Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis

Download figure
Open in new tab
Download powerpoint
FIGURE 1
Events included in these analyses. Shaded boxes indicate events that were included in the analyses of adjudicated events. This figure indicates only the types of event included in these analyses, not the timing at which investigators and the adjudication committee decided whether an event was an acute exacerbation.
Download figure
Open in new tab
Download powerpoint
FIGURE 2
Seasonality of acute exacerbations. Northern hemisphere only. Three investigator-reported acute exacerbations were reported in the southern hemisphere. Some patients had more than one acute exacerbation during the trials.

TABLE 1

Baseline characteristics of patients who had or did not have at least one investigator-reported acute exacerbation

	Patients with investigator-reported acute exacerbation	Patients with no investigator-reported acute exacerbation
Patients	69	992
Age years	69.1±7.3	66.6±8.1
Male	58 (84.1%)	783 (78.9%)
Race
Asian	20 (29.0%)	302 (30.4%)
Other (white/black/missing^#)	49 (71.0%)	690 (69.6%)
Weight kg	76.7±17.8	79.2±16.5
Ex- or current smoker	53 (76.8%)	712 (71.8%)
Concomitant medications
Corticosteroids	17 (24.6%)	208 (21.0%)
Bronchodilators	11 (15.9%)	190 (19.2%)
Proton pump or histamine receptor-2 inhibitor	33 (47.8%)	373 (37.6%)
Supplemental oxygen	16 (23.2%)	76 (7.7%)
Emphysema^¶	22 (31.9%)	398 (40.1%)
Honeycombing on HRCT	39 (56.5%)	528 (53.2%)
FVC mL	2303±617	2748±780
FVC % predicted	68.8±14.6	80.3±17.8
FEV₁/FVC ratio %	84.0±5.6	81.5±5.9
D_LCO % predicted	43.2±17.2	47.5±13.1
SGRQ total score	49.1±18.0	38.9±18.8

Data are presented as mean±sd, unless otherwise indicated. HRCT: high-resolution computed tomography; FVC: forced vital capacity; FEV₁: forced expiratory volume in 1 s; D_LCO: diffusing capacity of the lung for carbon monoxide; SGRQ: St George's Respiratory Questionnaire. Patients were categorised into subgroups depending on whether, between randomisation and the end of the post-treatment follow-up period, they experienced or did not experience an investigator-reported acute exacerbation. ^#: in France, regulations do not permit the collection of data on race; ^¶: based on qualitative assessment of HRCT scans.

TABLE 2

Risk prediction models for investigator-reported and adjudicated confirmed or suspected acute exacerbations

Step	Risk factor analysis			Final model
	Model variable^#	p-value^¶	AIC⁺	HR (95% CI)^§

Investigator-reported acute exacerbations	FVC % predicted at baseline^ƒ	<0.0001	830.217	0.67 (0.55–0.80)
	Supplemental oxygen use at baseline	0.0018	824.565	2.47 (1.37–4.47)
	Antacid medication use at baseline	0.0873	823.706	1.50 (0.91–2.47)
	Randomisation to nintedanib	0.1150	823.271	0.66 (0.40–1.08)

Adjudicated confirmed or suspected acute exacerbations	FVC % predicted at baseline	0.0006	483.723	0.67 (0.53–0.86)
	Randomisation to nintedanib	0.0010	475.169	0.33 (0.16–0.66)
	Antacid medication use at baseline	0.0676	473.938	1.78 (0.92–3.43)
	Former or current smoker	0.0938	472.805	2.13 (0.89–5.13)
	Supplemental oxygen use at baseline	0.1322	472.870	1.85 (0.80–4.29)

FVC: forced vital capacity. ^#: covariates that achieved p<0.2 in the stepwise selection procedure are shown. The variables are shown in the order that they were selected into the model. ^¶: p-value of the likelihood chi-squared test used in the decision to add the variable to the model. ⁺: Akaike information criterion (AIC) was calculated for the model at the end of each selection step. Lower AIC values indicate better performance of the model. ^§: based on the final model, i.e. including all the variables that were selected during the stepwise selection procedure. ^ƒ: hazard ratio (95% CI) is calculated for FVC % predicted 10% higher at baseline.

TABLE 3

Mortality following acute exacerbation

Mortality rate^¶	Patients with investigator-reported acute exacerbations		Patients with events adjudicated as confirmed or suspected acute exacerbations^#		Patients with all events adjudicated as not acute exacerbations^#
Mortality rate^¶	Nintedanib (n=34)	Placebo (n=35)	Nintedanib (n=14)	Placebo (n=25)	Nintedanib (n=23)	Placebo (n=13)
30-day	7 (20.6)	14 (40.0)	3 (21.4)	9 (36.0)	4 (17.4)	5 (38.5)
90-day	10 (29.4)	15 (42.9)	5 (35.7)	12 (48.0)	6 (26.1)	7 (53.9)
180-day	12 (35.3)	20 (57.1)	6 (42.9)	15 (60.0)	7 (30.4)	7 (53.9)

^#: analyses based on patients who had one or more adjudicated confirmed or suspected acute exacerbation or who had one or more event that was adjudicated and all events were adjudicated as not acute exacerbations; ^¶: calculated as the number (%) of patients who died within 30, 90 or 180 days of onset of a first exacerbation event. The three categories of patient shown in this table are not mutually exclusive.