Oral Everolimus Following Dilation in Idiopathic Subglottic Stenosis: A Phase 1 Nonrandomized Clinical Trial

Abstract

Importance: Current medical therapies in idiopathic subglottic stenosis (iSGS) are insufficient in preventing the development and progression of scar tissue. An inhibitor of mammalian target of rapamycin, everolimus is an immunosuppressive medication shown to be effective in reducing fibrosis across a variety of fibroproliferative disorders, including preclinical models of iSGS.

Objective: To evaluate the effect of oral everolimus on postoperative recurrence of stenosis in iSGS.

Design, setting, and participants: This open-label, single-arm, phase 1, nonrandomized clinical trial analyzed 7 perimenopausal participants diagnosed with iSGS and followed-up at a tertiary care academic center for 6 months after dilation surgery. The trial was conducted from November 1, 2022, through May 15, 2024.

Intervention: Participants took a 1.5-mg daily oral dose of everolimus for 42 days after surgery.

Main outcomes and measures: The primary outcome measure was safety as determined by adverse events. Secondary outcome measures included change in peak expiratory flow from baseline through 180 days after surgery; change in the luminal area, measured by computed tomographic (CT) scan, from the 14th and the 180th day; and changes in quality-of-life scores.

Results: Of the 8 perimenopausal participants, 7 (median age, 50 years [IQR, 45.0-52.5 years]) completed the study. Compared with baseline at all time points, there was an increase in peak expiratory flow. The median difference in liters per minute was 125 (95% CI, 90-270) on day 7 after surgery; 150 (95% CI, 110-290) on day 14; 138 (95% CI, 116-280) on day 28; 160 (95% CI, 100-270) on day 42; 155 (95% CI, 110-270) on day 60; 140 (95% CI, 100-270) on day 90; and 100 (95% CI, 20-240) on day 180. A decrease in the CT luminal area was observed from the day-14 measure to the day-180 measure (median stenosis, 7.2%; IQR, 1.9%-15.4%). During the trial, 1 participant (14.3%) each developed oral ulcers, a urinary tract infection, and a skin infection.

Conclusions and relevance: In this interventional nonrandomized clinical trial of iSGS, adjuvant everolimus was well-tolerated with minor adverse events. Participants sustained postdilation peak expiratory flow for 13 weeks. These results support proceeding to a phase 2 trial to study drug efficacy and a more detailed investigation of adverse effects.

Trial registration: ClinicalTrials.gov Identifier: NCT05153668.

Figure 1.. Change in Peak Expiratory Flow Values

A, Percentage change in peak expiratory flow relative to 14 days after surgery. The most notable decrease in peak expiratory flow occurs after 90 days. B, Absolute peak expiratory flow values appear stable until 90 days after surgery, after which peak expiratory flow begins to decline. Patient 2 withdrew from the study for personal reasons.

Figure 2.. Axial Computed Tomographic Scans Visualizing Progression of Subglottic Stenosis 14 and 180 Days After Surgery

A, The areas circumscribed (blue lines) by cricoid cartilage (outer circle) and the inner border of scar tissue (inner circle) were calculated. Respectively, participant 1 experienced an 18.8% decrease and participant 3, a 2.4% decrease in patent luminal area between day 14 and day 180 after surgery. B, Increase in percentage of stenosis assessed via computed tomographic (CT) quantification of patent luminal area and change in peak expiratory flow between day 14 and day 180 after surgery demonstrated a significant logarithmic relationship (predicted regression line).