Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction
Condition: Restrictive Chronic Lung Allograft Dysfunction; Lung Transplant Rejection
Study type: Interventional
Phase: Phase 2

Summary: 
      Despite advances in lung transplantation, the median survival remains only 55% at 5 years.
      The main limitation to long term survival is the development of chronic lung allograft
      dysfunction. In approximately 30% of cases, chronic lung allograft dysfunction has a
      restrictive phenotype (RCLAD) characterized by fibrosis with rapid progression to respiratory
      failure. Approximately 60% of patients with RCLAD die within one year, as currently there are
      no therapies available.

      RCLAD, like Idiopathic Pulmonary Fibrosis (IPF), is characterized by fibroblast
      proliferation, extracellular matrix deposition, and architectural distortion leading to
      progressive lung scarring and death. Given their similarities, there is keen interest in the
      international transplant community to investigate whether the anti-fibrotic drug pirfenidone
      can slow the progression of RCLAD as it does of IPF. Pirfenidone has been proved to be safe
      and effective in patients with IPF, and is approved by the Food and Drug Administration.

      This protocol will evaluate the safety and tolerability of pirfenidone in lung transplant
      recipients with RCLAD. Transplant recipients take carefully adjusted immunosuppressive
      medications for life to prevent rejection of the allograft. Current literature suggests the
      dose of tacrolimus, the main anti-rejection drug, may need to be adjusted when taken in
      combination with pirfenidone. The investigators will assess the side effects of pirfenidone
      in combination with the immunosuppressive regimen and determine the magnitude of the
      adjustment in tacrolimus dose. The results of this pilot study will provide the foundation
      for a multicenter randomized control trial to evaluate the efficacy of pirfenidone in slowing
      the progression of RCLAD.
    

Detailed description: 
      Despite advances in lung transplantation, median survival remains only 55% at 5 years. The
      primary cause of death is chronic lung allograft dysfunction (CLAD), occurring in 43% of
      recipients at 5 years. Recently, it has been recognized that CLAD can have an obstructive
      (BOS) or a restrictive (RCLAD) phenotype, also known as restrictive allograft syndrome (RAS),
      and that both may coexist. These phenotypes differ not only in their spirometric,
      radiographic and histologic features but also in their rates of progression and survival.
      Thus, there is a critical need to find therapies other than re-transplantation, which remains
      the only effective therapeutic option and explore the pathobiology driving RCLAD.

      RCLAD shares features with Idiopathic Pulmonary Fibrosis (IPF), including its progressive and
      lethal course, extracellular matrix deposition, architectural distortion, fibroblast
      proliferation, and short telomeres in lung epithelial cells. These common features suggest
      RCLAD and IPF may share molecular pathogenesis. As a result, some have explored using FDA
      approved anti-fibrotic medications for IPF in RCLAD in case reports.

      This proposal aims to gather the preliminary data needed to design a multicenter randomized
      controlled trial (RCT) of pirfenidone for RCLAD. To do so, the investigators first need
      evidence of tolerability, to understand drug interactions with the immunosuppressive regimen
      used to maintain allograft function and early evidence that pirfenidone may slow FVC decline
      and radiographic progression in RCLAD.

      Evidence that pirfenidone is well tolerated in transplant recipients and that it slows the
      progression of RCLAD would be paradigm shifting. Further, identifying subjects at risk for
      RCLAD before the onset of spirometric changes would allow to start therapeutic interventions
      sooner, maximizing their benefit. Finding biomarkers that predict response to pirfenidone
      would identify patients most likely to benefit.
    

Intervention name(s): Pirfenidone
Intervention type(s): Drug
Intervention description(s): Subjects will receive pirfenidone for 52 weeks, titrated to 2403 mg/day (3 capsules, 3× daily) after a 4-week titration period (1 capsule, 3x daily for 2 weeks, 2 capsules, 3x daily for 2 weeks) for a total of 56 weeks of pirfenidone. Eligible participants will continue pirfenidone beyond 56 weeks.
Other intervention name(s): Esbriet
Intervention MeSH terms: Pirfenidone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment