Studying the Treatment Effect of Pirfenidone in Chronic Lung Allograft Dysfunction (STOP-CLAD)

A Phase Two Randomized, Double-blinded, Placebo-controlled Study Combining Physiological, Radiographic, and Biological Biomarkers to Study the Anti-fibrotic Effect of Pirfenidone in CLAD Post Lung-transplantation

Greater than 50% of lung transplant recipients show signs of chronic lung allograft dysfunction (CLAD) by 5 years post-transplantation.Therapies to prevent or slow CLAD are lacking. Anti-fibrotic therapies may offer an avenue to prevent progression of CLAD and prolong allograft survival. This study investigates if Pirfenidone therapy will stabilize lung function decline and slow progression of Functional small airways disease (fSAD) in lung transplant recipients with CLAD.

Study Overview

• Status: Terminated
• Conditions: Chronic Lung Allograft Dysfunction; Disorder Related to Lung Transplantation
• Intervention / Treatment: Drug: Pirfenidone Capsule; Drug: Placebo Capsule

Detailed Description

The study aimed to enroll lung transplant recipients with an established diagnosis of CLAD. The patients were randomized to receive an anti-fibrotic drug Pirfenidone or Placebo pills for 6 month period. High-resolution CT scan of the chest was utilized to measure the primary endpoint of change in functional small airway disease (fSAD). Pulmonary function testing and spirometry were utilized to measure the secondary endpoint of change in FEV1 and FVC.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • The University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Lung transplant recipients 18 years of age or older
• Greater than 6 months after single or bilateral lung transplantation
• Baseline FEV1 and FVC values (mean of two highest value measured 3 weeks apart) > 50% predicted (to assure viable graft)
• Diagnosis of CLAD (two consecutive spirometric values of FEV1 alone or both FEV1 and FVC < 80% of baseline)

Exclusion Criteria

• Acute Rejection (AR) diagnosis by biopsy in the 28 days prior to enrollment
• Treatment with pulse steroids, Anti-thymocyte Globulin (ATG), extracorporeal photopheresis (ECP), plasmapheresis, or Immunoglobulin therapy aimed at CLAD within the 28 days prior to enrollment
• If the subject is receiving chronic Azithromycin therapy, the dose must be stable for the 28 days prior to enrollment
• Presence of active pulmonary infection at the time of enrollment as determined by an investigator in consultation with the treating pulmonologist
• Diagnosis of bronchial stenosis either a) requiring stenting, or b) thought to be responsible for the spirometric decline by principal investigator
• Abnormal liver function tests (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 x upper limit of normal (ULN), Alkaline phosphatase > 2.5 x ULN, total bilirubin > ULN) or known cirrhosis (>2 times upper limit of normal of AST/ALT/AP)
• Total white blood cell (WBC) < 3.0 K/uL
• Moderate to Severe Renal insufficiency (CrCl <15 mL/min calculated by the Cockcroft-Gault equation)
• Use of any medication known to cause significant interactions with pirfenidone (strong CYP1A2 inhibitors such as Fluvoxamine or Enoxacin or inducers)
• Pregnancy or lactation. Women of child-bearing potential will have a pregnancy test at enrollment and must agree to maintain highly effective contraception with two methods of birth control from the date of consent through the end of the study.
• Tobacco use within 6 months
• History of alcohol abuse in the past 1 year as determined by the treating pulmonologist
• Any condition other than CLAD that will likely result in death in the next 1 year
• Any condition in the judgement of the principal investigator that would preclude participation in this study
• EKG with QTc interval > 500 msec at screening
• Listed for repeat lung transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pirfenidone Capsule; Method of Administration: Oral (capsule) Dosing: Days 1 through 7, 267 mg three times daily;; Days 8 through 14, 534 mg three times daily;; Days 15 through end of treatment (24 weeks), 801 mg three times daily	Drug: Pirfenidone Capsule; Dosing: Days 1 through 7, 267 mg three times daily; Days 8 through 14, 534 mg three times daily; Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks; Other Names: Esbriet
Placebo Comparator: Placebo Capsule; Method of Administration: Oral (capsule) Dosing: Days 1 through 7, 267 mg three times daily;; Days 8 through 14, 534 mg three times daily;; Days 15 through end of treatment (24 weeks), 801 mg three times daily	Drug: Placebo Capsule; Dosing: Days 1 through 7, 267 mg three times daily;; Days 8 through 14, 534 mg three times daily;; Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping	Evaluate if pirfenidone compared to placebo will stabilize progression of fSAD by comparison of inspiratory and expiratory high resolution computed tomography (HRCT) images through co-registration to provide quantitative measures of fSAD.	Baseline, 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1)	Measured by spirometry	Baseline, 24 weeks
Change in Forced Vital Capacity (FVC) Over 24 Weeks	Measured by spirometry	Baseline, 24 weeks
Number of Adverse Events Related to Study Treatment	Safety of pirfenidone will be measured by adverse events determined to be related to the study drug through review of medical history, physical exam and laboratory findings.	28 weeks
Number of Subjects With Treatment Intolerance	Subjects permanently discontinuing study medication before 24 weeks	24 weeks

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Vibha Lama, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2018
• Primary Completion (Actual): July 23, 2021
• Study Completion (Actual): August 20, 2021

Study Registration Dates

• First Submitted: March 14, 2018
• First Submitted That Met QC Criteria: March 14, 2018
• First Posted (Actual): March 22, 2018

Study Record Updates

• Last Update Posted (Actual): August 17, 2022
• Last Update Submitted That Met QC Criteria: July 23, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Lung Transplant; CLAD; Chronic Rejection
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Pirfenidone
• Other Study ID Numbers: HUM00131610

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.: No