A Phase I Evaluation of the Safety and Tolerability of Pirfenidone in Idiopathic Subglottic Stenosis

Overview

Idiopathic subglottic stenosis (iSGS) is a rare condition where scar tissue forms just below the vocal cords and in the upper windpipe, making the airway narrow. People with iSGS often feel short of breath, hear noisy breathing, and notice changes in their voice. Many need repeated operations and steroid injections to open the airway, but the narrowing usually comes back, so these treatments are not a cure. Recent research from a Canadian iSGS registry and biobank has shown that this disease is driven by overactive scarring pathways, similar to those seen in idiopathic pulmonary fibrosis (IPF), a serious lung disease. Pirfenidone is an oral medication already approved for IPF that works by slowing down the cells and signals that cause scarring. Because the same scarring pathways appear to be active in iSGS, pirfenidone may be able to slow or reduce the build-up of scar tissue in the airway. In this study, adults with iSGS will be randomly assigned (like flipping a coin) to receive either pirfenidone or a placebo (a look-alike pill with no active drug) for 52 weeks, in addition to their usual intralesional steroid injections. The pirfenidone dose will be increased gradually over the first two weeks up to a regular dose taken three times a day with food, which is the same schedule used in patients with IPF. Participants and their doctors will not know which treatment they are getting until the end of the study, unless this needs to be revealed for safety reasons. The main goal of this trial is to see how safe pirfenidone is for people with iSGS and how well they can tolerate taking it for one year. The study team will watch closely for side effects such as stomach upset, skin rash or sensitivity to sunlight, tiredness, and changes in liver blood tests. They will also look for early signs that pirfenidone may help, such as longer time until the next airway dilation, better breathing tests, and improvements in breathlessness and voice-related quality of life scores. Participants will be followed for a total of up to two years, including one year on study medication and one year of follow-up. This study may not directly help every person who takes part, but the results will provide important information about whether pirfenidone is safe in iSGS and whether it could become the first medication to slow down this scarring airway disease.

Detailed description

Idiopathic subglottic stenosis (iSGS) is a progressive fibro-inflammatory airway disease characterized by recurrent scarring and narrowing of the subglottic and upper tracheal airway in otherwise healthy adults, predominantly women. Current management relies on repeated endoscopic dilations and serial intralesional steroid injections, which temporarily restore airway patency but are not curative and are associated with high rates of restenosis and substantial symptom burden. Molecular and single-cell transcriptomic studies from the Canadian Airways Research (CARE) Group biobank have demonstrated a fibrotic gene expression signature in iSGS, with transforming growth factor (TGF)-mediated fibroblast activation and extracellular matrix deposition that closely parallels idiopathic pulmonary fibrosis (IPF).

Pirfenidone is an oral antifibrotic agent approved for IPF that inhibits TGF-driven fibroblast proliferation, collagen synthesis, and profibrotic cytokine release and has an established long-term safety profile in chronic fibrotic lung disease. On this mechanistic basis, pirfenidone is being repurposed as a potential disease-modifying therapy for iSGS. This multi-centre, randomized, double-blind, placebo-controlled Phase I trial will evaluate the safety, tolerability, and preliminary efficacy of pirfenidone in adults with iSGS receiving standardized intralesional steroid therapy.

Approximately 40 participants aged 18-65 years with a diagnosis of iSGS will be enrolled across two tertiary airway centres (London Health Sciences Centre - Victoria Hospital and St. Michael's Hospital, University of Toronto). Participants will be randomized in a 1:1 ratio to receive oral pirfenidone or matching placebo for 52 weeks, in addition to protocolized intralesional steroid injections. Pirfenidone will be titrated from 801 mg/day in Week 1 to 1,602 mg/day in Week 2 and 2,403 mg/day (801 mg three times daily) from Week 3 onward, as tolerated. Study drug and placebo will be identical in appearance, and participants, investigators, and study staff will remain blinded to treatment allocation unless unblinding is required for safety.

