Idiopathic Pulmonary Fibrosis, Lung Transplant; Complications
Conditions
Brief summary
The aim of this study is to assess the utility of nintedanib therapy in addition to usual transplant care in single lung transplant recipients with idiopathic pulmonary fibrosis (IPF). The investigators hypothesize that in IPF subjects who undergo single lung transplantation the administration of nintedanib 150 mg twice daily in addition to usual transplant care will result in better preservation of lung function at 24 months.
Detailed description
Lung transplantation is the only treatment option that augments survival in patients with idiopathic pulmonary fibrosis (IPF). Despite several advancements in lung transplantation over the past three decades, long-term survival rates have remained low compared to other solid organ transplantations. The median survival after lung transplantation is only 5.8 years. Multiple factors account for the relatively low survival post-transplant, but chronic rejection resulting in obliterative bronchiolitis is a predominate cause. Further research is needed to develop medical therapeutic interventions that improve survival in IPF patients who undergo only single lung transplantation. Nintedanib, a novel tyrosine kinase inhibitor, exhibits antifibrotic properties via multiple mechanisms including the inhibition of the receptor tyrosine kinases platelet derived growth factor (PDGF) receptor, fibroblast growth factor (FGF) receptor, and vascular endothelial growth factor (VEGF) receptor. Several mediators of pulmonary fibrosis including VEGF, FGF, and transforming growth factor beta (TGF-β) have also been implicated in the pathogenesis of bronchiolitis obliterans syndrome (BOS), the most common type of chronic lung allograft rejection. Nintedanib is safe to continue until the time of lung transplantation and has not been shown to worsen perioperative outcomes in small case series, single center cohorts and our center's personal experience. The current practice in lung transplant medicine is to discontinue antifibrotic therapy after lung transplantation in IPF. In IPF patients who undergo single lung transplant, nintedanib therapy has the potential to preserve lung function in both the native fibrotic lung and the new lung allograft. The investigators propose a randomized and placebo-controlled single center pilot trial comparing nintedanib therapy plus usual care to usual care only in IPF patients after single lung transplant. The investigators hypothesize that in IPF subjects who undergo single lung transplantation the administration of nintedanib 150 mg twice daily in addition to usual transplant care will result in better preservation of lung function at 24 months.
Interventions
DRUGNintedanib
Nintedanib (BIBF 1120, Ofev)
DRUGPlacebo Oral Tablet
Placebo
Sponsors
Boehringer Ingelheim
Temple University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Adults between the ages of 35-70. * Lung transplantation listing diagnosis of pulmonary fibrosis * Recipient of single lung transplantation within the past 60 days
Exclusion criteria
* History of intolerability to nintedanib (i.e. discontinued nintedanib in the pre-transplant period due to adverse drug effects) * Liver transaminase elevation (AST or ALT \> 1.5X the upper limit of normal) * Total bilirubin \> 1.5X the upper limit of normal * Drugs that interfere with the metabolism or elimination of nintedanib or its metabolites - St. John's wort, carbamazepine, phenytoin, rifampin, dexamethasone, and others. * Any history of bronchial anastomosis dehiscence or stenosis * Bleeding risk, defined as any of the following: * Full-dose therapeutic anticoagulation (i.e. vitamin K antagonist, direct thrombin inhibitors, etc.) * History of hemorrhagic central nervous system (CNS) event within 12 months of enrollment * Coagulation parameters: international normalized ratio (INR) \> 2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by \> 1.5X the upper limit of normal at enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in FVC | Baseline to 24 months | Change in forced vital capacity (FVC) |
| Change in FEV1 | Baseline to 24 months | Change in forced expiratory volume in 1 second (FEV1) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bronchial stenosis | Baseline to 24 months | Incidence of surgical anastomosis bronchial stenosis |
| Bronchial dehiscence | Baseline to 24 months | Incidence of surgical anastomosis bronchial stenosis |
| Acute cellular rejection | Baseline to 24 months | Incidence of acute cellular rejection of lung allograft |
| Drug discontinuation | Baseline to 24 months | Study drug discontinuation rate due to adverse drug event |
| Adverse drug events | Baseline to 24 months | Incidence of adverse drug events (i.e. elevation of liver transaminases greater than 3 times the upper limit of normal, diarrhea, nausea, vomiting, anorexia, GERD) |
| Vascular endothelial growth factor (VEGF) - serum | Baseline to day 30 | Change in serum biomarker concentration for VEGF (pg/mL) |
| Vascular endothelial growth factor (VEGF) - BAL | Baseline to day 30 | Change in BAL concentration for VEGF (pg/mL) |
| Fibroblast growth factor (FGF) - serum | Baseline to day 30 | Change in serum concentration for FGF (pg/mL) |
| Fibroblast growth factor (FGF) - BAL | Baseline to day 30 | Change in BAL concentration for FGF (pg/mL) |
| Platelet derived growth factor (PDGF) - serum | Baseline to day 30 | Change in serum concentration for PDGF (pg/mL) |
| Platelet derived growth factor (PDGF) - BAL | Baseline to day 30 | Change in BAL biomarker concentration for PDGF (pg/mL) |
| Peripheral blood flow cytometry - CD4 T cells | Day 30 | CD4 T cell concentration in peripheral blood (cells/µL) |
| Peripheral blood flow cytometry - CD8 T cells | Day 30 | CD8 T cell concentration in peripheral blood (cells/µL) |
| Peripheral blood flow cytometry - macrophages | Day 30 | Macrophage concentration in peripheral blood (cells/µL) |
| Peripheral blood flow cytometry - neutrophils | Day 30 | Neutrophil concentration in peripheral blood (cells/µL) |
| Survival | baseline to 24 months | Survival and time to death/cause of death (if applicable) of study subjects |
| Bronchiolitis obliterans syndrome | Baseline to 24 months | Incidence of bronchiolitis obliterans syndrome (BOS) |
Countries
United States
Outcome results
None listed