A Study of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing Interstitial Lung Disease
- Registration Number
- NCT03099187
- Lead Sponsor
- Hoffmann-La Roche
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 253
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pirfenidone 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. Placebo 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.
- Primary Outcome Measures
Name Time Method Rate of Decline in Forced Vital Capacity (FVC) Over the 24-week Double-blind Treatment Period Up to Week 24 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.
- Secondary Outcome Measures
Name Time Method Change in 6-minute Walk Distance (6MWD) Baseline (Day 1) to Week 24 Comparison of 6-minute walk distance before beginning and after completing study therapy.
Change in Cough Visual Analog Scale (VAS) Score Baseline (Day 1) to Week 24 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.
Categorical Change in FVC of >5% Baseline (Day 1) to Week 24 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.
Change in University of California, San Diego-Shortness of Breath Questionnaire Score Baseline (Day 1) to Week 24 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.
Change in Score in Leicester Cough Questionnaire Score Baseline (Day 1) to Week 24 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.
Number of Participants With Non-elective Hospitalization, Both Respiratory and All Cause Baseline (Day 1) to Week 24 Participants with non-elective hospitalization are reported.
Change in Percent Predicted FVC Baseline (Day 1) to Week 24 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.
Change in FVC Baseline (Day 1) to Week 24 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.
Change in Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Baseline (Day 1) to Week 24 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.
Change in Total and Sub-scores of the Saint George's Respiratory Questionnaire (SGRQ) Baseline (Day 1) to Week 24 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.
Percentage of Participants With Investigator-reported Acute Exacerbations Baseline (Day 1) to Week 24 Percentage of participants with acute exacerbation arereported.
Time to First Investigator-reported Acute Exacerbations Baseline (Day 1) to Week 24 Time to first investigator reported acute exacerbations from start of treatment are reported.
Time to Death From Respiratory Diseases Baseline (Day 1) to Week 24 Time to first documented death due to respiratory diseases from start of treatment will be reported.
Number of Participants With Dose Reductions and Treatment Interruptions During the Double-Blind Period From administration of the first dose of study drug to Week 24 Number of participants with dose reduction and treatment interruptions are reported.
Progression-free Survival (PFS) Baseline (Day 1) to Week 24 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.
Categorical Change in FVC of >10% Baseline (Day 1) to Week 24 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.
Number of Participants With Dose Reductions and Treatment Interruptions During the 12-month Safety Follow-up From the Follow-up Visit at Week 28 through the follow-up period of 12 Months Number of participants with dose reduction and treatment interruptions are reported.
Time to Death From Any Cause Baseline (Day 1) to Week 24 Time to first documented death from start of treatment is reported.
Number of Participants Withdrawn From Trial Treatment or Trial Discontinuations During the Double-Blind Period Baseline (Day 1) to Week 24 Number of participants withdrawn from trial treatment or trial discontinuations are reported.
Number of Participants Withdrawn From Trial Treatment or Trial Discontinuations During the 12-month Safety Follow-up 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 are reported.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Baseline (Day 1) to Week 28 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.
Trial Locations
- Locations (66)
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
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
🇨🇿Praha 2, Czechia
Gentofte Hospital, Lungemedicinsk Afdeling
🇩🇰Hellerup, 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
University General Hospital of Athens "Attikon", B' University Pulmonary Clinic
🇬🇷Chaidari, Greece
Mater Misericordiae University hospital
🇮🇪Dublin, Ireland
Carmel Medical Center; Pulmonary Institute
🇮🇱Haifa, Israel
Soroka; Pulmonary Clinic
🇮🇱Beer Sheba, Israel
Shaare Zedek Medical Center; Pulmonary Inst.
🇮🇱Jerusalem, Israel
Beilinson Medical Center; Pulmonary Inst.
