Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects

Study Overview
=================
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.

Official Title
-----------------
Nintedanib Plus Usual Transplant Care Compared to Usual Transplant Care Alone After Single Lung Transplantation in Patients With Idiopathic Pulmonary Fibrosis: a Pilot Randomized Controlled Trial

Conditions
-----------------
Idiopathic Pulmonary Fibrosis, Lung Transplant; Complications

Intervention / Treatment
-----------------
* Drug: Nintedanib
* Drug: Placebo Oral Tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nintedanib<br>Nintedanib 150 mg tablet by mouth twice daily for 24 months. | Drug: Nintedanib<br>* Nintedanib (BIBF 1120, Ofev)<br>* Other names: Ofev;|
| Placebo Comparator: Placebo<br>Placebo tablet by mouth twice daily for 24 months | Drug: Placebo Oral Tablet<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FEV1 | Change in forced expiratory volume in 1 second (FEV1) | Baseline to 24 months | 
| Change in FVC | Change in forced vital capacity (FVC) | Baseline to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchiolitis obliterans syndrome | Incidence of bronchiolitis obliterans syndrome (BOS) | Baseline to 24 months | 
| Bronchial stenosis | Incidence of surgical anastomosis bronchial stenosis | Baseline to 24 months | 
| Bronchial dehiscence | Incidence of surgical anastomosis bronchial stenosis | Baseline to 24 months | 
| Acute cellular rejection | Incidence of acute cellular rejection of lung allograft | Baseline to 24 months | 
| Drug discontinuation | Study drug discontinuation rate due to adverse drug event | Baseline to 24 months | 
| Adverse drug events | 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) | Baseline to 24 months | 
| Vascular endothelial growth factor (VEGF) - serum | Change in serum biomarker concentration for VEGF (pg/mL) | Baseline to day 30 | 
| Vascular endothelial growth factor (VEGF) - BAL | Change in BAL concentration for VEGF (pg/mL) | Baseline to day 30 | 
| Vascular endothelial growth factor (VEGF) - serum | Change in serum concentration for VEGF (pg/mL) | Baseline to day 300 | 
| Vascular endothelial growth factor (VEGF) - BAL | Change in BAL concentration for VEGF (pg/mL) | Baseline to day 300 | 
| Fibroblast growth factor (FGF) - serum | Change in serum concentration for FGF (pg/mL) | Baseline to day 30 | 
| Fibroblast growth factor (FGF) - BAL | Change in BAL concentration for FGF (pg/mL) | Baseline to day 30 | 
| Fibroblast growth factor (FGF) - serum | Change in serum concentration for FGF (pg/mL) | Baseline to day 300 | 
| Fibroblast growth factor (FGF) - BAL | Change in BAL biomarker concentration for FGF (pg/mL) | Baseline to day 300 | 
| Platelet derived growth factor (PDGF) - serum | Change in serum concentration for PDGF (pg/mL) | Baseline to day 30 | 
| Platelet derived growth factor (PDGF) - BAL | Change in BAL biomarker concentration for PDGF (pg/mL) | Baseline to day 30 | 
| Platelet derived growth factor (PDGF) - serum | Change in serum biomarker concentration for PDGF (pg/mL) | Baseline to day 300 | 
| Platelet derived growth factor (PDGF) - BAL | Change in BAL biomarker concentration for PDGF (pg/mL) | Baseline to day 300 | 
| Peripheral blood flow cytometry - CD4 T cells | CD4 T cell concentration in peripheral blood (cells/µL) | Day 30 | 
| Peripheral blood flow cytometry - CD4 T cells | CD4 T cell concentration in peripheral blood (cells/µL) | Day 300 | 
| Peripheral blood flow cytometry - CD8 T cells | CD8 T cell concentration in peripheral blood (cells/µL) | Day 30 | 
| Peripheral blood flow cytometry - CD8 T cells | CD8 T cell concentration in peripheral blood (cells/µL) | Day 300 | 
| Peripheral blood flow cytometry - macrophages | Macrophage concentration in peripheral blood (cells/µL) | Day 30 | 
| Peripheral blood flow cytometry - macrophages | Macrophage concentration in peripheral blood (cells/µL) | Day 300 | 
| Peripheral blood flow cytometry - neutrophils | Neutrophil concentration in peripheral blood (cells/µL) | Day 30 | 
| Peripheral blood flow cytometry - neutrophils | Neutrophil concentration in peripheral blood (cells/µL) | Day 300 | 
| Survival | Survival and time to death/cause of death (if applicable) of study subjects | baseline to 24 months |