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Low enrollment
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| Name | Class |
|---|---|
| Boehringer Ingelheim | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nintedanib | Experimental | Nintedanib 150 mg tablet by mouth twice daily for 24 months. |
|
| Placebo | Placebo Comparator | Placebo tablet by mouth twice daily for 24 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nintedanib | Drug | Nintedanib (BIBF 1120, Ofev) |
|
|
| 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 |
| 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 |
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Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Jonathan A Galli, MD | Temple University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Temple University Hospital | Philadelphia | Pennsylvania | 19140 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12928646 | Background | 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. | |
| 27772668 | Background | 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. |
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| ID | Term |
|---|---|
| D054990 | Idiopathic Pulmonary Fibrosis |
| ID | Term |
|---|---|
| D011658 | Pulmonary Fibrosis |
| D017563 | Lung Diseases, Interstitial |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| C530716 | nintedanib |
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| Placebo Oral Tablet | Drug | Placebo |
|
| 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 |
| 25734735 | Background | 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. |
| 19913395 | Background | 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. |
| 12065382 | Background | 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. |
| 25745043 | Background | 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. |
| 25979625 | Background | 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. |
| Background | 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. |
| 26996931 | Background | 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. |
| 27863518 | Background | 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. |
| Background | 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 |
| 28734935 | Background | 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. |