Differing severities of acute exacerbations of idiopathic pulmonary fibrosis (IPF): insights from the INPULSIS® trials

Abstract

Background: Given the broad definition of an acute exacerbation of IPF, it is likely that acute exacerbations are heterogeneous in their aetiology, severity and clinical course. We used pooled data from the INPULSIS® trials of nintedanib versus placebo to investigate whether acute exacerbations reported as serious adverse events were associated with higher mortality than those reported as non-serious adverse events and to assess the effect of nintedanib on these types of events.

Methods: Adverse events considered by an investigator to be an acute exacerbation were adjudicated as a confirmed acute exacerbation, suspected acute exacerbation, or not an acute exacerbation. Time to first investigator-reported acute exacerbation or confirmed/suspected acute exacerbation reported as a serious adverse event or non-serious adverse event over the 52-week treatment period was assessed post-hoc. Deaths were assessed based on data collected over the 52-week treatment period.

Results: Of 63 patients who had ≥1 investigator-reported acute exacerbation, 48 (76.2%) had a first acute exacerbation reported as a serious adverse event. Thirty-six (3.4%) patients had ≥1 confirmed/suspected acute exacerbation, of whom 31 had a first event reported as a serious adverse event. Investigator-reported acute exacerbations reported as serious adverse events occurred in 23 patients in the nintedanib group and 26 in the placebo group. Confirmed/suspected acute exacerbations reported as serious adverse events occurred in 10 and 21 patients in these groups, respectively. Nintedanib significantly reduced the risk of a first acute exacerbation reported as a serious adverse event (HR 0.57 [95% CI: 0.32, 0.99]; p = 0.0476) and the risk of a first confirmed/suspected acute exacerbation reported as a serious adverse event (HR 0.30 [95% CI: 0.14, 0.64]; p = 0.0019) versus placebo. A higher proportion of patients with investigator-reported acute exacerbations reported as serious adverse events died than patients with acute exacerbations reported as non-serious adverse events (61.2% versus 7.1%).

Conclusion: Different severities of acute exacerbation of IPF may exist. Acute exacerbations reported as serious adverse events in the INPULSIS® trials were associated with high mortality. Nintedanib significantly reduced the risk of acute exacerbations reported as serious adverse events.

Trial registration: ClinicalTrials.gov NCT01335464 and NCT01335477 .

Keywords: Disease progression; Nintedanib; Serious adverse events; Treatment outcome; Tyrosine kinase inhibitor.

Conflict of interest statement

Ethics approval and consent to participate

The INPULSIS® trials were conducted in accordance with the principles of the Declaration of Helsinki and the Harmonized Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonization and were approved by local authorities. The clinical protocol was approved by an independent ethics committee or institutional review board at each participating centre. All patients provided written informed consent before study entry.

Consent for publication

Not applicable.

Competing interests

HK, MT, SG are employees of Boehringer Ingelheim. LR reports grants and personal fees from InterMune, and personal fees from Boehringer Ingelheim, Biogen, Cipla, ImmuneWorks, MedImmune, Pliant Therapeutics, Roche, Sanofi-Aventis, Shionogi, and Takeda. MK and his institution received grants and reimbursement for speakers bureaus and consulting from Boehringer Ingelheim and Roche and fees for consulting from Galapagos.

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Figures

Fig. 1

Time to death since onset of first investigator-reported acute exacerbation reported as a serious adverse event, first acute exacerbation reported as a non-serious adverse event, and in patients with no acute exacerbation. Thirteen patients with no acute exacerbation died beyond day 372

Fig. 2

Time to (a) first investigator-reported and (b) adjudicated confirmed or suspected acute exacerbation reported as a serious adverse event in patients treated with nintedanib or placebo