Pirfenidone for Idiopathic Subglottic Stenosis: A Pilot Trial of Tolerability and Feasibility

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 multicentre, randomized (1:1), double blinded, placebo controlled pilot trial will determine the tolerability of pirfenidone over 52 weeks and the feasibility of a placebo controlled trial in adults with iSGS receiving standardized intralesional steroid injections.

Hypothesis: Pirfenidone will be tolerable in iSGS, with no excess of adverse events beyond its established profile and at least 80% of participants still taking study drug at 52 weeks.

Forty four participants (22 per site) 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, Unity Health 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 determine the tolerability of 52 weeks of pirfenidone treatment in iSGS. The primary endpoint is the proportion of participants who experience a moderate or worse (Grade ≥2, CTCAE v5.0) adverse event during 52 weeks of treatment. Tolerability is further described by the proportion still taking study drug at 52 weeks, rates of dose reduction, interruption and discontinuation, 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 unblinded safety data under a signed charter 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 and Voice Handicap Index-10 (VHI-10). Endoscopic laryngoscopic assessments will document airway patency and subglottic mucosal appearance over time, and may be correlated with clinical and functional outcomes.

Sample size: The primary endpoint is the proportion of participants who experience a moderate or worse (Grade ≥2) adverse event during 52 weeks of treatment. Assuming this occurs in 10% of placebo and 50% of pirfenidone recipients, 19 participants per arm provide 80% power to detect the difference (Fisher's exact test, one sided α = 0.05). A one sided test is used because the question is directional: whether pirfenidone increases moderate or worse adverse events relative to placebo. The primary analysis includes every participant who receives at least one dose of study drug, so later withdrawals do not reduce the analysis population, and enrolment of 22 per arm (N = 44) already exceeds the 19 per arm required. The 10% placebo assumption reflects events attributed to study drug rather than to the dilations and steroid injections that both arms receive. With 22 per arm, the proportion still taking study drug at 52 weeks will be estimated with a 95% confidence interval of approximately ±20 percentage points.

Statistical analysis: Reporting will follow the CONSORT extension for randomized pilot and feasibility trials. Tolerability and feasibility outcomes will be summarized by arm with exact (Clopper-Pearson) 95% confidence intervals and between arm risk differences. Consistent with pilot trial methodology, the trial is not powered for efficacy; clinical outcomes are exploratory and reported as estimates. Time to first dilation will be described using Kaplan-Meier estimates and a Cox proportional hazards model, reported as a hazard ratio with 95% confidence interval for planning a Phase III trial. Peak expiratory flow and patient reported outcomes will be analyzed with linear mixed effects models. Analyses of adverse events and dose maintenance will include all participants receiving at least one dose; clinical outcomes will be analyzed by intention to treat, including all randomized participants. Participants who withdraw are counted as no longer taking study drug, and missing repeated measures are handled within the mixed effects models under a missing at random assumption.

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 tolerability of systemic antifibrotic therapy in iSGS and the feasibility of a placebo controlled trial, while generating early evidence on its potential to reduce procedure frequency and improve respiratory and voice-related quality of life. If tolerability is established, the results will inform the design of a large Phase III efficacy trial across the CARE network and may represent a critical step toward introducing the first disease-modifying pharmacologic therapy for this rare airway disorder.