Lung function in idiopathic pulmonary fibrosis--extended analyses of the IFIGENIA trial

Abstract

Background: The randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set.

Methods: We analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients.

Results: In trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower.

Conclusion: This descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.

Trial registration: ClinicalTrials.gov NCT00639496.

Figure 1

Categorical analyses in steps of 5% change from baseline during the one year study period. a: VC: Higher percentages of patients receiving NAC (black columns) showed any improvement and improvement of 5% or more as compared to baseline, whereas higher percentages of patients receiving placebo (white columns) showed any deterioration or decreases of VC of more than 5, 10, 15, 20, and 25% from baseline; this difference was significant at the 5% level (* p < 0.05 NAC vs plac). b: DLco^#: A higher percentage of patients receiving NAC (black columns) showed improvement and a lower percentage of patients receiving NAC (black columns) showed deterioration of DLco as compared to placebo (white columns). The differences were statistically significant at the levels <-40%, <-35%, <-5%, >5%, any deterioration, and any improvement (* p < 0.05 NAC vs plac for each of these comparisons). ^# numbers refer to DLco Hb corrected. c: CPI: A higher percentage of patients receiving NAC (black columns) showed improvement (i.e. decrease) and a lower percentage of patients receiving NAC (black columns) showed deterioration (i.e. increase) of the CPI as compared to placebo (white columns). The differences were statistically not significant.

Figure 2

Effects of NAC on CPI, VC, and DLco, depending on baseline CPI being lower or higher than 50 points. a: Effect of NAC therapy on change in CPI from baseline, depending on baseline CPI being lower or higher than 50 points. Black columns = NAC; white columns = placebo. LS means and 95% confidence interval for changes from baseline in a model including treatment and CPI category as fixed factors are plotted. * p = 0.0002 vs BL-CPI< = 50 NAC. ◆ p = 0.016 vs. BL-CPI< = 50 Placebo b: Effect of NAC therapy on change in VC from baseline, depending on baseline CPI being lower or higher than 50 points. Black columns = NAC; white columns = placebo. LS means and 95% confidence interval for changes from baseline in a model including treatment and CPI category as fixed factors are plotted. * p = 0.0031 vs BL-CPI< = 50 NAC. p = 0.0066 between both NAC subunits. c: Effect of NAC therapy on change in DLco from baseline, depending on baseline CPI being lower or higher than 50 points. Black columns = NAC; white columns = placebo. LS means and 95% confidence interval for changes from baseline in a model including treatment and CPI category as fixed factors are plotted. * p = 0.0015 vs BL-CPI< = 50 NAC. ◆ p = 0.067 vs. BL-CPI< = 50 Placebo.