Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects

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

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.

Study Overview

• Status: Terminated
• Conditions: Idiopathic Pulmonary Fibrosis; Lung Transplant; Complications
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Nintedanib

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Francine McGonagle, BSN, RN; Phone Number: 215-707-2682; Email: Francine.McGonagle@tuhs.temple.edu
• Study Contact Backup: Name: Shubhra Srivastava-Malhotra; Phone Number: 215-707-0945; Email: Shubhra.Srivastava-Malhotra@tuhs.temple.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Temple University
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Jonathan A Galli, MD, Temple University

Publications and helpful links

General Publications

• Suhling H, Bollmann B, Gottlieb J. Nintedanib in restrictive chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant. 2016 Jul;35(7):939-40. doi: 10.1016/j.healun.2016.01.1220. Epub 2016 Feb 9. No abstract available.
• Thabut G, Mal H, Castier Y, Groussard O, Brugiere O, Marrash-Chahla R, Leseche G, Fournier M. Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg. 2003 Aug;126(2):469-75. doi: 10.1016/s0022-5223(03)00600-7.
• Lund LH, Edwards LB, Dipchand AI, Goldfarb S, Kucheryavaya AY, Levvey BJ, Meiser B, Rossano JW, Yusen RD, Stehlik J; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant. 2016 Oct;35(10):1158-1169. doi: 10.1016/j.healun.2016.08.017. Epub 2016 Aug 21. No abstract available.
• Schaffer JM, Singh SK, Reitz BA, Zamanian RT, Mallidi HR. Single- vs double-lung transplantation in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis since the implementation of lung allocation based on medical need. JAMA. 2015 Mar 3;313(9):936-48. doi: 10.1001/jama.2015.1175.
• Elicker BM, Golden JA, Ordovas KG, Leard L, Golden TR, Hays SR. Progression of native lung fibrosis in lung transplant recipients with idiopathic pulmonary fibrosis. Respir Med. 2010 Mar;104(3):426-33. doi: 10.1016/j.rmed.2009.10.019. Epub 2009 Nov 12.
• Wahidi MM, Ravenel J, Palmer SM, McAdams HP. Progression of idiopathic pulmonary fibrosis in native lungs after single lung transplantation. Chest. 2002 Jun;121(6):2072-6. doi: 10.1378/chest.121.6.2072.
• 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.
• 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.
• Sjoland AA, Callerfelt AK, Thiman L, et al. Prostacyclin and VEGF in the rejection process after lung transplantation-A possible biomarker [abstract]. Eur Respir J. 2016; PA4040.
• Delanote I, Wuyts WA, Yserbyt J, Verbeken EK, Verleden GM, Vos R. Safety and efficacy of bridging to lung transplantation with antifibrotic drugs in idiopathic pulmonary fibrosis: a case series. BMC Pulm Med. 2016 Nov 18;16(1):156. doi: 10.1186/s12890-016-0308-z.
• Dorey-Stein Z, Galli JA, Criner GJ. Effect of antifibrotic therapy in patients with idiopathic pulmonary fibrosis awaiting lung transplantation [abstract]. Am J Respir Crit Care Med. 2017;195:A5386
• Leuschner G, Stocker F, Veit T, Kneidinger N, Winter H, Schramm R, Weig T, Matthes S, Ceelen F, Arnold P, Munker D, Klenner F, Hatz R, Frankenberger M, Behr J, Neurohr C. Outcome of lung transplantation in idiopathic pulmonary fibrosis with previous anti-fibrotic therapy. J Heart Lung Transplant. 2017 Jul 5:S1053-2498(17)31886-7. doi: 10.1016/j.healun.2017.07.002. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2019
• Primary Completion (Actual): December 21, 2021
• Study Completion (Actual): December 21, 2021

Study Registration Dates

• First Submitted: May 7, 2018
• First Submitted That Met QC Criteria: June 7, 2018
• First Posted (Actual): June 19, 2018

Study Record Updates

• Last Update Posted (Actual): April 7, 2023
• Last Update Submitted That Met QC Criteria: April 5, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 1199-0329

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No