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

Abstract

BackgroundThe 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.MethodsWe analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients.ResultsIn 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.ConclusionThis 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 RegistrationRegistered at http://www.ClinicalTrials.gov; number NCT00639496.

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

“…The direction and magnitude of longitudinal changes in FVC and corrected DLCO observed in the MUSIC trial readily mirror those observed in several other studies in subjects with IPF [8,9,27,28]. Similarly, the median increase from baseline up to month 12 in composite physiologic index observed in the present study was of a similar order of magnitude to that reported elsewhere among placebo recipients over a similar study duration [29]. Data are presented as n or n (%).…”

Exertional dyspnoea in interstitial lung diseases: the clinical utility of cardiopulmonary exercise testing

“…A number of randomised controlled trials have examined the effects of pharmaceutical treatments on exercise capacity in IPF. Small but nonsignificant changes in peak exercise capacity were found in a large placebo-controlled trial of N-acetylcysteine [74]. A large trial comparing pirfenidone to placebo did not find a difference in nadir oxygen saturation on a 6-min treadmill test after 6 months, despite improvements in vital capacity and a reduced rate of acute exacerbation in the treatment group [75].…”

Recent advances in the pathogenesis and clinical evaluation of pulmonary fibrosis

“…Other beneficial effects of NAC include the inhibition of pro-fibrotic fibroblast response to TGF-b1 and the dose-dependent inhibitory effect on interleukin (IL)-8 and MMP-9 release, and intracellular adhesion molecule expression by BAL macrophages and lymphocytes from patients with IPF and sarcoidosis [40,41]. In agreement with these observations, NAC has been found to have favourable effects on the lung function of patients with IPF, and mainly in those with less progressed disease [13,14].…”

“…However, following the ERS research seminar which took place in Athens, Greece (November 11-12, 2010), pirfenidone has received marketing authorisation in the European Union. To date, it has been shown that the combination of low-dose steroids, azathioprine and NAC may provide some benefit, mainly in patients with mild-to-moderate disease defined by a composite physiological index ,50 [13,14]. Pirfenidone, a drug with antifibrotic and anti-inflammatory properties has been proven to significantly slow the decline of forced vital capacity and to increase progression-free survival with an acceptable safety profile [116][117][118][119].…”

“…Recently, it has been demonstrated that N-acetyl-cysteine (NAC), a drug with antioxidant properties, can slow the decline of lung function, mainly in less severe cases of IPF [13,14]. The exact mechanism of action is not known but it has been hypothesised that NAC prevents EMT in AECs in vitro, at least in part through replenishment of intracellular glutathione stores and limitation of TGF-b1-induced intracellular reactive oxygen species (ROS) generation [15].…”