Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects

• ClinicalTrials.gov Identifier: NCT03562416
• Recruitment Status: Recruiting
• First Posted: June 19, 2018
• Last Update Posted: July 10, 2019
• Sponsor: Temple University
• Collaborator: Boehringer Ingelheim
• Information provided by (Responsible Party): Temple University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Idiopathic Pulmonary Fibrosis; Lung Transplant; Complications	Drug: Nintedanib; Drug: Placebo Oral Tablet	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: July 5, 2019
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in FEV1 [ Time Frame: Baseline to 24 months ]
   Change in forced expiratory volume in 1 second (FEV1)
2. Change in FVC [ Time Frame: Baseline to 24 months ]
   Change in forced vital capacity (FVC)

Secondary Outcome Measures :

1. Bronchiolitis obliterans syndrome [ Time Frame: Baseline to 24 months ]
   Incidence of bronchiolitis obliterans syndrome (BOS)
2. Bronchial stenosis [ Time Frame: Baseline to 24 months ]
   Incidence of surgical anastomosis bronchial stenosis
3. Bronchial dehiscence [ Time Frame: Baseline to 24 months ]
   Incidence of surgical anastomosis bronchial stenosis
4. Acute cellular rejection [ Time Frame: Baseline to 24 months ]
   Incidence of acute cellular rejection of lung allograft
5. Drug discontinuation [ Time Frame: Baseline to 24 months ]
   Study drug discontinuation rate due to adverse drug event
6. Adverse drug events [ Time Frame: Baseline to 24 months ]
   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)
7. Vascular endothelial growth factor (VEGF) - serum [ Time Frame: Baseline to day 30 ]
   Change in serum biomarker concentration for VEGF (pg/mL)
8. Vascular endothelial growth factor (VEGF) - BAL [ Time Frame: Baseline to day 30 ]
   Change in BAL concentration for VEGF (pg/mL)
9. Vascular endothelial growth factor (VEGF) - serum [ Time Frame: Baseline to day 300 ]
   Change in serum concentration for VEGF (pg/mL)
10. Vascular endothelial growth factor (VEGF) - BAL [ Time Frame: Baseline to day 300 ]
    Change in BAL concentration for VEGF (pg/mL)
11. Fibroblast growth factor (FGF) - serum [ Time Frame: Baseline to day 30 ]
    Change in serum concentration for FGF (pg/mL)
12. Fibroblast growth factor (FGF) - BAL [ Time Frame: Baseline to day 30 ]
    Change in BAL concentration for FGF (pg/mL)
13. Fibroblast growth factor (FGF) - serum [ Time Frame: Baseline to day 300 ]
    Change in serum concentration for FGF (pg/mL)
14. Fibroblast growth factor (FGF) - BAL [ Time Frame: Baseline to day 300 ]
    Change in BAL biomarker concentration for FGF (pg/mL)
15. Platelet derived growth factor (PDGF) - serum [ Time Frame: Baseline to day 30 ]
    Change in serum concentration for PDGF (pg/mL)
16. Platelet derived growth factor (PDGF) - BAL [ Time Frame: Baseline to day 30 ]
    Change in BAL biomarker concentration for PDGF (pg/mL)
17. Platelet derived growth factor (PDGF) - serum [ Time Frame: Baseline to day 300 ]
    Change in serum biomarker concentration for PDGF (pg/mL)
18. Platelet derived growth factor (PDGF) - BAL [ Time Frame: Baseline to day 300 ]
    Change in BAL biomarker concentration for PDGF (pg/mL)
19. Peripheral blood flow cytometry - CD4 T cells [ Time Frame: Day 30 ]
    CD4 T cell concentration in peripheral blood (cells/µL)
20. Peripheral blood flow cytometry - CD4 T cells [ Time Frame: Day 300 ]
    CD4 T cell concentration in peripheral blood (cells/µL)
21. Peripheral blood flow cytometry - CD8 T cells [ Time Frame: Day 30 ]
    CD8 T cell concentration in peripheral blood (cells/µL)
22. Peripheral blood flow cytometry - CD8 T cells [ Time Frame: Day 300 ]
    CD8 T cell concentration in peripheral blood (cells/µL)
23. Peripheral blood flow cytometry - macrophages [ Time Frame: Day 30 ]
    Macrophage concentration in peripheral blood (cells/µL)
24. Peripheral blood flow cytometry - macrophages [ Time Frame: Day 300 ]
    Macrophage concentration in peripheral blood (cells/µL)
25. Peripheral blood flow cytometry - neutrophils [ Time Frame: Day 30 ]
    Neutrophil concentration in peripheral blood (cells/µL)
26. Peripheral blood flow cytometry - neutrophils [ Time Frame: Day 300 ]
    Neutrophil concentration in peripheral blood (cells/µL)
27. Survival [ Time Frame: baseline to 24 months ]
    Survival and time to death/cause of death (if applicable) of study subjects

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Francine McGonagle, BSN, RN; 215-707-2682; Francine.McGonagle@tuhs.temple.edu

Contact: Shubhra Srivastava-Malhotra; 215-707-0945; Shubhra.Srivastava-Malhotra@tuhs.temple.edu

Locations

United States, Pennsylvania

Temple University Hospital; Recruiting

Philadelphia, Pennsylvania, United States, 19140

Contact: Francine McGonagle, BSN,RN 215-707-2682 Francine.McGonagle@tuhs.temple.edu

Contact: Shubhra Srivastava-Malhotra 215-707-0945 Shubhra.Srivastava-Malhotra@tuhs.temple.edu

Principal Investigator: Jonathan A Galli, MD

Sub-Investigator: Gerard J Criner, MD

Sub-Investigator: Patrick Mulhall, MD

Sub-Investigator: Kartik Shenoy, MD

Sub-Investigator: James Brown, MD

Sub-Investigator: Thomas Rogers, PhD

Sponsors and Collaborators

Temple University

Boehringer Ingelheim

Investigators

• Principal Investigator: Jonathan A Galli, MD; Temple University

More Information

Publications:

Thabut G, Mal H, Castier Y, Groussard O, Brugière O, Marrash-Chahla R, Lesèche G, Fournier M. Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg. 2003 Aug;126(2):469-75.

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. Review.

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.

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. Review.

Xu Z, Ramachandran S, Gunasekaran M, Zhou F, Trulock E, Kreisel D, Hachem R, Mohanakumar T. MicroRNA-144 dysregulates the transforming growth factor-β 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.

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.

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.

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. pii: S1053-2498(17)31886-7. doi: 10.1016/j.healun.2017.07.002. [Epub ahead of print]

• Responsible Party: Temple University
• ClinicalTrials.gov Identifier: NCT03562416
• Other Study ID Numbers: 1199-0329
• First Posted: June 19, 2018
• Last Update Posted: July 10, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Idiopathic Interstitial Pneumonias; Lung Diseases, Interstitial; Nintedanib; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action