The INPULSIS trials of idiopathic pulmonary fibrosis treatment: explaining further discrepancies on exacerbations

Abstract

In a recent paper on the INPULSIS trials, two duplicate 1-year randomised controlled trials evaluating nintedanib in the treatment of idiopathic pulmonary fibrosis (IPF) [1], we provided the methodological explanation for the apparent inconsistent results arising from the two different definitions of exacerbations used in those studies [2]. These trials reported vastly different findings in their pooled analysis [1]. Indeed, the risk of an investigator-reported acute exacerbation was lower by 36% with nintedanib compared with placebo but not statistically significant ( p=0.08), while, after adjudication according to a complex definition involving multiple criteria, the risk was lower by 68% and statistically significant ( p=0.001). We explained that such differences in risk reductions and in statistical significance are simply the result of including outcome events that are not actual exacerbations, leading to the phenomenon of treatment effect dilution and false nonsignificant effects [2]. The correct risk reduction of 68% based on the accurate adjudicated events is diluted to a less impressive and now nonsignificant risk reduction of 36% when "false" events were added in the same proportion to both groups.

Role of antifibrotics in the management of idiopathic inflammatory myopathy associated interstitial lung disease

“…When only adjudicated acute exacerbations were analyzed, both INPULSIS studies had a reduced frequency of acute exacerbations on nintedanib. 69 Thus, nintedanib reduces both the rate of FVC decline and frequency of acute exacerbations in IPF. It was FDA approved for this indication in 2014.…”

Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review

“…Other studies also identified a positive effect of a treatment with RTX with plasma exchange and intravenous immunoglobulin, polymyxin B-immobilized fiber column perfusion in patients diagnosed with IPF and intravenous thrombomodulin in CTD patients [159,164]. Recently, the effective use of Nintedanib in AE in IPF patients has been described in two patients [165,166], and, of note, in INPULSIS-2 trial there was a significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; p = 0.005), even if the reliability of this result is still controversial [167,168].…”