Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction

NCT ID: NCT03359863

Last Updated: 2023-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-07
• Study Completion Date: 2021-10-28

Brief 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.

Conditions

Restrictive Chronic Lung Allograft Dysfunction; Lung Transplant Rejection

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment Arm

Subjects will receive Pirfenidone as part of treatment for their restrictive chronic lung allograft dysfunction (RCLAD).

Group Type: EXPERIMENTAL

Pirfenidone

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Esbriet

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Aida A Venado Estrada, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

University of California, San Francisco

San Francisco, California, United States

Countries

United States

References

Valapour M, Skeans MA, Smith JM, Edwards LB, Cherikh WS, Callahan ER, Israni AK, Snyder JJ, Kasiske BL. Lung. Am J Transplant. 2016 Jan;16 Suppl 2:141-68. doi: 10.1111/ajt.13671.

Reference Type: BACKGROUND

PMID: 26755267 (View on PubMed)

Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014 Feb;33(2):127-33. doi: 10.1016/j.healun.2013.10.022. Epub 2013 Oct 24.

Reference Type: BACKGROUND

PMID: 24374027 (View on PubMed)

Saito T, Horie M, Sato M, Nakajima D, Shoushtarizadeh H, Binnie M, Azad S, Hwang DM, Machuca TN, Waddell TK, Singer LG, Cypel M, Liu M, Paul NS, Keshavjee S. Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction. J Heart Lung Transplant. 2016 Jan;35(1):59-66. doi: 10.1016/j.healun.2015.07.005. Epub 2015 Aug 13.

Reference Type: BACKGROUND

PMID: 26342441 (View on PubMed)

Pakhale SS, Hadjiliadis D, Howell DN, Palmer SM, Gutierrez C, Waddell TK, Chaparro C, Davis RD, Keshavjee S, Hutcheon MA, Singer LG. Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation. J Heart Lung Transplant. 2005 Sep;24(9):1260-8. doi: 10.1016/j.healun.2004.08.026.

Reference Type: BACKGROUND

PMID: 16143243 (View on PubMed)

Ofek E, Sato M, Saito T, Wagnetz U, Roberts HC, Chaparro C, Waddell TK, Singer LG, Hutcheon MA, Keshavjee S, Hwang DM. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013 Mar;26(3):350-6. doi: 10.1038/modpathol.2012.171. Epub 2012 Sep 28.

Reference Type: BACKGROUND

PMID: 23018877 (View on PubMed)

Sato M, Hwang DM, Waddell TK, Singer LG, Keshavjee S. Progression pattern of restrictive allograft syndrome after lung transplantation. J Heart Lung Transplant. 2013 Jan;32(1):23-30. doi: 10.1016/j.healun.2012.09.026.

Reference Type: BACKGROUND

PMID: 23260703 (View on PubMed)

Sato M, Waddell TK, Wagnetz U, Roberts HC, Hwang DM, Haroon A, Wagnetz D, Chaparro C, Singer LG, Hutcheon MA, Keshavjee S. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011 Jul;30(7):735-42. doi: 10.1016/j.healun.2011.01.712. Epub 2011 Mar 17.

Reference Type: BACKGROUND

PMID: 21419659 (View on PubMed)

Todd JL, Jain R, Pavlisko EN, Finlen Copeland CA, Reynolds JM, Snyder LD, Palmer SM. Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction. Am J Respir Crit Care Med. 2014 Jan 15;189(2):159-66. doi: 10.1164/rccm.201306-1155OC.

Reference Type: BACKGROUND

PMID: 24325429 (View on PubMed)

Verleden SE, de Jong PA, Ruttens D, Vandermeulen E, van Raemdonck DE, Verschakelen J, Vanaudenaerde BM, Verleden GM, Vos R. Functional and computed tomographic evolution and survival of restrictive allograft syndrome after lung transplantation. J Heart Lung Transplant. 2014 Mar;33(3):270-7. doi: 10.1016/j.healun.2013.12.011. Epub 2013 Dec 17.

Reference Type: BACKGROUND

PMID: 24461432 (View on PubMed)

Verleden GM, Vos R, Verleden SE, De Wever W, De Vleeschauwer SI, Willems-Widyastuti A, Scheers H, Dupont LJ, Van Raemdonck DE, Vanaudenaerde BM. Survival determinants in lung transplant patients with chronic allograft dysfunction. Transplantation. 2011 Sep 27;92(6):703-8. doi: 10.1097/TP.0b013e31822bf790.

Reference Type: BACKGROUND

PMID: 21836537 (View on PubMed)

Woodrow JP, Shlobin OA, Barnett SD, Burton N, Nathan SD. Comparison of bronchiolitis obliterans syndrome to other forms of chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant. 2010 Oct;29(10):1159-64. doi: 10.1016/j.healun.2010.05.012. Epub 2010 Jun 26.

Reference Type: BACKGROUND

PMID: 20580267 (View on PubMed)

Verleden SE, Ruttens D, Vandermeulen E, Bellon H, Dubbeldam A, De Wever W, Dupont LJ, Van Raemdonck DE, Vanaudenaerde BM, Verleden GM, Benden C, Vos R. Predictors of survival in restrictive chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant. 2016 Sep;35(9):1078-84. doi: 10.1016/j.healun.2016.03.022. Epub 2016 Apr 16.

Reference Type: BACKGROUND

PMID: 27212563 (View on PubMed)

Verleden SE, Todd JL, Sato M, Palmer SM, Martinu T, Pavlisko EN, Vos R, Neyrinck A, Van Raemdonck D, Saito T, Oishi H, Keshavjee S, Greer M, Warnecke G, Gottlieb J, Haverich A. Impact of CLAD Phenotype on Survival After Lung Retransplantation: A Multicenter Study. Am J Transplant. 2015 Aug;15(8):2223-30. doi: 10.1111/ajt.13281. Epub 2015 Apr 30.

Reference Type: BACKGROUND

PMID: 25940517 (View on PubMed)

Fernandez IE, Heinzelmann K, Verleden S, Eickelberg O. Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction. Ann Am Thorac Soc. 2015 Mar;12 Suppl 1:S34-41. doi: 10.1513/AnnalsATS.201410-476MG.

Reference Type: BACKGROUND

PMID: 25830833 (View on PubMed)

Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips JA 3rd, Lansdorp PM, Loyd JE, Armanios MY. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13051-6. doi: 10.1073/pnas.0804280105. Epub 2008 Aug 27.

Reference Type: BACKGROUND

PMID: 18753630 (View on PubMed)

Vos R, Verleden SE, Ruttens D, Vandermeulen E, Yserbyt J, Dupont LJ, Van Raemdonck DE, De Raedt N, Gheysens O, De Jong PA, Verleden GM, Vanaudenaerde BM. Pirfenidone: a potential new therapy for restrictive allograft syndrome? Am J Transplant. 2013 Nov;13(11):3035-40. doi: 10.1111/ajt.12474. Epub 2013 Sep 18.

Reference Type: BACKGROUND

PMID: 24102752 (View on PubMed)

Suhling H, Bollmann B, Gottlieb J. Nintedanib in restrictive chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant. 2016 Jul;35(7):939-40. doi: 10.1016/j.healun.2016.01.1220. Epub 2016 Feb 9. No abstract available.

Reference Type: BACKGROUND

PMID: 26996931 (View on PubMed)

Lancaster L, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, Fishman RS, Glaspole I, Glassberg MK, King TE Jr, Lederer DJ, Lin Z, Nathan SD, Pereira CA, Swigris JJ, Valeyre D, Noble PW. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials. BMJ Open Respir Res. 2016 Jan 12;3(1):e000105. doi: 10.1136/bmjresp-2015-000105. eCollection 2016.

Reference Type: BACKGROUND

PMID: 26835133 (View on PubMed)

Khanna D, Albera C, Fischer A, Khalidi N, Raghu G, Chung L, Chen D, Schiopu E, Tagliaferri M, Seibold JR, Gorina E. An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial. J Rheumatol. 2016 Sep;43(9):1672-9. doi: 10.3899/jrheum.151322. Epub 2016 Jul 1.

Reference Type: BACKGROUND

PMID: 27370878 (View on PubMed)

King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18.

Reference Type: BACKGROUND

PMID: 24836312 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

16-20710

Identifier Type: -

Identifier Source: org_study_id