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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Lung Diseases, Interstitial

Intervention / Treatment
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* Drug: Pirfenidone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pirfenidone<br>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<br>* Pirfenidone 267 mg capsules three times in a day.<br>|
| Experimental: Placebo<br>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<br>* Matching placebo capsules three times in a day.<br>|

What is the study measuring?
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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 |