nemocnice Jihlava
  • Olomouc, Czechia, 775 20
    • Fakultni nemocnice Olomouc; Pneumologicka klinika
  • Praha 2, Czechia, 128 08
    • Vseobecna fakultni nemocnice v Praze; I. klinika tuberkulozy a respiracnich nemoci
• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus Universitetshospital; Lungesygdomme, Forskning
  • Hellerup, Denmark, 2900
    • Gentofte Hospital, Lungemedicinsk Afdeling
  • Odense C, Denmark, 5000
    • Odense Universitetshospital, Lungemedicinsk Afdeling J
• Germany
  • Bad Berka, Germany, 99437
    • Zentralklinik Bad Berka GmbH; Pneumologie
  • Berlin, Germany, 13125
    • Evang. Lungenklinik Berlin Klinik für Pneumologie
  • Gießen, Germany, 35392
    • Klinik der Justus-Liebig-Universität; Innere Medizin
  • Heidelberg, Germany, 69126
    • Thoraxklinik Heidelberg gGmbH
  • 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
• Ireland
  • Dublin, Ireland, 7
    • Mater Misericordiae University Hospital
  • Dublin, Ireland
    • St Vincents University Hospital
• 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
  • Lombardia
    • Milano, Lombardia, Italy, 20123
      • Ospedale San Giuseppe; U.O. di Pneumologia
  • Marche
    • Torrette Di Ancona, Marche, Italy, 60100
      • A.O.U. Ospedali Riuniti Umberto I -G.M. Lancisi-G. Salesi Ancona; SOD Pneumologia
  • Piemonte
    • Orbassano (TO), Piemonte, Italy, 10043
      • A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone
  • Toscana
    • Firenze, Toscana, Italy, 50134
      • Azienda Ospedaliero-Universitaria Careggi; SOD Pneumologia e Fisiopatologia Toracico Polmonare
• Poland
  • Gdańsk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne;Klinika Alergologii i Pneumonologii
  • Lodz, Poland, 90-153
    • Uniwersytecki Szpital Kliniczny Nr 1 im.N.Barlickiego Oddzial Kliniczny Pneumonologii i Alergologii
  • Warszawa, Poland, 01-138
    • Instytut Gruźlicy i Chorób Płuc, I Klinika Chorób Płuc
• Portugal
  • Aveiro, Portugal, 3814-501
    • Hospital Infante D. Pedro; Servico de Pneumologia
  • Coimbra, Portugal, 3000-075
    • HUC; Servico de Pneumologia A
  • Porto, Portugal, 4200
    • Hospital de Sao Joao; Servico de Pneumologia
  • Vila Nova De Gaia, Portugal, 4434-502
    • CHVNG/E_Unidade 1; Servico de Pneumologia
• Spain
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre; Servicio de Neumologia
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa; Servicio de Neumologia
  • Madrid, Spain, 28040
    • Hospital Clínico San Carlos - 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
• United Kingdom
  • Birmingham, United Kingdom, B17 0NH
    • University Hospital Birmingham Queen Elizabeth Hospital
  • Bristol, United Kingdom, BS10-5NB
    • Southmead Hospital; Respiratory Department
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital NHS Foundation Trust; Respiratory Department
  • Edinburgh, United Kingdom, EH16 4SA
    • Edinburgh Royal Infirmary; Respiratory Department
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon and Exeter Hospital (Wonford)
  • Leicester, United Kingdom, LE3 9QP
    • Glenfield Hospital
  • London, United Kingdom, NW1 2BU
    • University College London Hospital; Respiratory Medicine
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital; Respiratory Department
  • Manchester, United Kingdom, M23 9LT
    • Wythenshawe Hospital; North West Lung Research Centre
  • Sheffield, United Kingdom, S5 7AU
    • Northern General Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton University Hospitals NHS Trust
  • Stoke on Trent, United Kingdom, ST4 6QG
    • Royal Stoke University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Pirfenidone; Pirfenidone 267 mg capsules three times in a day.
