The designs of the INPULSIS and INSTAGE trials have been published [
6,
7]. Briefly, in the INPULSIS trials, patients with FVC ≥50% predicted and DLco 30–79% predicted were randomised 3:2 to receive nintedanib 150 mg twice daily (bid) or placebo for 52 weeks, with a follow-up visit 4 weeks later. The primary endpoint was the annual rate of decline in FVC (mL/year) [
6]. In the INSTAGE trial, patients with IPF and DLco ≤35% predicted were randomised 1:1 to receive nintedanib 150 mg bid plus sildenafil or nintedanib 150 mg bid plus placebo for 24 weeks, with a follow-up visit 4 weeks later. The primary endpoint was the change from baseline in SGRQ total score at week 12 [
7]. In all these trials, FVC data were converted to per cent predicted values using the European Community for Steel and Coal equations [
8]. In the INPULSIS trials, DLco data were converted to % predicted using the equation published by Crapo [
9]. In INSTAGE, sites used different equations to calculate per cent predicted values for DLco.
Spirometry was performed at baseline and weeks 2, 4, 6, 12 and 24 in the INPULSIS trials [
6], and at baseline and weeks 4, 8, 12, 18 and 24 in the INSTAGE trial [
7]. The SGRQ was completed by patients at baseline and weeks 6, 12 and 24 in the INPULSIS trials [
6], and at baseline and weeks 4, 12 and 24 in the INSTAGE trial [
7]. The SGRQ assesses health-related quality of life (HRQL); there are 50 items and the total score ranges from 0 to 100, with higher scores indicating worse HRQL [
10]. In the INPULSIS trials, acute exacerbations were defined as events that met the following criteria: unexplained worsening or development of dyspnoea within 30 days; new diffuse pulmonary infiltrates on chest X-ray and/or HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since last visit; causes of the acute worsening, including infection, left heart failure, pulmonary embolism, or any identifiable cause of acute lung injury excluded as per routine clinical practice and microbiological studies [
6]. In the INSTAGE trial, an acute exacerbation was defined as an event that met the following criteria: acute worsening or development of dyspnoea, typically of less than 1-month duration; computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on background pattern consistent with usual interstitial pneumonia pattern; deterioration not fully explained by cardiac failure or fluid overload; extra-parenchymal causes (e.g. pneumothorax, pleural effusion, pulmonary embolism) were excluded [
7]. In both the INPULSIS and INSTAGE trials, acute exacerbations were adjudicated by a blinded committee as confirmed, suspected, or not acute exacerbations [6.7]. In the INPULSIS trials, events deemed to be acute exacerbations but did not meet all protocol-specified criteria for an acute exacerbation were classified as suspected acute exacerbations [
6]. In the INSTAGE trial, events deemed to be acute exacerbations but had missing CT data were classified as suspected acute exacerbations [
7]. In the INSTAGE trial, confirmed/suspected acute exacerbations were further adjudicated as idiopathic or triggered based on the criteria described in the 2016 international working group report [
7,
11]. All confirmed/suspected acute exacerbations in the INPULSIS trials were idiopathic [
6].
In the current analyses, we investigated changes from baseline in FVC (mL) and SGRQ total score at weeks 12 and 24; the rate of decline in FVC (mL) over 24 weeks; and the proportions of patients who had an absolute decline in FVC ≥5% predicted or died, had an adjudicated confirmed or suspected idiopathic acute exacerbation, or who died from any cause over 24 weeks in patients who received nintedanib alone in the INPULSIS and INSTAGE trials and in patients who received placebo in the INPULSIS trials. For each endpoint, the same statistical approach was used as in the primary analyses [
6,
7]. Changes from baseline in FVC and SGRQ total score at weeks 12 and 24 were analysed using mixed effects models for repeated measures. The rate of decline in FVC over 24 weeks was analysed using a random coefficient regression model. These models allowed for missing data, assuming they were missing at random.
Adverse events were reported by the investigators irrespective of causality and coded based on preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) (version 20.1 in INPULSIS and version 21.0 in INSTAGE) [
6,
7]. In the INPULSIS trials, adverse events with onset between the first dose of trial drug and day 195 (or between the first dose and 28 days after the last dose for patients who discontinued trial drug before week 24) were included [
6]. In the INSTAGE trial, adverse events with onset between the first dose and up to 28 days after the last dose of trial drug were included. Safety analyses were descriptive [
7]. All efficacy and safety analyses were based on patients who received ≥1 dose of trial drug.