A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients with Rheumatoid Arthritis Interstitial Lung Disease

Abstract

Background Interstitial lung disease (ILD) is a known complication of rheumatoid arthritis (RA) with a lifetime risk in any individual of 7.7%. The TRAIL1 trial was a randomized, double-blinded, placebo-controlled, phase 2 study of safety, tolerability, and efficacy of pirfenidone for the treatment of patients with RA-ILD. Methods The TRAIL1 was a phase 2 trial intended to enroll 270 adult patients (18 to 85 years) with established RA-ILD at 33 sites in 4 countries. Patients were randomly assigned (1:1) to 2,403 mg oral pirfenidone or placebo daily. The primary endpoint was the incidence of the composite endpoint of decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or greater or death during the 52-week treatment period. Key secondary endpoints included change in absolute and FVC% over 52 weeks. Findings. The trial was stopped early due to slow recruitment and soon after the shutdown of clinical trials as a consequence of the coronavirus disease 2019 (COVID-19) pandemic. Data from 123 patients enrolled were analyzed. The primary endpoint was met by 11.1% on pirfenidone vs. 15% on placebo [OR=0.67 (0.22, 2.03), p=0.48]. Subjects receiving pirfenidone had a slower rate of decline in lung function as measured by estimated annual change in FVC(ml) (-66 vs. -146, p=0.0082) and FVC(%) (-1.02 vs. -3.21, p=0.0028). This effect on decline was also seen when analyzed within participants with baseline usual interstitial pneumonia (UIP) pattern on HRCT (FVC(ml) (-43 vs. -169, p=0.0014) and FVC% (-0.2 vs. -3.81, p=0.0002)). There was no significant difference in the rate of treatment-emergent serious adverse events. Interpretation Due to early termination of the study, results should be interpreted with caution. Despite being underpowered to evaluate the primary endpoint, pirfenidone slowed the rate of decline of FVC over time in subjects with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials.

The role of antifibrotics in the treatment of rheumatoid arthritis–associated interstitial lung disease

“…The primary endpoint met by 11% on pirfenidone versus 15% on placebo [OR = 0.67 (0.22, 2.03), p = 0.48]. 110 Although pirfenidone was found to be safe and slowed decline of FVC over time in patients with RA-ILD, TRAIL1 was underpowered to detect a difference in the composite primary endpoint. This effect was more pronounced in those with a UIP pattern on baseline HRCT.…”

“…109 Only 123 patients were randomized of the intended 270; the study was stopped due to slow recruitment exacerbated by the COVID-19 pandemic. 110 Patients were administered pirfenidone 2403 mg/day as an add-on to existing treatment. The primary endpoint of the study was the incidence of the composite endpoint of decline in FVC % predicted of over 10% or death during the 52-week study period.…”

Aktuelles zur RA-ILD

“…Daneben wurde Pirfenidon zur Therapie der RA-ILD in der Phase-II-Studie TRAIL1 untersucht [59]. Hierbei wurde Pirfenidon zusätzlich zur exisitierenden immunsuppressiven Therapie verabreicht.…”

“…Diese Studie musste ebenfalls aufgrund einer langsamen Rekrutierung abgebrochen werden. Ein geringerer Abfall der FVC unter Pirfenidon konnte auch hier bestätigt werden [59].…”

Interstitial lung disease in rheumatoid arthritis: A multidisciplinary problem in rheumatology and pulmonology

“…Эффективность пирфенидона при РА-ИЗЛ изучалась в рамках РПКИ фазы II (TRAIL1) (табл. 3), которое было приостановлено из-за невозможности набрать достаточное число пациентов в запланированные сроки на фоне пандемии COVID-19 [204]. Тем не менее результаты, касающиеся 123 пациентов с РА-ИЗЛ, свидетельствуют о том, что лечение пирфенидоном приводит к замедлению снижения ФЖЕЛ на 55%, а в подгруппе пациентов с ОИП-паттерном фиброза -на 75%.…”