Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction (PIRCLAD)

June 14, 2023 updated by: University of California, San Francisco

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143
        • University of California, San Francisco

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment Arm
Subjects will receive Pirfenidone as part of treatment for their restrictive chronic lung allograft dysfunction (RCLAD).
Drug: Pirfenidone
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 Names:
  • Esbriet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tolerability of Pirfenidone
Time Frame: From initiation of pirfenidone until discontinuation or until 56 weeks, which ever comes first.
The primary outcome will be the number of subjects that discontinue pirfenidone due to a treatment emergent adverse event (TEAE)
From initiation of pirfenidone until discontinuation or until 56 weeks, which ever comes first.
Conversion Ratio of Tacrolimus Dose
Time Frame: From initiation of pirfenidone until discontinuation or until 56 weeks, which ever comes first.
The outcome will be the ratio of tacrolimus-while-taking-pirfenidone to tacrolimus-before-pirfenidone corrected for the subject's specific steady-state tacrolimus concentration.
From initiation of pirfenidone until discontinuation or until 56 weeks, which ever comes first.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Annual Change in Forced Vital Capacity (FVC)
Time Frame: FVC change from baseline (screening) to 1 year or death, whichever comes first.
The investigators will evaluate change in FVC from baseline to 1 year after pirfenidone start based on pulmonary function tests done as part of routine clinical care (usually obtained every 3 months) or death, whichever comes first.
FVC change from baseline (screening) to 1 year or death, whichever comes first.
Annual Change in Percent of Lung Affected by Reticulation on Chest CT Scan
Time Frame: Change between chest CT at screening and in 1-year follow up CT scan performed as part of routine clinical care or death, whichever comes first.
The investigators will evaluate the annual change in percent of lung affected by reticulation comparing the chest CT scan at screening and a 1-year follow up CT scan performed as part of routine clinical care or death, whichever comes first.
Change between chest CT at screening and in 1-year follow up CT scan performed as part of routine clinical care or death, whichever comes first.
Annual Change in Forced Expiratory Volume in 1 Second (FEV1)
Time Frame: FEV1 change from baseline (screening) to 1 year or death, whichever comes first.
The investigators will evaluate change in FEV1 from baseline to 1 year based on pulmonary function tests done as part of routine clinical care (usually obtained every 3 months) or death, whichever comes first.
FEV1 change from baseline (screening) to 1 year or death, whichever comes first.
Annual Change in Traction Bronchiectasis Score on Chest CT Scan
Time Frame: Change between Chest CT at screening and 1-year follow up CT scan performed as part of routine clinical care or death, whichever comes first.
The investigators will evaluate the change in traction bronchiectasis score on chest CT scan at screening and in a 1-year follow up CT scan performed as part of routine clinical care or death, whichever comes first. The extent of traction bronchiectasis was first scored in each of the six lung lobes separately (right upper, middle, and lower lobes, and left upper, lingula, and lower lobes) as 0-absent, 1-mild, 2-moderate, or 3-severe, and then summed into a total traction bronchiectasis score [range 0-18 points], with higher values reflecting greater extent of traction bronchiectasis.
Change between Chest CT at screening and 1-year follow up CT scan performed as part of routine clinical care or death, whichever comes first.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Collaborators

Genentech, Inc.

Investigators

  • Principal Investigator: Aida A Venado Estrada, MD, University of California, San Francisco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 7, 2018

Primary Completion (Actual)

October 28, 2021

Study Completion (Actual)

October 28, 2021

Study Registration Dates

First Submitted

November 15, 2017

First Submitted That Met QC Criteria

November 30, 2017

First Posted (Actual)

December 2, 2017

Study Record Updates

Last Update Posted (Actual)

June 29, 2023

Last Update Submitted That Met QC Criteria

June 14, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 16-20710

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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