Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects

Idiopathic Pulmonary Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03562416
• Other study ID #: 1199-0329
• Status: Terminated
• Phase: Phase 2
• Start date: July 5, 2019
• Est. completion date: December 21, 2021

Study information

• Verified date: April 2023
• Source: Temple University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: December 21, 2021
• Est. primary completion date: December 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Lung Transplant; Complications
• Pulmonary Fibrosis

Intervention

Drug:
• Nintedanib
Nintedanib (BIBF 1120, Ofev)
• Placebo Oral Tablet
Placebo

Locations

Country	Name	City	State
United States	Temple University Hospital	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Temple University	Boehringer Ingelheim

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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.

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. — View Citation

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. — View Citation

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. — View 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. — View 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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in FEV1	Change in forced expiratory volume in 1 second (FEV1)	Baseline to 24 months
Primary	Change in FVC	Change in forced vital capacity (FVC)	Baseline to 24 months
Secondary	Bronchiolitis obliterans syndrome	Incidence of bronchiolitis obliterans syndrome (BOS)	Baseline to 24 months
Secondary	Bronchial stenosis	Incidence of surgical anastomosis bronchial stenosis	Baseline to 24 months
Secondary	Bronchial dehiscence	Incidence of surgical anastomosis bronchial stenosis	Baseline to 24 months
Secondary	Acute cellular rejection	Incidence of acute cellular rejection of lung allograft	Baseline to 24 months
Secondary	Drug discontinuation	Study drug discontinuation rate due to adverse drug event	Baseline to 24 months
Secondary	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
Secondary	Vascular endothelial growth factor (VEGF) - serum	Change in serum biomarker concentration for VEGF (pg/mL)	Baseline to day 30
Secondary	Vascular endothelial growth factor (VEGF) - BAL	Change in BAL concentration for VEGF (pg/mL)	Baseline to day 30
Secondary	Vascular endothelial growth factor (VEGF) - serum	Change in serum concentration for VEGF (pg/mL)	Baseline to day 300
Secondary	Vascular endothelial growth factor (VEGF) - BAL	Change in BAL concentration for VEGF (pg/mL)	Baseline to day 300
Secondary	Fibroblast growth factor (FGF) - serum	Change in serum concentration for FGF (pg/mL)	Baseline to day 30
Secondary	Fibroblast growth factor (FGF) - BAL	Change in BAL concentration for FGF (pg/mL)	Baseline to day 30
Secondary	Fibroblast growth factor (FGF) - serum	Change in serum concentration for FGF (pg/mL)	Baseline to day 300
Secondary	Fibroblast growth factor (FGF) - BAL	Change in BAL biomarker concentration for FGF (pg/mL)	Baseline to day 300
Secondary	Platelet derived growth factor (PDGF) - serum	Change in serum concentration for PDGF (pg/mL)	Baseline to day 30
Secondary	Platelet derived growth factor (PDGF) - BAL	Change in BAL biomarker concentration for PDGF (pg/mL)	Baseline to day 30
Secondary	Platelet derived growth factor (PDGF) - serum	Change in serum biomarker concentration for PDGF (pg/mL)	Baseline to day 300
Secondary	Platelet derived growth factor (PDGF) - BAL	Change in BAL biomarker concentration for PDGF (pg/mL)	Baseline to day 300
Secondary	Peripheral blood flow cytometry - CD4 T cells	CD4 T cell concentration in peripheral blood (cells/µL)	Day 30
Secondary	Peripheral blood flow cytometry - CD4 T cells	CD4 T cell concentration in peripheral blood (cells/µL)	Day 300
Secondary	Peripheral blood flow cytometry - CD8 T cells	CD8 T cell concentration in peripheral blood (cells/µL)	Day 30
Secondary	Peripheral blood flow cytometry - CD8 T cells	CD8 T cell concentration in peripheral blood (cells/µL)	Day 300
Secondary	Peripheral blood flow cytometry - macrophages	Macrophage concentration in peripheral blood (cells/µL)	Day 30
Secondary	Peripheral blood flow cytometry - macrophages	Macrophage concentration in peripheral blood (cells/µL)	Day 300
Secondary	Peripheral blood flow cytometry - neutrophils	Neutrophil concentration in peripheral blood (cells/µL)	Day 30
Secondary	Peripheral blood flow cytometry - neutrophils	Neutrophil concentration in peripheral blood (cells/µL)	Day 300
Secondary	Survival	Survival and time to death/cause of death (if applicable) of study subjects	baseline to 24 months