Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction
Condition: Restrictive Chronic Lung Allograft Dysfunction; Lung Transplant Rejection
Intervention: Pirfenidone
Intervention description: 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.
Intervention MeSH terms: Pirfenidone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject who underwent bilateral lung transplantation at University of California San
             Francisco (UCSF) and have a diagnosis of RCLAD based on the International Heart and
             Lung Transplant (ISHLT) classification. The diagnosis of RCLAD is based on spirometry
             (Forced Expiratory Volume in 1 second (FEV1) ≤ 80% and FVC ≤ 80% of best
             post-transplant baseline) and CT scan (e.g. pleuroparenchymal fibroelastosis)
             findings.

        Exclusion Criteria:

          -  FVC decline related to non-RCLAD causes (e.g. pulmonary edema, pleural effusion, etc).

          -  Patients with any severe comorbidity complicating RCLAD which might determine their
             prognosis and functional level (e.g. active malignant disease) within the last 12
             months

          -  Patients who have resumed smoking after transplantation

          -  Renal insufficiency (creatinine clearance < 30 ml/min calculated by the CKD-Epi
             formula)

          -  Total bilirubin above the upper limit of the normal range (ULN)

          -  Aspartate or alanine aminotransferase (AST or ALT) > 3 times the ULN.

          -  Known allergy of hypersensitivity to Pirfenidone

          -  Pregnancy

          -  Ongoing use or expected use of any of the following therapies:

          -  Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin).

          -  Moderate inhibitors of CAYP1A2 (e. g. mexiletine, thiabendazole, or
             phenylpropanolamine). Ciprofloxacin will be allowed only at doses equal or less than
             500 mg BID.

          -  Inability to provide informed consent.