The primary objective is to assess the safety and tolerability of 52 weeks of pirfenidone treatment in iSGS, measured by the incidence and severity of treatment-emergent adverse events (TEAEs), dose reductions, treatment discontinuations, and protocol-defined laboratory abnormalities, particularly elevations in liver enzymes. Safety monitoring will include regular clinical assessments, vital signs, complete blood counts, renal function, and liver function tests at baseline, early after initiation, and at 3-month intervals. An independent Data Safety Monitoring Board will periodically review blinded safety data and provide recommendations regarding trial continuation or modification.

Secondary and exploratory outcomes will characterize preliminary efficacy signals. These include time from randomization to first endoscopic dilation, total number of dilations during the 52-week treatment period, changes in peak expiratory flow, and patient-reported outcomes assessed using the Dyspnea Index, modified Medical Research Council (mMRC) dyspnea scale, and Voice Handicap Index (VHI). Endoscopic laryngoscopic assessments will document airway patency and subglottic mucosal appearance over time, and may be correlated with clinical and functional outcomes. The study is powered for the primary safety endpoint and will provide effect size estimates for future Phase II/III trials.

Concomitant medications will be managed to minimize interactions with pirfenidone, with exclusion of strong CYP1A2 inhibitors, CYP1A2 inducers such as smoking, and other antifibrotic agents. Participants will receive education on dosing with food, sun protection to reduce photosensitivity risk, adherence strategies, and timely reporting of side effects. Compliance will be assessed via pill counts, medication diaries, and scheduled visits every 3 months, supplemented with interim contact as needed.

This trial is designed to establish the feasibility and safety of systemic antifibrotic therapy in iSGS while generating early evidence on its potential to reduce procedure frequency and improve respiratory and voice-related quality of life. The results will inform the design of subsequent larger, confirmatory studies and may represent a critical step toward introducing the first disease-modifying pharmacologic therapy for this rare airway disorder.

Interventions

• Drug Pirfenidone 267 MG [Esbriet]
  Oral pirfenidone administered in tablet form as systemic antifibrotic therapy for idiopathic subglottic stenosis. Participants assigned to the experimental arm will follow a standard titration regimen: 801 mg/day (267 mg three times daily) during Week 1, 1,602 mg/day (534 mg three times daily) during Week 2, and 2,403 mg/day (801 mg three times daily) from Week 3 through Week 52, as tolerated. Doses are taken with food to reduce gastrointestinal side effects. Pirfenidone is given in addition to
• Drug Placebo
  Oral placebo tablets formulated to be visually identical to pirfenidone capsules, including appearance, packaging, and dosing schedule. Participants assigned to the placebo comparator arm will receive placebo using the same titration and maintenance schedule as the pirfenidone arm (three times daily with food for 52 weeks). Placebo is given in addition to standardized intralesional steroid injections as part of protocolized airway management, to allow blinded comparison with active pirfenidone t

Primary outcome measures

• Incidence and severity of treatment-emergent adverse events over 52 weeks [Time frame: From first dose of study through week 52 of treatment.]

Secondary outcome measures (4)

• Time to first dilation [Time frame: From randomization through end of study follow-up, up to 24 months.]
• Change in peak expiratory flow [Time frame: Baseline and approximately every 3 months during the 52 week treatment period.]
• Change in Dyspnea Index Score [Time frame: Baseline and approximately every 3 months during the 52-week treatment and every followup appointment during the second year.]
• Change in Voice Handicap Index (VHI) [Time frame: Baseline and approximately every 3 months during the 52-week treatment period and every follow up appointment during the followup period in the second year.]

