Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction

NCT03359863 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 16-20710
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Restrictive Chronic Lung Allograft Dysfunction; Lung Transplant Rejection

Outcome Measures

Primary Outcomes (2)

• Tolerability of Pirfenidone

  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

  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 Outcomes (4)

• Annual Change in Forced Vital Capacity (FVC)

  FVC change from baseline (screening) to 1 year or death, whichever comes first.

• Annual Change in Forced Expiratory Volume in 1 Second (FEV1)

  FEV1 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

  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 Traction Bronchiectasis Score on Chest CT Scan

  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.

Study Arms (1)

Treatment Arm

EXPERIMENTAL

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

Drug: Pirfenidone

Interventions

Pirfenidone 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.

Also known as: Esbriet

Treatment Arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Genentech, Inc.: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (20)

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  PMID: 26755267 BACKGROUND

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  PMID: 24374027 BACKGROUND

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  PMID: 26342441 BACKGROUND

• 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.

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• 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.

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• 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.

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• 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.

  PMID: 21419659 BACKGROUND

• 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.

  PMID: 24325429 BACKGROUND

• 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.

  PMID: 24461432 BACKGROUND

• 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.

  PMID: 21836537 BACKGROUND

• 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.

  PMID: 20580267 BACKGROUND

• 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.

  PMID: 27212563 BACKGROUND

• 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.

  PMID: 25940517 BACKGROUND

• 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.

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• 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.

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• 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.

  PMID: 24102752 BACKGROUND

• 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.

  PMID: 26996931 BACKGROUND

• 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.

  PMID: 26835133 BACKGROUND

• 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.

  PMID: 27370878 BACKGROUND

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  PMID: 24836312 BACKGROUND

MeSH Terms

Interventions

pirfenidone

Limitations and Caveats

Small, single-center cohort with an open-label intervention.

Results Point of Contact

• Title: Aida Venado, MD, MAS
• Organization: University of California at San Francisco

aida.venado@ucsf.edu

4153532577

Study Officials

• Aida A Venado Estrada, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2017
• First Posted: December 2, 2017
• Study Start: March 7, 2018
• Primary Completion: October 28, 2021
• Study Completion: October 28, 2021
• Last Updated: June 29, 2023
• Results First Posted: January 9, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)