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The Lancet. Respiratory Medicine May 2021Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive... (Randomized Controlled Trial)
Randomized Controlled Trial
Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial.
BACKGROUND
Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs.
METHODS
We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting.
FINDINGS
Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed.
INTERPRETATION
In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC.
FUNDING
German Center for Lung Research, Roche Pharma.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Early Termination of Clinical Trials; Female; Humans; Intention to Treat Analysis; Lung Diseases, Interstitial; Male; Middle Aged; Pulmonary Fibrosis; Pyridones; Respiratory Function Tests; Symptom Assessment
PubMed: 33798455
DOI: 10.1016/S2213-2600(20)30554-3 -
Respiratory Research Sep 2018Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored.
METHODS
We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA.
RESULTS
Low μM concentrations of Nintedanib (1 μM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs.
CONCLUSIONS
Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients.
Topics: Alveolar Epithelial Cells; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Culture Techniques; Female; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Lung; Mice; Mice, Inbred C57BL; Pyridones
PubMed: 30219058
DOI: 10.1186/s12931-018-0876-y -
Journal of Cellular and Molecular... Sep 2021Radiation-induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into radiation pneumonia (RP) and...
Radiation-induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into radiation pneumonia (RP) and radiation-induced lung fibrosis (RILF). Once RILF occurs, patients will eventually develop irreversible respiratory failure; thus, a new treatment strategy to prevent RILI is urgently needed. This study explored the therapeutic effect of pirfenidone (PFD), a Food and Drug Administration (FDA)-approved drug for (IPF) treatment, and its mechanism in the treatment of RILF. In vivo, C57BL/6 mice received a 50 Gy dose of X-ray radiation to the whole thorax with or without the administration of PFD. Collagen deposition and fibrosis in the lung were reversed by PFD treatment, which was associated with reduced M2 macrophage infiltration and inhibition of the transforming growth factor-β1 (TGF-β1)/Drosophila mothers against the decapentaplegic 3 (Smad3) signalling pathway. Moreover, PFD treatment decreased the radiation-induced expression of TGF-β1 and phosphorylation of Smad3 in alveolar epithelial cells (AECs) and vascular endothelial cells (VECs). Furthermore, IL-4-induced M2 macrophage polarization and IL-13-induced M2 macrophage polarization were suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase-1 (ARG-1), chitinase 3-like 3 (YM-1) and TGF-β1. Notably, the PFD-induced inhibitory effects on M2 macrophage polarization were associated with downregulation of nuclear factor kappa-B (NF-κB) p50 activity. Additionally, PFD could significantly inhibit ionizing radiation-induced chemokine secretion in MLE-12 cells and consequently impair the migration of RAW264.7 cells. PFD could also eliminate TGF-β1 from M2 macrophages by attenuating the activation of TGF-β1/Smad3. In conclusion, PFD is a potential therapeutic agent to ameliorate fibrosis in RILF by reducing M2 macrophage infiltration and inhibiting the activation of TGF-β1/Smad3.
Topics: Animals; Bone Marrow Cells; Female; Fibrosis; Lung Injury; Macrophage Activation; Mice; Mice, Inbred C57BL; Pyridones; RAW 264.7 Cells; Smad3 Protein; Transforming Growth Factor beta1
PubMed: 34327818
DOI: 10.1111/jcmm.16821 -
Respirology (Carlton, Vic.) May 2016Idiopathic pulmonary fibrosis (IPF) is a deadly disease with a median survival of approximately three years in historical cohorts. Despite increased knowledge of disease... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a deadly disease with a median survival of approximately three years in historical cohorts. Despite increased knowledge of disease pathophysiology and selection of more targeted therapy, main clinical trials yielded negative results. However, two agents, pirfenidone and nintedanib, were recently shown to be effective in IPF and received marketing authorization worldwide. Both drugs significantly reduce functional decline and disease progression with an acceptable safety profile. Yet, none of these drugs actually improves or even stabilizes the disease or the symptoms perceived by the patient. Several other treatments and combinations are currently tested, and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.
Topics: Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Immunomodulation; Immunosuppressive Agents; Indoles; Male; Middle Aged; Practice Guidelines as Topic; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27072575
DOI: 10.1111/resp.12778 -
The European Respiratory Journal Apr 2023
Topics: Humans; Fibrosis; Pyridones
PubMed: 37105587
DOI: 10.1183/13993003.00240-2023 -
Therapeutic Delivery Aug 2023Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary...
Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary hypertension. In our experiment we used the drugs pirfenidone, nintetanib and macitentan. We performed nebulization experiments with three jet nebulizers and three ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5 μm in mass median aerodynamic diameter. Pirfenidone versus nintetanib had smaller droplet size formation at both inhaled technologies (1.37 < 2.23 and 1.92 < 3.11, jet and ultrasound respectively). Pirfenidone and nintetanib can be administered as aerosol in any type of nebulization system.
