Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects
- Conditions
- Idiopathic Pulmonary FibrosisLung Transplant; Complications
- Interventions
- Drug: Placebo Oral Tablet
- Registration Number
- NCT03562416
- Lead Sponsor
- Temple University
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 1
- Adults between the ages of 35-70.
- Lung transplantation listing diagnosis of pulmonary fibrosis
- Recipient of single lung transplantation within the past 60 days
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Nintedanib Nintedanib Nintedanib 150 mg tablet by mouth twice daily for 24 months. Placebo Placebo Oral Tablet Placebo tablet by mouth twice daily for 24 months
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method Bronchial stenosis Baseline to 24 months Incidence of surgical anastomosis bronchial stenosis
Peripheral blood flow cytometry - CD8 T cells Day 300 CD8 T cell concentration in peripheral blood (cells/µL)
Vascular endothelial growth factor (VEGF) - serum Baseline to day 300 Change in serum concentration for VEGF (pg/mL)
Bronchiolitis obliterans syndrome Baseline to 24 months Incidence of bronchiolitis obliterans syndrome (BOS)
Drug discontinuation Baseline to 24 months Study drug discontinuation rate due to adverse drug event
Fibroblast growth factor (FGF) - BAL Baseline to day 300 Change in BAL biomarker concentration for FGF (pg/mL)
Peripheral blood flow cytometry - macrophages Day 300 Macrophage concentration in peripheral blood (cells/µL)
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)
Platelet derived growth factor (PDGF) - serum Baseline to day 300 Change in serum biomarker concentration for PDGF (pg/mL)
Platelet derived growth factor (PDGF) - BAL Baseline to day 300 Change in BAL biomarker concentration for PDGF (pg/mL)
Fibroblast growth factor (FGF) - serum Baseline to day 300 Change in serum concentration for FGF (pg/mL)
Peripheral blood flow cytometry - CD4 T cells Day 300 CD4 T cell concentration in peripheral blood (cells/µL)
Peripheral blood flow cytometry - neutrophils Day 300 Neutrophil concentration in peripheral blood (cells/µL)
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
Vascular endothelial growth factor (VEGF) - BAL Baseline to day 300 Change in BAL concentration for VEGF (pg/mL)
Survival baseline to 24 months Survival and time to death/cause of death (if applicable) of study subjects
Trial Locations
- Locations (1)
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States