🇮🇱Petach Tikva, Israel
Kaplan Medical Center
🇮🇱Rehovot, Israel
Ospedale San Giuseppe; U.O. di Pneumologia
🇮🇹Milano, Lombardia, Italy
Ospedale Morgagni-Pierantoni; U.O. Pneumologia
🇮🇹Forlì, Emilia-Romagna, Italy
Azienda Ospedaliero-Universitaria Careggi; SOD Pneumologia e Fisiopatologia Toracico Polmonare
🇮🇹Firenze, Toscana, Italy
HUC; Servico de Pneumologia A
🇵🇹Coimbra, Portugal
Hospital de Sao Joao; Servico de Pneumologia
🇵🇹Porto, Portugal
Hospital Universitario Marques de Valdecilla; Servicio de neumologia
🇪🇸Santander, Cantabria, 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
Papworth Hospital NHS Foundation Trust; Respiratory Department
🇬🇧Cambridge, United Kingdom
Royal Devon and Exeter Hospital (Wonford)
🇬🇧Exeter, United Kingdom
University College London Hospital; Respiratory Medicine
🇬🇧London, United Kingdom
Northern General Hospital
🇬🇧Sheffield, United Kingdom
Aarhus Universitetshospital; Lungesygdomme, Forskning
🇩🇰Aarhus N, Denmark
Odense Universitetshospital, Lungemedicinsk Afdeling J
🇩🇰Odense C, Denmark
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
Royal Adelaide Hospital; Respiratory Clinical Trials Unit, Thoracic Medicine
🇦🇺Adelaide, South Australia, Australia
Fiona Stanley Hospital; Advanced Lung Disease Unit
🇦🇺Murdoch, Western Australia, Australia
A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone
🇮🇹Orbassano (TO), Piemonte, Italy
A.O.U. Ospedali Riuniti Umberto I -G.M. Lancisi-G. Salesi Ancona; SOD Pneumologia
🇮🇹Torrette Di Ancona, Marche, Italy
Instytut Gruźlicy i Chorób Płuc, I Klinika Chorób Płuc
🇵🇱Warszawa, Poland
Hospital Infante D. Pedro; Servico de Pneumologia
🇵🇹Aveiro, Portugal
Respiratory Department
🇦🇺Heidelberg, Victoria, Australia
The Alfred Hospital
🇦🇺Prahan, Victoria, Australia
Cliniques Universitaires St-Luc
🇧🇪Bruxelles, Belgium
University General Hospital of Heraklio, Pulmonary Clinic
🇬🇷Heraklio, Greece
St Vincents University Hospital
🇮🇪Dublin, Ireland
Pacifica Lung Research Center/St. Paul's Hospital
🇨🇦Vancouver, British Columbia, Canada
UZ Leuven Gasthuisberg
🇧🇪Leuven, Belgium
CHVNG/E_Unidade 1; Servico de Pneumologia
🇵🇹Vila Nova De Gaia, Portugal
ULB Hôpital Erasme
🇧🇪Brussels, Belgium
Uniwersyteckie Centrum Kliniczne;Klinika Alergologii i Pneumonologii
🇵🇱Gdańsk, Poland
Uniwersytecki Szpital Kliniczny Nr 1 im.N.Barlickiego Oddzial Kliniczny Pneumonologii i Alergologii
🇵🇱Lodz, Poland
Sotiria Hospital for Diseases of the Chest, Academic Department of Pneumonology
🇬🇷Athens, Greece
Hadassah Medical Center; Pulmonary Institute
🇮🇱Jerusalem, Israel
Meir Medical Center; Pulmonary Dept
🇮🇱Kfar Saba, Israel
Hospital Universitari de Bellvitge ; Servicio de Neumologia
🇪🇸Hospitalet de Llobregat, Barcelona, Spain
Southmead Hospital; Respiratory Department
🇬🇧Bristol, United Kingdom
Royal Brompton Hospital; Respiratory Department
🇬🇧London, United Kingdom
Edinburgh Royal Infirmary; Respiratory Department
🇬🇧Edinburgh, United Kingdom
Glenfield Hospital
🇬🇧Leicester, United Kingdom
Southampton University Hospitals NHS Trust
🇬🇧Southampton, United Kingdom
Royal Stoke University Hospital
🇬🇧Stoke on Trent, United Kingdom
Hospital Universitario La Princesa; Servicio de Neumologia
🇪🇸Madrid, Spain
Wythenshawe Hospital; North West Lung Research Centre
🇬🇧Manchester, United Kingdom
St. Joseph's Healthcare Hamilton
🇨🇦Hamilton, Ontario, Canada