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

Primary Purpose

Silicosis, Progressive Massive Fibrosis, Complicated Silicosis

Status

Recruiting

Phase

Phase 2

Locations

Spain

Study Type

Interventional

Intervention

Pirfenidone Oral Tablet

About this trial

This is an interventional treatment trial for Silicosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

Antonio León JiménezRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

No intervention - standard of care

Experimental - Pirfenidone plus standard of care

Arm Description

A group of patients with PMF will be treated per standard of care on site

A group of patients with PMF will be treated with pirfenidone plus standard of care on site

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Number of adverse events (AE) and adverse reactions (AR), of serious adverse events (SAE) and serious and unexpected adverse reactions (SUSAR).

Respiratory symptoms (cough, expectoration and dyspnea) and quality of life related to health using the EQ-5D 5L test.

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.

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)

Full Information

NCT ID

NCT05118256

First Posted

October 1, 2021

Last Updated

December 27, 2021

Sponsor

Instituto de investigación e innovación biomédica de Cádiz

1. Study Identification

Unique Protocol Identification Number

NCT05118256

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2021

Overall Recruitment Status

Recruiting

Study Start Date

November 15, 2021 (Actual)

Primary Completion Date

November 15, 2022 (Anticipated)

Study Completion Date

November 15, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Instituto de investigación e innovación biomédica de Cádiz

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Silicosis, Progressive Massive Fibrosis, Complicated Silicosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Masking Description

Although this is an open study for participants and clinicians, professionals in charge of molecular and cellular analysis, HRCT and PET will be blind to the arm that each subject is assigned.

Allocation

Randomized

Enrollment

18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

No intervention - standard of care

Arm Type

No Intervention

Arm Description

A group of patients with PMF will be treated per standard of care on site

Arm Title

Experimental - Pirfenidone plus standard of care

Arm Type

Experimental

Arm Description

A group of patients with PMF will be treated with pirfenidone plus standard of care on site

Intervention Type

Drug

Intervention Name(s)

Pirfenidone Oral Tablet

Other Intervention Name(s)

Esbriet

Intervention Description

Patients will be treated with pirfenidone (oral tablets) during 6 months

Primary Outcome Measure Information:

Title

Metabolic pulmonary activity assessed by PET-CT Scan (18 FFDG)

Description

Time Frame

baseline (day 1), month 6, month 12

Secondary Outcome Measure Information:

Title

Cell biomarkers in peripheral blood: - Pro/anti fibrotic and pro/anti inflammatory biomarkers

Description

Time Frame

baseline (day 1), month 3, month 6, month 9, month 12

Title

Number of adverse events (AE) and adverse reactions (AR), of serious adverse events (SAE) and serious and unexpected adverse reactions (SUSAR).

Description

Number of adverse events (AE) and adverse reactions (AR), of serious adverse events (SAE) and serious and unexpected adverse reactions (SUSAR).

Time Frame

baseline (day 1), month 3, month 6, month 9, month 12

Title

Respiratory symptoms (cough, expectoration and dyspnea) and quality of life related to health using the EQ-5D 5L test.

Description

Respiratory symptoms (cough, expectoration and dyspnea) and quality of life related to health using the EQ-5D 5L test.

Time Frame

baseline (day 1), month 3, month 6, month 9, month 12

Title

Respiratory function variables

Description

Time Frame

baseline (day 1), month 3, month 6, month 9 and month 12

Title

Description

Time Frame

baseline (day 1), month 6, month 12

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Laura Quintana, phD

Phone

+34 639390856

laura.quintana@inibica.es

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Antonio León Jiménez, MD

Organizational Affiliation

Fundación Cádiz- INIBICA

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Antonio Campos Caro, phD

Organizational Affiliation

Fundación Cádiz- INIBICA

Official's Role

Principal Investigator

Facility Information:

Facility Name

Antonio León Jiménez

City

Cadiz

ZIP/Postal Code

11009

Country

Spain

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Antonio León Jiménez, MD

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

The study results will be published in scientific pneumologic journal and available in PubMed and clinicaltrials website

Learn more about this trial

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

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