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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

Tracking Information
First Submitted Date  ICMJE May 7, 2018
First Posted Date  ICMJE June 19, 2018
Last Update Posted Date July 10, 2019
Actual Study Start Date  ICMJE July 5, 2019
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2018)
  • Change in FEV1 [ Time Frame: Baseline to 24 months ]
    Change in forced expiratory volume in 1 second (FEV1)
  • Change in FVC [ Time Frame: Baseline to 24 months ]
    Change in forced vital capacity (FVC)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2019)
  • Bronchiolitis obliterans syndrome [ Time Frame: Baseline to 24 months ]
    Incidence of bronchiolitis obliterans syndrome (BOS)
  • Bronchial stenosis [ Time Frame: Baseline to 24 months ]
    Incidence of surgical anastomosis bronchial stenosis
  • Bronchial dehiscence [ Time Frame: Baseline to 24 months ]
    Incidence of surgical anastomosis bronchial stenosis
  • Acute cellular rejection [ Time Frame: Baseline to 24 months ]
    Incidence of acute cellular rejection of lung allograft
  • Drug discontinuation [ Time Frame: Baseline to 24 months ]
    Study drug discontinuation rate due to adverse drug event
  • 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)
  • Vascular endothelial growth factor (VEGF) - serum [ Time Frame: Baseline to day 30 ]
    Change in serum biomarker concentration for VEGF (pg/mL)
  • Vascular endothelial growth factor (VEGF) - BAL [ Time Frame: Baseline to day 30 ]
    Change in BAL concentration for VEGF (pg/mL)
  • Vascular endothelial growth factor (VEGF) - serum [ Time Frame: Baseline to day 300 ]
    Change in serum concentration for VEGF (pg/mL)
  • Vascular endothelial growth factor (VEGF) - BAL [ Time Frame: Baseline to day 300 ]
    Change in BAL concentration for VEGF (pg/mL)
  • Fibroblast growth factor (FGF) - serum [ Time Frame: Baseline to day 30 ]
    Change in serum concentration for FGF (pg/mL)
  • Fibroblast growth factor (FGF) - BAL [ Time Frame: Baseline to day 30 ]
    Change in BAL concentration for FGF (pg/mL)
  • Fibroblast growth factor (FGF) - serum [ Time Frame: Baseline to day 300 ]
    Change in serum concentration for FGF (pg/mL)
  • Fibroblast growth factor (FGF) - BAL [ Time Frame: Baseline to day 300 ]
    Change in BAL biomarker concentration for FGF (pg/mL)
  • Platelet derived growth factor (PDGF) - serum [ Time Frame: Baseline to day 30 ]
    Change in serum concentration for PDGF (pg/mL)
  • Platelet derived growth factor (PDGF) - BAL [ Time Frame: Baseline to day 30 ]
    Change in BAL biomarker concentration for PDGF (pg/mL)
  • Platelet derived growth factor (PDGF) - serum [ Time Frame: Baseline to day 300 ]
    Change in serum biomarker concentration for PDGF (pg/mL)
  • Platelet derived growth factor (PDGF) - BAL [ Time Frame: Baseline to day 300 ]
    Change in BAL biomarker concentration for PDGF (pg/mL)
  • Peripheral blood flow cytometry - CD4 T cells [ Time Frame: Day 30 ]
    CD4 T cell concentration in peripheral blood (cells/µL)
  • Peripheral blood flow cytometry - CD4 T cells [ Time Frame: Day 300 ]
    CD4 T cell concentration in peripheral blood (cells/µL)
  • Peripheral blood flow cytometry - CD8 T cells [ Time Frame: Day 30 ]
    CD8 T cell concentration in peripheral blood (cells/µL)
  • Peripheral blood flow cytometry - CD8 T cells [ Time Frame: Day 300 ]
    CD8 T cell concentration in peripheral blood (cells/µL)
  • Peripheral blood flow cytometry - macrophages [ Time Frame: Day 30 ]
    Macrophage concentration in peripheral blood (cells/µL)
  • Peripheral blood flow cytometry - macrophages [ Time Frame: Day 300 ]
    Macrophage concentration in peripheral blood (cells/µL)
  • Peripheral blood flow cytometry - neutrophils [ Time Frame: Day 30 ]
    Neutrophil concentration in peripheral blood (cells/µL)
  • Peripheral blood flow cytometry - neutrophils [ Time Frame: Day 300 ]
    Neutrophil concentration in peripheral blood (cells/µL)
  • Survival [ Time Frame: baseline to 24 months ]
    Survival and time to death/cause of death (if applicable) of study subjects
Original Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2018)
  • Bronchiolitis obliterans syndrome [ Time Frame: Baseline to 24 months ]
    Incidence of bronchiolitis obliterans syndrome (BOS)
  • Bronchial stenosis [ Time Frame: Baseline to 24 months ]
    Incidence of surgical anastomosis bronchial stenosis
  • Bronchial dehiscence [ Time Frame: Baseline to 24 months ]
    Incidence of surgical anastomosis bronchial stenosis
  • Acute cellular rejection [ Time Frame: Baseline to 24 months ]
    Incidence of acute cellular rejection of lung allograft
  • Drug discontinuation [ Time Frame: Baseline to 24 months ]
    Study drug discontinuation rate due to adverse drug event
  • 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)
  • Vascular endothelial growth factor (VEGF) [ Time Frame: Baseline to day 30 ]
    Change in serum biomarker concentration for VEGF (pg/mL)
  • Vascular endothelial growth factor (VEGF) [ Time Frame: Baseline to day 300 ]
    Change in serum biomarker concentration for VEGF (pg/mL)
  • Fibroblast growth factor (FGF) [ Time Frame: Baseline to day 30 ]
    Change in serum biomarker concentration for FGF (pg/mL)
  • Fibroblast growth factor (FGF) [ Time Frame: Baseline to day 300 ]
    Change in serum biomarker concentration for FGF (pg/mL)
  • Platelet derived growth factor (PDGF) [ Time Frame: Baseline to day 30 ]
    Change in serum biomarker concentration for PDGF (pg/mL)
  • Platelet derived growth factor (PDGF) [ Time Frame: Baseline to day 300 ]
    Change in serum biomarker concentration for PDGF (pg/mL)
  • BAL flow cytometry - CD4 T cells [ Time Frame: Day 30 ]
    CD4 T cell concentration in BAL fluid (cells/µL)
  • BAL flow cytometry - CD4 T cells [ Time Frame: Day 300 ]
    CD4 T cell concentration in BAL fluid (cells/µL)
  • BAL flow cytometry - CD8 T cells [ Time Frame: Day 30 ]
    CD8 T cell concentration in BAL fluid (cells/µL)
  • BAL flow cytometry - CD8 T cells [ Time Frame: Day 300 ]
    CD8 T cell concentration in BAL fluid (cells/µL)
  • BAL flow cytometry - macrophages [ Time Frame: Day 30 ]
    Macrophage concentration in BAL fluid (cells/µL)
  • BAL flow cytometry - macrophages [ Time Frame: Day 300 ]
    Macrophage concentration in BAL fluid (cells/µL)
  • BAL flow cytometry - neutrophils [ Time Frame: Day 30 ]
    Neutrophil concentration in BAL fluid (cells/µL)
  • BAL flow cytometry - neutrophils [ Time Frame: Day 300 ]
    Neutrophil concentration in BAL fluid (cells/µL)
  • Survival [ Time Frame: baseline to 24 months ]
    Survival and time to death/cause of death (if applicable) of study subjects
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Continuation of Nintedanib After Single Lung Transplantation in IPF Subjects
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Idiopathic Pulmonary Fibrosis
  • Lung Transplant; Complications
Intervention  ICMJE
  • Drug: Nintedanib
    Nintedanib (BIBF 1120, Ofev)
    Other Names:
    • BIBF 1120
    • Ofev
  • Drug: Placebo Oral Tablet
    Placebo
Study Arms  ICMJE
  • Experimental: Nintedanib
    Nintedanib 150 mg tablet by mouth twice daily for 24 months.
    Intervention: Drug: Nintedanib
  • Placebo Comparator: Placebo
    Placebo tablet by mouth twice daily for 24 months
    Intervention: Drug: Placebo Oral Tablet
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 7, 2018)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 35 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03562416
Other Study ID Numbers  ICMJE 1199-0329
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Temple University
Study Sponsor  ICMJE Temple University
Collaborators  ICMJE Boehringer Ingelheim
Investigators  ICMJE
Principal Investigator: Jonathan A Galli, MD Temple University
PRS Account Temple University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP