Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction
| Status: | Recruiting |
|---|---|
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 2/9/2018 |
| Start Date: | January 8, 2018 |
| End Date: | December 2019 |
| Contact: | Aida A Venado Estrada, MD |
| Email: | aida.venado@ucsf.edu |
| Phone: | 415-443-1977 |
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.
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.
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.
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.
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.
We found this trial at
1
site
San Francisco, California 94143
Principal Investigator: Aida A Venado Estrada, MD
Phone: 415-443-1977
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