Pirfenidone for the Reduction of Metabolic, Inflammatory and Fibrogenic Activity in Complicated Silicosis

Study Overview
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Brief Summary
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Silicosis is one of the leading causes of occupational respiratory disease worldwide. It is due to inhalation of respirable crystalline silica and can lead to progressive massive fibrosis (PMF), respiratory failure, and death. It is estimated that it causes more than 10,000 deaths a year worldwide, mainly in developing countries, although the level of underdiagnosis is high. In developed countries the incidence of the disease has been progressively decreasing in recent years, mainly due to the implementation of effective prevention measures, better occupational health surveillance systems and the displacement of mining activity to other countries, in a way that in the United Kingdom 216 cases were reported from 1996 to 2017. At the moment, there is no curative treatment for the disease, and the only therapeutic option is lung transplantation (when the disease evolves to PMF and subsequent respiratory failure). Meanwhile, the only accepted treatment is supportive treatment, with the administration of oxygen therapy in case of respiratory failure, early treatment of respiratory infections, vaccinations and respiratory rehabilitation. In recent years, molecules with antifibrogenic capacity have been developed and have demonstrated their ability to decrease pulmonary fibrogenic activity in diseases such as Idiopathic Pulmonary Fibrosis (IPF). This has been a milestone in the treatment of this disease and, therefore, its possible application to other diseases that share fibrogenic mechanisms with IPF, as PMF. The two molecules with the most clinical experience and approved for IPF are nintedanib and pirfenidone. The antifibrotic properties of pirfenidone have raised great expectations and many clinical trials are currently being carried out in other lung diseases that cause fibrosis, that is why we decide to study the efficacy of pirfenidone in reducing metabolic, inflammatory, and fibrogenic lung disease in patients with artificial stone silicosis and progressive massive fibrosis (PMF).

Detailed Description
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Hypothesis: Pirfenidone reduces pulmonary metabolic activity in patients with Progressive Massive Fibrosis (PMF). Objetives: Main objetive: To evaluate the efficacy of pirfenidone in reducing pulmonary metabolic activity quantified by PET-CT Scan (F-FDG) in patients with Progressive Massive Fibrosis (PMF). Secundary objetives: To evaluate the efficacy of pirfenidone in reducing pulmonary inflammatory and fibrogenic activity in patients with Progressive Massive Fibrosis (PMF), quantified by cell biomarkers, and the relation with the pulmonary metabolic activity. To assess changes brought about by pirfenidone in the different cells biomarkers patterns and metabolic activity resulted by PET/TC with 18-FDG To assess radiological changes in HRCT (High Resolution Computed Tomography) that occur after administration of pirfenidone and the relation with biomarkers and with 18F FDG acquisition. To assess wheter administration of pirfenidone generates changes on standard funtional respiratory explorations, and the relation with inflammatory and metabolic activity. 5. To assess clinical changes (if any) and safety of pirfenidone after administration to patients with PMF. Methodology: An Open, Randomised, Controlled, 2 arms and Unicenter Clinical Trial to Assess the Efficiency of Pirfenidone for the Reduction of Pulmonary Metabolic, Inflammatory and Fibrogenic Activity in Patients With Silicosis Due to Artificial Stone and PMF.

Official Title
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An Open, Randomised, Controlled and Unicenter Clinical Trial to Assess the Efficiency of Pirfenidone for the Reduction of Pulmonary Metabolic, Inflammatory and Fibrogenic Activity in Patients With Silicosis Due to Artificial Stone and PMF

Conditions
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Silicosis, Progressive Massive Fibrosis, Complicated Silicosis

Intervention / Treatment
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* Drug: Pirfenidone Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Age over 18 years and under 65. 2. Man with a diagnosis of silicosis in the form of PMF by lung or lymph node biopsy, or by radiological criteria. 3. History of exposure to silica in work with artificial stone for at least 5 years. 4. Patients capable of consenting to their participation in the study by providing written informed consent, or, if they are not trained, through a legal repressentative. Exclusion Criteria: 1. Participation in another clinical trial in the 6 months prior to the start of participation in this study. 2. Hypersensitivity to any of the components of pirfenidone. 3. Biological or farmacological treatment for any other disease or condition related to silicosis or PMF. Exception: prednisona (or equivalent) dose 20mg per day or lower. 4. Concomitant treatment with a drug that can causes pirfenidone interactions: Cytotoxic drugs, immunosuppressants, cytokine modulators including but not limited to azathioprine, bosentan, ambrisentan, cyclophosphramide, cyclosporine, etarnecept, iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate , tacrolimus, montelukast, tetrathiomolybdate, TNF-alpha inhibitors, imatinib mesylate, interferon gamma 1-beta, and tyrosine kinase inhibitors. Strong CYP1A2 inhibitors (eg fluvoxamine, enoxacin), P-glycoprotein or CYP3A4 inhibitors (eg Ketoconazole, erythromycin), or their inducers (eg rifampicin, carbamazepine, phenytoin). Other moderate CYP1A2 inhibitors (eg amiodarone or propafenone) which will also be prohibited. Any investigational therapy in an active clinical trial. Grapefruit juice. 5. Active infectious disease. 6. Any pathology that may condition the evolution of respiratory diseases, including cancer, HIV, HBV, HCV, liver cirrhosis, liver failure, severe kidney failure or any other that in the opinion of the investigator may interfere with the results of the study. 7. Active smoking. 8. Laboratory test abnormalities at screening timepoint - Total bilirrubin >2 ULN - AST/SGOT or ALT/SGPT > 2.5 ULN - Alkaline phosphatase >3.0 ULN - Creatinine clearance <40 mL/min (Cockcroft-Gault). 9. Concomitant treatments that may cause serious digestive events. 10. Digestive surgery or similar procedures that may cause digestive intolerances. 11. Not availability to complete all the trial visits. 12. Angiodema

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No intervention - standard of care<br>A group of patients with PMF will be treated per standard of care on site | |
| Experimental: Experimental - Pirfenidone plus standard of care<br>A group of patients with PMF will be treated with pirfenidone plus standard of care on site | Drug: Pirfenidone Oral Tablet<br>* Patients will be treated with pirfenidone (oral tablets) during 6 months<br>* Other names: Esbriet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic pulmonary activity assessed by PET-CT Scan (18 FFDG) | Metabolic pulmonary activity assessed by PET-CT Scan (18 FFDG) in patients treated with pirfenidone vs control patients. The variables will be analyzed in lung and mediastinum independently and the measurement of the metabolic response will be based on the standardized uptake value (SUV) at its maximum (SUVmax) and mean (SUVmean) values. | baseline (day 1), month 6, month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cell biomarkers in peripheral blood: - Pro/anti fibrotic and pro/anti inflammatory biomarkers | Pro/anti fibrotic and pro/anti inflammatory biomarkers: cytokines (IL-1α, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IL-18, IP-10, TGF-β, TNF-α, IFN-γ, MIP-1α, MIP-1β, MCP-1, PDGF, bFGF, MMP1, -2, -7, -9, -10). Immunological biomarkers: CD45, CD45RO, CD45RA, CD3, CD4, CD8, CD19, CD27, CD56, CD126, CD25, INF-γ, IL-4, FoxP3, CD196 y CD161 Note: There are no previous studies in patients with artificial stone silicosis in which they have analyzed the indicated biomarkers. This is a comprehensive preliminary analysis of biomarkers and we want to correlate the obtained values with the results derived from PET-CT in both groups of patients in the trial. | baseline (day 1), month 3, month 6, month 9, month 12 | 
| Number of adverse events (AE) and adverse reactions (AR), of serious adverse events (SAE) and serious and unexpected adverse reactions (SUSAR). | Number of adverse events (AE) and adverse reactions (AR), of serious adverse events (SAE) and serious and unexpected adverse reactions (SUSAR). | baseline (day 1), month 3, month 6, month 9, month 12 | 
| Respiratory symptoms (cough, expectoration and dyspnea) and quality of life related to health using the EQ-5D 5L test. | Respiratory symptoms (cough, expectoration and dyspnea) and quality of life related to health using the EQ-5D 5L test. | baseline (day 1), month 3, month 6, month 9, month 12 | 
| Respiratory function variables | Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second, ratio Forced Expiratory in the first second / Forced Vital Capacity and Diffusing Capacity of the lungs for carbon monoxide, obtained through standardized respiratory function tests. | baseline (day 1), month 3, month 6, month 9 and month 12 | 
| Radiological categorization by chest radiology and by High Resolution Computed Tomography, following the International Classification of High-resolution Computed Tomography for Occupational and Environmental Respiratory Diseases (ICOERD) | Radiological categorization by chest radiology and by High Resolution Computed Tomography, following the International Classification of High-resolution Computed Tomography for Occupational and Environmental Respiratory Diseases (ICOERD) | baseline (day 1), month 6, month 12 |