A Study of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing Interstitial Lung Disease
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| ClinicalTrials.gov Identifier: NCT03099187 |
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Recruitment Status :
Completed
First Posted : April 4, 2017
Results First Posted : January 3, 2020
Last Update Posted : January 13, 2021
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Sponsor:
Hoffmann-La Roche
Information provided by (Responsible Party):
Hoffmann-La Roche
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Lung Diseases, Interstitial | Drug: Pirfenidone Drug: Placebo | Phase 2 |
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 (Clinical Trial) |
| Actual Enrollment : | 253 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | Multicenter, International, Double-blind, Two-Arm, Randomized, Placebo-controlled Phase II Trial of Pirfenidone in Patients With Unclassifiable Progressive Fibrosing ILD |
| Actual Study Start Date : | May 15, 2017 |
| Actual Primary Completion Date : | November 21, 2018 |
| Actual Study Completion Date : | January 10, 2020 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Pulmonary alveolar microlithiasis
Drug Information available for:
Pirfenidone
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Pirfenidone
Pirfenidone 267 mg capsules three times in a day. |
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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.
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Drug: Placebo
Matching placebo capsules three times in a day. |
Primary Outcome Measures :
- Rate of Decline in Forced Vital Capacity (FVC) Over the 24-week Double-blind Treatment Period [ Time Frame: 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 :
- Change in Percent Predicted FVC [ Time Frame: 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 [ Time Frame: 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.
- Categorical Change in FVC of >5% [ Time Frame: 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.
- Categorical Change in FVC of >10% [ Time Frame: 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 Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) [ Time Frame: 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 6-minute Walk Distance (6MWD) [ Time Frame: Baseline (Day 1) to Week 24 ]Comparison of 6-minute walk distance before beginning and after completing study therapy.
- Change in University of California, San Diego-Shortness of Breath Questionnaire Score [ Time Frame: 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 [ Time Frame: 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.
- Change in Cough Visual Analog Scale (VAS) Score [ Time Frame: 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.
- Change in Total and Sub-scores of the Saint George's Respiratory Questionnaire (SGRQ) [ Time Frame: 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.
- Number of Participants With Non-elective Hospitalization, Both Respiratory and All Cause [ Time Frame: Baseline (Day 1) to Week 24 ]Participants with non-elective hospitalization are reported.
- Percentage of Participants With Investigator-reported Acute Exacerbations [ Time Frame: Baseline (Day 1) to Week 24 ]Percentage of participants with acute exacerbation arereported.
- Time to First Investigator-reported Acute Exacerbations [ Time Frame: Baseline (Day 1) to Week 24 ]Time to first investigator reported acute exacerbations from start of treatment are reported.
- Progression-free Survival (PFS) [ Time Frame: Baseline (Day 1) to Week 24 ]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.
- Progression-free Survival (PFS) [ Time Frame: 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.
- Time to Death From Any Cause [ Time Frame: Baseline (Day 1) to Week 24 ]Time to first documented death from start of treatment is reported.
- Time to Death From Respiratory Diseases [ Time Frame: 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 Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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.
- Number of Participants With Dose Reductions and Treatment Interruptions During the Double-Blind Period [ Time Frame: From administration of the first dose of study drug to Week 24 ]Number of participants with dose reduction and treatment interruptions are reported.
- Number of Participants With Dose Reductions and Treatment Interruptions During the 12-month Safety Follow-up [ Time Frame: 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.
- Number of Participants Withdrawn From Trial Treatment or Trial Discontinuations During the Double-Blind Period [ Time Frame: 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 [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years to 85 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03099187
Locations
Show 66 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
Study Documents (Full-Text)
Documents provided by Hoffmann-La Roche:
Documents provided by Hoffmann-La Roche:
Study Protocol [PDF] June 28, 2018
Statistical Analysis Plan [PDF] July 20, 2020
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Hoffmann-La Roche |
| ClinicalTrials.gov Identifier: | NCT03099187 |
| Other Study ID Numbers: |
MA39189 2016-002744-17 ( EudraCT Number ) |
| First Posted: | April 4, 2017 Key Record Dates |
| Results First Posted: | January 3, 2020 |
| Last Update Posted: | January 13, 2021 |
| Last Verified: | December 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
| 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 |
Additional relevant MeSH terms:
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Lung Diseases Lung Diseases, Interstitial Respiratory Tract Diseases Pirfenidone Analgesics Sensory System Agents Peripheral Nervous System Agents |
Physiological Effects of Drugs Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Anti-Inflammatory Agents Antirheumatic Agents Antineoplastic Agents |