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Although results are promising, findings should be interpreted with caution, as the study was underpowered and terminated early due to the COVID-19 pandemic.
Although the composite primary endpoint was not met, pirfenidone was able to slow the rate of decline of forced vital capacity (FVC) in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), according to a study published in The Lancet.1 However, investigators emphasize that results should be interpreted with caution, as the study was underpowered and terminated early due to the COVID-19 pandemic.
“Respiratory system involvement is common in rheumatoid arthritis (RA) and leads to increased morbidity and mortality,” investigators stated. “Although any lung compartment can be involved, interstitial lung disease is the leading cause of excess morbidity and mortality associated with pulmonary complications in patients with rheumatoid arthritis. The prevalence of RA-ILD ranges from 19% to 63% depending on the population screened,with a lifetime risk of the disease developing in any one patient of 7.7%.”
TRIAL1 (NCT02808871) was a randomized, double-blind, placebo-controlled, phase 2 study performed in 34 academic centers within the United Kingdom, the United States, Australia, and Canada. Eligible patients were aged 18-85 years, met the 2019 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for RA, and had diagnosed interstitial lung disease via high-resolution computed tomography (HRCT) scan imaging and, if possible, lung biopsy. Patients who had a history of other known causes of ILD, a history of smoking, and co-existent clinically significant chronic obstructive pulmonary disease (COPD) or asthma were excluded.
Patients were assigned (1:1) to receive either 2403 mg oral pirfenidone (267 mg tablets taken 3 times a day) or placebo daily for a total of 52 weeks. Patients in the pirfenidone group were titrated to full dose over the course of 14 days. The primary endpoint was defined as the incidence of the composite endpoint of a decline from baseline in percent predicted FVC (FVC%) of 10% or more or death during the treatment period. Other endpoints included changes in absolute and FVC%, the proportion of patients with a decline in FVC% of at least 10%, and the frequency of progression, as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) for those in the pirfenidone group.
Between May 15, 2017, and March 31, 2020, 123 patients were ultimately included in the study, of which 63 patients (51%) received pirfenidone and 60 (49%) were assigned to placebo. Unfortunately, the trial was stopped early due in part to slow recruitment and the shutdown of clinical and research operation activities because of the COVID-19 pandemic. Most patients were men (60% in the pirfenidone cohort; 65% in the placebo cohort), aged 60 years or older (mean age 66.0 years in the pirfenidone group; 69.5 years in the placebo group), and White (89% in the pirfenidone group; 93% in the placebo group).
Differences in proportions of patients who met the primary endpoint was not significant, with 7 (11%) of patients in the pirfenidone group and 9 (15%) of patients in the placebo group reporting a decline in FVC% from baseline of 10% or more or death (odds ratio [OR] 0.67 [95% CI 0.2 to 2.03]; p=0.48). Decline in FVC% by 10% or more was similar among both groups (5 [8%] patients in the pirfenidone cohort vs 7 [12%] in the placebo cohort; OR 0.52 [95% CI 0.14–1.90]; p=0.32). Frequency of progression as evaluated via OMERACT was also similar among the pirfenidone-treated group and the placebo group (25% vs 32%, respectively; OR 0.68 [0.30–1.54]; p=0.35)
However, patients receiving pirfenidone had a slower rate of decline in lung function, as determined by the estimated annual change in absolute FVC (–66 vs –146; p=0.0082) as well as FVC% (–1.2 vs –3.21; p=0.0028). Rates of treatment-emergent serious adverse events were comparable between both arms, with 100% of patients receiving pirfenidone reporting adverse events compared with 94% in the placebo group. The most common adverse events were nausea, fatigue, and diarrhea. There were no treatment-related deaths.
The early termination of the study did not allow investigators to reach the primary endpoint and may have hindered them from finding a safety or tolerability signal. Further, the inclusion criteria of at least 10% of fibrosis on HRCT may have incorporated an element of selection bias. As only 12% of patients in the placebo group had a decline of 10% or more in FVC over 1 year, and previous guidelines suggest a decline in 5% or more in FVC is a meaningful threshold for disease progression in patients with progressive pulmonary fibrosis, future trials should consider less severe physiology endpoints.
“Our data suggest that patients with a usual interstitial pneumonia pattern on HRCT have a faster progression and might have a more robust response to therapy,” investigators concluded. “Future studies in patients with RA-ILD with antifibrotics should be stratified by HRCT pattern.”
Solomon JJ, Danoff SK, Woodhead FA, et al. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study [published online ahead of print, 2022 Sep 2]. Lancet Respir Med. 2022;S2213-2600(22)00260-0. doi:10.1016/S2213-2600(22)00260-0