Topics: Humans; Pulmonary Fibrosis; Respiratory Aerosols and Droplets; Nebulizers and Vaporizers; Particle Size
PubMed: 37584210
DOI: 10.4155/tde-2023-0045 -
Nature Medicine Aug 2021In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral... (Randomized Controlled Trial)
Randomized Controlled Trial
In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral antifibrotic agent without hemodynamic effect, is efficacious and safe for the treatment of HFpEF is unknown. In this double-blind, phase 2 trial ( NCT02932566 ), we enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated levels of natriuretic peptides. Eligible patients underwent cardiovascular magnetic resonance and those with evidence of myocardial fibrosis, defined as a myocardial extracellular volume of 27% or greater, were randomly assigned to receive pirfenidone or placebo for 52 weeks. Forty-seven patients were randomized to each of the pirfenidone and placebo groups. The primary outcome was change in myocardial extracellular volume, from baseline to 52 weeks. In comparison to placebo, pirfenidone reduced myocardial extracellular volume (between-group difference, -1.21%; 95% confidence interval, -2.12 to -0.31; P = 0.009), meeting the predefined primary outcome. Twelve patients (26%) in the pirfenidone group and 14 patients (30%) in the placebo group experienced one or more serious adverse events. The most common adverse events in the pirfenidone group were nausea, insomnia and rash. In conclusion, among patients with HFpEF and myocardial fibrosis, administration of pirfenidone for 52 weeks reduced myocardial fibrosis. The favorable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials.
Topics: Aged; Female; Heart Failure; Humans; Male; Pyridones; Time Factors; Treatment Outcome
PubMed: 34385704
DOI: 10.1038/s41591-021-01452-0 -
Advances in Therapy Sep 2023In the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis... (Clinical Trial)
Clinical Trial
INTRODUCTION
In the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis (IPF). This analysis compared the efficacy and safety of pirfenidone in advanced IPF versus non-advanced IPF.
METHODS
Data were included from the following studies of pirfenidone: ASCEND (NCT01366209); CAPACITY (004 [NCT00287716] and 006 [NCT00287729]); RECAP (NCT00662038; advanced IPF defined as percent predicted forced vital capacity [%FVC] < 50% and/or percent predicted carbon monoxide diffusing capacity [%DLco] < 35% at baseline); PASSPORT (NCT02699879; advanced IPF defined as baseline %FVC < 50%); and SP-IPF (NCT02951429; patients with advanced IPF [defined as %DLco ≤ 40% at screening] at risk of group 3 pulmonary hypertension).
RESULTS
In the pooled ASCEND/CAPACITY studies, the annual mean rate of FVC decline from baseline to Week 52 was significantly lower for pirfenidone versus placebo in advanced (p = 0.0035) and non-advanced IPF (p = 0.0001). Rate of all-cause mortality over 52 weeks was numerically lower for pirfenidone versus placebo in advanced and non-advanced IPF. In RECAP, the mean annual rate of FVC decline from baseline to Week 180 of pirfenidone treatment was similar in patients with advanced (- 141.5 mL) and non-advanced IPF (- 153.5 mL). In SP-IPF, the mean annual rate of FVC decline and rate of all-cause mortality from baseline to Week 52 in patients treated with placebo + pirfenidone were - 93.0 mL and 20.2%, respectively. No new safety signals were identified, and the safety profile of pirfenidone in patients with advanced IPF was generally consistent with that of non-advanced IPF.
CONCLUSIONS
These results highlight the benefit of pirfenidone treatment in patients with advanced and non-advanced IPF. As such, the indication for pirfenidone in the EU has now been updated to include the treatment of adult patients with advanced IPF.
TRIAL REGISTRATIONS
ASCEND (NCT01366209), CAPACITY 004 (NCT00287716), CAPACITY 006 (NCT00287729), RECAP (NCT00662038), PASSPORT (NCT02699879), and SP-IPF (NCT02951429).
Topics: Adult; Humans; Anti-Inflammatory Agents, Non-Steroidal; Idiopathic Pulmonary Fibrosis; Pyridones; Treatment Outcome; Vital Capacity
PubMed: 37391667
DOI: 10.1007/s12325-023-02565-3 -
Clinical Medicine (London, England) Feb 2016Idiopathic pulmonary fibrosis (IPF) is characterised by progressive accumulation of scar tissue in the lung and is associated with a median life expectancy of 2-4 years.... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is characterised by progressive accumulation of scar tissue in the lung and is associated with a median life expectancy of 2-4 years. Until recently, treatment options were limited, focusing on ineffective anti-inflammatory therapy, palliation, transplant or trial recruitment. Significant recent advances in the field have led to two novel anti-fibrotic agents, pirfenidone and nintedanib, which have been shown to significantly slow disease progression in IPF. This article outlines the approach to management of IPF, the role of specialist centres and specialist interstitial lung disease multidisciplinary review, and explores both the trial evidence and practical considerations in the use of these anti-fibrotic agents.
Topics: Anti-Inflammatory Agents; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones
PubMed: 26833513
DOI: 10.7861/clinmedicine.16-1-42 -
The American Journal of the Medical... May 2019The last years have led to advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF), mainly through the discovery of new pathological pathways and... (Review)
Review
The last years have led to advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF), mainly through the discovery of new pathological pathways and drugs and better design of clinical trials. The objective of this review is both to describe the current therapies approved for the treatment of IPF and the emerging therapeutic approaches. Currently, nintedanib and pirfenidone are the basis of IPF therapy, based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease progression. Nonetheless, the ideal IPF therapy is still lacking and trials are underway to test new therapeutic targets. The near future could bring to clinicians and patients a combined therapeutic strategy, hitting the disease from several simultaneous pathways and hopefully leading to clinical stabilization or improvement.
Topics: Anti-Inflammatory Agents; Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones
PubMed: 31010462
DOI: 10.1016/j.amjms.2019.02.006