Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects

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.

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