Clinical trial NCT03562416: Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Lung Transplant; Complications
Lead sponsor: Temple University
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2018-06-19
Enrollment: 1
Sex: ALL
Minimum age (years): 35
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in FEV1
timeFrame: Baseline to 24 months
measure: Change in FVC
timeFrame: Baseline to 24 months
Secondary outcomes:
measure: Bronchiolitis obliterans syndrome
timeFrame: Baseline to 24 months
measure: Bronchial stenosis
timeFrame: Baseline to 24 months
measure: Bronchial dehiscence
timeFrame: Baseline to 24 months
measure: Acute cellular rejection
timeFrame: Baseline to 24 months
measure: Drug discontinuation
timeFrame: Baseline to 24 months
measure: Adverse drug events
timeFrame: Baseline to 24 months
measure: Vascular endothelial growth factor (VEGF) - serum
timeFrame: Baseline to day 30
measure: Vascular endothelial growth factor (VEGF) - BAL
timeFrame: Baseline to day 30
measure: Vascular endothelial growth factor (VEGF) - serum
timeFrame: Baseline to day 300
measure: Vascular endothelial growth factor (VEGF) - BAL
timeFrame: Baseline to day 300
measure: Fibroblast growth factor (FGF) - serum
timeFrame: Baseline to day 30
measure: Fibroblast growth factor (FGF) - BAL
timeFrame: Baseline to day 30
measure: Fibroblast growth factor (FGF) - serum
timeFrame: Baseline to day 300
measure: Fibroblast growth factor (FGF) - BAL
timeFrame: Baseline to day 300
measure: Platelet derived growth factor (PDGF) - serum
timeFrame: Baseline to day 30
measure: Platelet derived growth factor (PDGF) - BAL
timeFrame: Baseline to day 30
measure: Platelet derived growth factor (PDGF) - serum
timeFrame: Baseline to day 300
measure: Platelet derived growth factor (PDGF) - BAL
timeFrame: Baseline to day 300
measure: Peripheral blood flow cytometry - CD4 T cells
timeFrame: Day 30
measure: Peripheral blood flow cytometry - CD4 T cells
timeFrame: Day 300
measure: Peripheral blood flow cytometry - CD8 T cells
timeFrame: Day 30
measure: Peripheral blood flow cytometry - CD8 T cells
timeFrame: Day 300
measure: Peripheral blood flow cytometry - macrophages
timeFrame: Day 30
measure: Peripheral blood flow cytometry - macrophages
timeFrame: Day 300
measure: Peripheral blood flow cytometry - neutrophils
timeFrame: Day 30
measure: Peripheral blood flow cytometry - neutrophils
timeFrame: Day 300
measure: Survival
timeFrame: baseline to 24 months
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
Study officials:
affiliation: Temple University
name: Jonathan A Galli, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015 May;45(5):1434-45. doi: 10.1183/09031936.00174914. Epub 2015 Mar 5.
citation: Xu Z, Ramachandran S, Gunasekaran M, Zhou F, Trulock E, Kreisel D, Hachem R, Mohanakumar T. MicroRNA-144 dysregulates the transforming growth factor-beta signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation. J Heart Lung Transplant. 2015 Sep;34(9):1154-62. doi: 10.1016/j.healun.2015.03.021. Epub 2015 Mar 27.
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