EXPERIMENTAL: 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.	Drug: Placebo; Matching placebo capsules three times in a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Decline in Forced Vital Capacity (FVC) Over the 24-week Double-blind Treatment Period	Rate of decline in FVC was measured in mL by daily handheld spirometer. The analyses were repeated due to an additional independent review of the home spirometry data.	Up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percent Predicted FVC	FVC was measured in liter (L) by spirometry. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.	Baseline (Day 1) to Week 24
Change in FVC	FVC was measured in liter (L) by spirometry. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.	Baseline (Day 1) to Week 24
Categorical Change in FVC of >5%	Categorical change in FVC was measured both by daily spirometry as well as by spirometry during clinical visits. Only the site spirometry data were used as the daily spirometry data were not normally distributed. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.	Baseline (Day 1) to Week 24
Categorical Change in FVC of >10%	Categorical change in FVC was measured both by daily spirometry as well as by spirometry during clinical visits. Only the site spirometry data were used as the daily spirometry data were not normally distributed. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.	Baseline (Day 1) to Week 24
Change in Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLco)	The DLco is a pulmonary function test that measures the capacity for the lung to carry out gas exchange between the inhaled breath and the pulmonary capillary blood vessels and the DLco %-predicted represents the DLco expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity.	Baseline (Day 1) to Week 24
Change in 6-minute Walk Distance (6MWD)	Comparison of 6-minute walk distance before beginning and after completing study therapy.	Baseline (Day 1) to Week 24
Change in University of California, San Diego-Shortness of Breath Questionnaire Score	University of California, San Diego Shortness of Breath Questionnaire (SOBQ) consists of 24-item on a scale of 0 to 5 with 0=not at all and 5=maximal or unable to do because of breathlessness. The total scores were calculated by summation of the 24 items scores and transformed into 0-100, with 0= poor quality of life , and 100= excellent quality of life.	Baseline (Day 1) to Week 24
Change in Score in Leicester Cough Questionnaire Score	The Leicester Cough Questionnaire is a patient-reported questionnaire evaluating the impact of cough on quality of life. The questionnaire comprises 19 items. Each item assesses symptoms, or the impact of symptoms, over the last 2 weeks on a seven-point Likert scale. Scores in three domains (physical, psychological and social) were calculated as a mean for each domain (range 1 to 7). A total score (range 3 to 21) was also calculated by adding the domain scores together. Higher scores indicate better quality of life.	Baseline (Day 1) to Week 24
Change in Cough Visual Analog Scale (VAS) Score	Cough VAS are 100-mm linear scales on which participants indicate the severity of their cough; 0 mm represents no cough and 100 mm the worst cough ever.	Baseline (Day 1) to Week 24
Change in Total and Sub-scores of the Saint George's Respiratory Questionnaire (SGRQ)	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: Symptoms (respiratory symptoms and severity); Activity (activities that cause or are limited by breathlessness); Impacts (social functioning and psychological disturbances due to airway disease). Each component sub-scores are calculated from the summed weights for the positive responses to questions. 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. It is calculated by summing all positive responses in the questionnaire and expressing the result as a percentage of the total weight for the questionnaire.	Baseline (Day 1) to Week 24
Number of Participants With Non-elective Hospitalization, Both Respiratory and All Cause	Participants with non-elective hospitalization are reported.	Baseline (Day 1) to Week 24
Percentage of Participants With Investigator-reported Acute Exacerbations	Percentage of participants with acute exacerbation arereported.	Baseline (Day 1) to Week 24
Time to First Investigator-reported Acute Exacerbations	Time to first investigator reported acute exacerbations from start of treatment are reported.	Baseline (Day 1) to Week 24
Progression-free Survival (PFS)	PFS is defined as the time to the first occurrence of a >10% absolute decline in percent predicted FVC, a >50 m decline of 6MWD, or death.	Baseline (Day 1) to Week 24
Progression-free Survival (PFS)	PFS is defined as the time to the first occurrence of a >10% relative decline in percent predicted FVC, non-elective respiratory hospitalization, or death.	Baseline (Day 1) to Week 24
Time to Death From Any Cause	Time to first documented death from start of treatment is reported.	Baseline (Day 1) to Week 24
Time to Death From Respiratory Diseases	Time to first documented death due to respiratory diseases from start of treatment will be reported.	Baseline (Day 1) to Week 24
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Baseline (Day 1) to Week 28
Number of Participants With Dose Reductions and Treatment Interruptions During the Double-Blind Period	Number of participants with dose reduction and treatment interruptions are reported.	From administration of the first dose of study drug to Week 24
Number of Participants With Dose Reductions and Treatment Interruptions During the 12-month Safety Follow-up	Number of participants with dose reduction and treatment interruptions are reported.	From the Follow-up Visit at Week 28 through the follow-up period of 12 Months
Number of Participants Withdrawn From Trial Treatment or Trial Discontinuations During the Double-Blind Period	Number of participants withdrawn from trial treatment or trial discontinuations are reported.	Baseline (Day 1) to Week 24
Number of Participants Withdrawn From Trial Treatment or Trial Discontinuations During the 12-month Safety Follow-up	Number of participants withdrawn from trial treatment or trial discontinuations are reported.	From the Follow-up Visit at Week 28 through the follow-up period of 12 Months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 15, 2017
• Primary Completion (ACTUAL): November 21, 2018
• Study Completion (ACTUAL): January 10, 2020

Study Registration Dates

• First Submitted: March 31, 2017
• First Submitted That Met QC Criteria: March 31, 2017
• First Posted (ACTUAL): April 4, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 13, 2021
• Last Update Submitted That Met QC Criteria: December 22, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Pirfenidone
• Other Study ID Numbers: MA39189; 2016-002744-17 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes