Consistent effect of nintedanib in patients with IPF and degrees of impairment in gas exchange*

Rationale: The efficacy and safety of nintedanib versus placebo in patients with IPF, FVC ≥ 50% predicted and DLco 30 – 79% predicted were investigated in the 52-week INPULSIS trials. In the 24-week INSTAGE trial, the efficacy and safety of nintedanib plus sildenafil versus nintedanib alone were evaluated in patients with IPF and DLco ≤ 35% predicted. We compared the effects of nintedanib in patients with more advanced (INSTAGE) and less advanced impairment in gas exchange (INPULSIS).

Methods: Change from baseline in FVC (mL) at weeks 12 and 24; the rate of decline in FVC over 24 weeks; and the proportions of patients who had an adjudicated confirmed or suspected idiopathic acute exacerbation, had an absolute decline in FVC ≥ 5% predicted or died, or who died from any cause over 24 weeks were analyzed in patients who received nintedanib alone in the INSTAGE and in patients who received nintedanib or placebo in INPULSIS. Safety was assessed based on adverse events over 24 weeks. Analyses were descriptive.

Results: A total of 136 patients received nintedanib alone in INSTAGE, and 638 and 423 patients received nintedanib and placebo, respectively, in the INPULSIS trials. Absolute changes in FVC in patients treated with nintedanib alone in the INSTAGE trial were consistent with changes in FVC in the INPULSIS trials ([Table 1]). Mean (SE) changes from baseline in FVC at week 24 were − 58.2 (19.6) mL in patients treated with nintedanib in INSTAGE, and − 52.8 (9.8) and − 106.4 (11.4) mL in patients with nintedanib and placebo, respectively, in INPULSIS. Over 24 weeks, adjudicated confirmed or suspected idiopathic acute exacerbations occurred in 3.7% of patients with nintedanib in INSTAGE, and 0.6% and 2.1% of patients with nintedanib and placebo, respectively, in INPULSIS. Over 24 weeks, diarrhea adverse events were reported in 48.5% of patients treated with nintedanib in INSTAGE, and 52.5% and 16.1% of patients treated with nintedanib and placebo, respectively, in INPULSIS, and led to premature treatment discontinuation in 2.2%, 3.8% and 0% of patients, respectively.

Table 1 

	INSTAGE	INPULSIS
	Nintedanib (n = 136)	Nintedanib (n = 638)	Placebo (n = 423)
* In addition, 5 (3.7%) of patients in INSTAGE had an adjudicated confirmed or suspected acute exacerbation over 24 weeks that was categorized as having a specific trigger rather than being idiopathic. In the INSTAGE trial, acute exacerbations could be classified by an independent adjudication committee as idiopathic or triggered based on the criteria described in Collard et al., Am J Respir Crit Care Med 2016; 194: 263 – 275. In the INPULSIS trials, acute exacerbations were required to be idiopathic by definition, based on criteria similar to those described in Collard et al., Am J Respir Crit Care Med 2007; 176: 636 – 643, and were reviewed by an independent adjudication committee.
Mean (SE) change from baseline in FVC (mL)
Week 12	− 25.5 (15.7)	− 25.4 (9.8)	− 78.8 (11.3)
Week 24	− 58.2 (19.6)	− 52.8 (9.8)	− 106.4 (11.4)
Rate of decline in FVC, mL/24 weeks	− 66.7	− 52.4	− 103.2
Adjudicated confirmed or suspected idiopathic acute exacerbation over 24 weeks, n (%)	5 (3.7)*	4 (0.6)	9 (2.1)
Absolute decline in FVC ≥ 5% predicted or death over 24 weeks, n (%)	69 (50.7)	190 (29.8)	174 (41.1)
Death over 24 weeks, n (%)	15 (11.0)	13 (2.0)	8 (1.9)

Conclusions: Based on data from the INSTAGE and INPULSIS trials, nintedanib appeared to have a similar effect on FVC decline over 24 weeks, and a similar safety and tolerability profile, in patients with IPF and more or less impairment in gas exchange.

* presented at ATS 2019