Pirfenidone in rheumatoid arthritis-associated interstitial lung disease

In the TRAIL1 study1Solomon 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.Lancet Respir Med. 2023; 11: 87-96Summary Full Text Full Text PDF PubMed Google Scholar the annual rate of decline in forced vital capacity (FVC) in the pirfenidone group was slower than in the placebo group (66 mL vs 146 mL, figure 2), especially in usual interstitial pneumonia fibrosis (43 mL vs 169 mL, figure 3). However, the linear outcomes in figures 2 and 3 seem inconsistent with the progressions observed in the supplementary figures 4–7 for absolute percent predicted FVC (FVC%) and absolute FVC volume in Solomon et al,1Solomon 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.Lancet Respir Med. 2023; 11: 87-96Summary Full Text Full Text PDF PubMed Google Scholar which show an FVC effect in favour of pirfenidone at week 13 (approximately 2%, 60 mL), but in favour of placebo at week 52 (approximately 1·5%, 200 ml). Supplementary figures 6 and 7 show that these patterns are valid for the non-usual interstitial pneumonia groups, while the FVC% graphs and the FVC volume graphs of the usual interstitial pneumonia groups are approximately parallel.1Solomon 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.Lancet Respir Med. 2023; 11: 87-96Summary Full Text Full Text PDF PubMed Google Scholar Thus, the non-usual interstitial pneumonia graphs in supplementary figures 6 and 7 seem compatible with the slightly smaller decrease in the non-usual interstitial pneumonia placebo group compared with the non-usual interstitial pneumonia pirfenidone group seen in figure 3. However, the parallel usual interstitial pneumonia-related graphs in supplementary figures 6 and 7 seem discordant with the divergent usual interstitial pneumonia graphs in figure 3 and divergent slopes in supplementary table 3 in favour of the pirfenidone group. The discrepancy between the linear model-based changes in FVC% and FVC volume (figures 2 and 3) and summarised measurements of absolute FVC% and FVC volume (supplementary figures 4–7) is not discussed in the paper.1Solomon 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.Lancet Respir Med. 2023; 11: 87-96Summary Full Text Full Text PDF PubMed Google Scholar It is unclear whether this inconsistency can be explained by missing values, as the titles of supplementary figures 4–7 indicate that the graphs are based on intention-to-treat values, whereas the patient number in the legends indicate that the graphs are based on observed values. The question is whether the results in figure 3 and supplementary table 3 reflect that the linear model amplifies favourable pirfenidone effects during the first 13 weeks (supplementary figures 4 and 5) forward into the remaining observation period. If so, the linear model might be inappropriate and conceal that a possible initial effect of pirfenidone gradually diminishes. There is no key to the true handling of missing data in intention-to-treat statistics,2Liu M Wei L Zhang J Review of guidelines and literature for handling missing data in longitudinal clinical trials with a case study.Pharm Stat. 2006; 5: 7-18Crossref PubMed Scopus (46) Google Scholar, 3Altman DG Missing outcomes in randomized trials: addressing the dilemma.Open Med. 2009; 3: e51-e53PubMed Google Scholar but a sensitivity analysis to test the robustness of the change in FVC seems reasonable, as previously suggested when handling missing data in longitudinal trials,2Liu M Wei L Zhang J Review of guidelines and literature for handling missing data in longitudinal clinical trials with a case study.Pharm Stat. 2006; 5: 7-18Crossref PubMed Scopus (46) Google Scholar, 3Altman DG Missing outcomes in randomized trials: addressing the dilemma.Open Med. 2009; 3: e51-e53PubMed Google Scholar for instance presenting the change in FVC% and FVC volume in the placebo group and the pirfenidone group as observed in all patients (n=123) and in patients completing the study (n=81). CTN has received a research grant and fees for lectures and advisory board meetings by Boehringer Ingelheim. NG and JL declare no competing interests. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 studyDue to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials. Full-Text PDF