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Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects

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

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.

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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


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




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



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03562416


Contacts
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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
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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
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Principal Investigator: Jonathan A Galli, MD Temple University
Publications:
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.
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

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Responsible Party: Temple University
ClinicalTrials.gov Identifier: NCT03562416    
Other Study ID Numbers: 1199-0329
First Posted: June 19, 2018    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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