Eligibility criteria

Inclusion criteria

• Adults 18-65 years of age
• Confirmed diagnosis of idiopathic subglottic stenosis (iSGS)
• History of at least 2 endoscopic dilations within the past 12 months or -Receiving regular intralesional steroid injections as part of iSGS management (every 3 months)
• Clinically stable at enrollment (no acute infection or active inflammation)
• Adequate liver and renal function on screening laboratory tests
• Willing and able to comply with study procedures, visits, and follow-up
• Ability to provide written informed consent
• For participants of childbearing potential: negative pregnancy test and agreement to use effective contraception during treatment and for the protocol-specified period after the last dose

Exclusion criteria

• Subglottic stenosis due to another identifiable cause (e.g., intubation, granulomatosis with polyangiitis, malignancy)
• Known hypersensitivity or allergic reaction to pirfenidone or any component of its formulation
• Severe hepatic impairment or active liver disease (AST or ALT above the upper limit of normal)
• Severe renal impairment or requirement for dialysis
• Concurrent use of fluvoxamine
• Use of high-dose ciprofloxacin or other strong CYP1A2 inhibitors where dose adjustment is not feasible
• Current smoking or unwillingness to abstain from smoking during treatment
• Pregnant or breastfeeding individuals
• Clinically significant comorbid illness that could increase risk or confound results (e.g., advanced cardiac, pulmonary, or autoimmune disease)
• History of photosensitivity disorders or inability to adhere to sun protection precautions
• Participation in another investigational clinical trial within the previous 30 days
• Any condition that, in the investigator's judgment, would interfere with safety monitoring, adherence, or study assessments

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Canada · 1 center

• Schulich School of Medicine and Dentistry — London

Publications

• Fernandez IE, Eickelberg O. The impact of TGF-beta on lung fibrosis: from targeting to biomarkers. Proc Am Thorac Soc. 2012 Jul;9(3):111-6. doi: 10.1513/pats.201203-023AW. PMID 22802283
• Zhong L, Zhao J, Huang L, Liu Y, Pang X, Zhan K, Li S, Xue Q, Pan X, Deng L. Runx2 activates hepatic stellate cells to promote liver fibrosis via transcriptionally regulating Itgav expression. Clin Transl Med. 2023 Jul;13(7):e1316. doi: 10.1002/ctm2.1316. PMID 37403784
• Fang Y, Chung SSW, Xu L, Xue C, Liu X, Jiang D, Li R, Korogi Y, Yuan K, Saqi A, Hibshoosh H, Huang Y, Lin CS, Takarada T, Tsukui T, Sheppard D, Sun X, Que J. RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition. Nature. 2025 Apr;640(8057):221-230. doi: 10.1038/s41586-024-08542-2. Epub 2025 Feb 5. PMID 39910313
• Marchioni A, Tonelli R, Andreani A, Cappiello GF, Fermi M, Trentacosti F, Castaniere I, Fantini R, Tabbi L, Andrisani D, Gozzi F, Bruzzi G, Manicardi L, Moretti A, Baroncini S, Samarelli AV, Pinelli M, De Santis G, Stefani A, Marchioni D, Mattioli F, Clini E. Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults. Int J Mol Sci. 2022 Feb 22;23(5):24 PMID 35269565
• Motz KM, Gelbard A. The role of inflammatory cytokines in the development of idiopathic subglottic stenosis. Transl Cancer Res. 2020 Mar;9(3):2102-2107. doi: 10.21037/tcr.2019.12.37. PMID 35117565
• Osegbe DN. Fertility after sclerotherapy for hydrocele. Lancet. 1991 Jan 19;337(8734):172. doi: 10.1016/0140-6736(91)90832-a. No abstract available. PMID 1670805
• Hseu AF, Benninger MS, Haffey TM, Lorenz R. Subglottic stenosis: a ten-year review of treatment outcomes. Laryngoscope. 2014 Mar;124(3):736-41. doi: 10.1002/lary.24410. Epub 2013 Oct 22. PMID 24122779
• Ying S, Zeng PYF, Fung K, Khan H, Cecchini MJ, MacInnis P, Anderson J, Karimi AH, Al Jawhri M, Pan H, Le N, Joris K, Mymryk JS, Dumeaux V, Barrett JW, Nichols AC, Lin RJ; Canadian Airways Research Group of the Canadian Society of Otolaryngology Collaborative Research Initiative. Effect of Serial Intralesional Steroid Injections on Risk of Recurrence in Idiopathic Subglottic Stenosis. Laryngoscope. PMID 40237535

Identifiers

NCT: NCT07654517 · 129042

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