Pirfenidone may slow lung function decline in patients with rheumatoid arthritis-ILD

In the phase 2 TRAIL1 trial, treatment with pirfenidone slowed the rate of lung function decline in patients with rheumatoid arthritis-associated interstitial lung disease and demonstrated a similar safety profile to that observed in other trials of the drug.

However, the results should be interpreted with caution, the researchers concluded, as the trial was terminated early and was underpowered to evaluate the primary endpoint, which was a composite of decline in percent predicted forced vital capacity of 10% or greater or death over 52 weeks of treatment.

Ivan O. Rosas, MD, professor and section chief of the department of medicine and pulmonary, critical care and sleep medicine at Baylor College of Medicine, presented the results at the European Respiratory Society International Conference.

The randomized, double-blind, placebo-controlled, phase 2 TRAIL1 trial included patients diagnosed with rheumatoid arthritis and 10% or more involvement with ILD to assess the efficacy, safety and tolerability of pirfenidone (Esbriet, Genentech).

Researchers aimed to enroll 270 patients for 80% power to detect differences between patients assigned pirfenidone and placebo. However, due to challenges during the COVID-19 pandemic, the study was stopped prematurely with after only 123 patients were enrolled, Rosas said during a presentation.

Sixty-three patients (mean age, 66 years; 60% men) were randomly assigned pirfenidone and 60 (mean age, 69.5 years; 65% men) were assigned placebo. After a dropout rate of 50%, 51 patients in the pirfenidone group and 51 patients in the placebo group completed the trial.

The primary outcome was decline in FVC percent predicted by 10% or more or death. Secondary outcomes included FVC decline in percent predicted and milliliters, FVC percent predicted decline of 10% or greater, frequency of progressive disease defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT), change in dyspnea-12 questionnaire, all-cause mortality, all-cause hospitalization, hospitalizations caused by respiratory issues and respiratory exacerbations requiring hospitalization.

Researchers reported no significance in the primary outcome, which occurred in 11% of patients in the pirfenidone group compared with 15% in the placebo group (OR = 0.67; 95% CI, 0.22-2.03; P = .48).

However, researchers reported a slower rate of decline in estimated annual change in FVC among patients who received pirfenidone compared with patients in the placebo group (–66 mL vs. –146 mL; P = .0082) and FVC percent in patients with (–1.02% vs. –3.21%; P = .0028).

Moreover, the effect of pirfenidone on FVC decline was also present when researchers evaluated patients with baseline usual interstitial pneumonia (UIP) pattern on CT (FVC decline: –43 mL vs. –169 mL; P = .0014 and –0.2% vs. –3.81%; P = .0002).

For secondary outcomes, there was no significant difference between groups in the decline in percent predicted FVC 10% or greater (P = .32), frequency of progressive disease (P = .35), dyspnea-12 questionnaire (P = .36), all-cause mortality (P = .99) or hospitalizations (P = .69), hospitalization caused by respiratory issues (P = .35) or respiratory exacerbations requiring hospitalization (P = .62).

Researchers reported no new safety events associated with pirfenidone that differ from other studies in RA-ILD, according to the results.

“This is ... the first randomized antifibrotic trial focused on patients with rheumatoid arthritis. The trial was underpowered. Pirfenidone was associated with a significantly lower rate of decline in FVC, which is what we’re excited about. And this seemed to be really focused on patients who had a UIP pattern,” Rosas said. “We should probably consider repeating this study, focusing more on patients with a UIP pattern in patients with rheumatoid arthritis-ILD,” Rosas said. “And this is a phase 2, so we’ll need some follow-up studies to independently verify our findings.”