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

Collard, Harold R.; Richeldi, Luca; Kim, Dong Soon; Taniguchi, Hiroyuki; Tschoepe, Inga; Luisetti, Maurizio; Roman, Jesse; Tino, Gregory; Schlenker‐Herceg, Rozsa; Hallmann, Christoph; Bois, Roland M. du

doi:10.1183/13993003.01339-2016

Cited by 117 publications

(119 citation statements)

References 23 publications

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“…Acute exacerbations of IPF (identified using different methodologies) were reported in 2-16% of placebo-treated patients over 24-60 weeks, while mortality ranged from 2.5-13.3% over approximately 28-96 weeks [16,[18][19][20][21][22][23][24][25][26][30][31][32][33]. Data from the INPULSIS trials suggests that events adjudicated as confirmed or suspected acute exacerbations were associated with similar post-event mortality as other forms of acute respiratory worsening [68]. This supports the perspective of an international working group that the requirement for an event to be idiopathic should be removed from the definition of an acute exacerbation [5].…”

Section: Lessons Learned On the Natural History Of Idiopathic Pulmonamentioning

confidence: 99%

Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years

Raghu

2017

Eur Respir J

126

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Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. A major breakthrough in treatment came when, after decades of clinical trials which failed to identify an efficacious treatment regimen, two therapies were successful in Phase-III trials. The advent of these therapies, nintedanib and pirfenidone, meant that for the first time IPF patients had two treatment options that could reduce disease progression. This review summarises the key lessons to be obtained from the clinical trials that led to the current international clinical practice guidelines for the treatment of IPF and provides insights for the design of future clinical trials that are needed if we are to improve outcomes that are clinically meaningful to IPF patients.

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Section: Lessons Learned On the Natural History Of Idiopathic Pulmonamentioning

confidence: 99%

Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years

Raghu

2017

Eur Respir J

126

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“…As expected, the risk of idiopathic acute exacerbations was higher in patients with more advanced disease in the INSTAGE trial than in patients in the INPULSIS trials. A wealth of data has demonstrated that low FVC and/or low DLco are risk factors for acute exacerbations in patients with IPF [11,32,33], possibly because patients with more advanced disease are more vulnerable to insults such as infection that may lead to an acute exacerbation [11]. Similarly, the risk of mortality was higher in patients with more severe impairment in DLco in the INSTAGE trial than in patients in the INPULSIS trials, consistent with previous studies identifying low DLco as a risk factor for mortality in patients with IPF [4,33,34].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis

et al. 2020

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Background: The two 52-week INPULSIS trials investigated nintedanib versus placebo in patients with IPF, FVC ≥50% predicted and DLco 30-79% predicted. The 24-week INSTAGE trial investigated nintedanib plus sildenafil versus nintedanib alone in patients with IPF and DLco ≤35% predicted. We used data from INPULSIS and INSTAGE to compare the effects of nintedanib in patients with IPF with less versus more severe impairment in gas exchange at baseline. Methods: Analyses were conducted in patients treated with nintedanib alone in the INPULSIS and INSTAGE trials and in patients treated with placebo in the INPULSIS trials. Outcomes included the rate of decline in FVC over 24 weeks, the proportions of patients who had a confirmed or suspected idiopathic acute exacerbation over 24 weeks, deaths over 24 weeks, and adverse events. Analyses were descriptive. Results: In total, 638 and 136 patients received nintedanib alone in the INPULSIS and INSTAGE trials, respectively, and 423 patients received placebo in the INPULSIS trials. Rates of FVC decline were − 52.3 and − 66.7 mL/24 weeks in patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and − 102.8 mL/24 weeks in patients treated with placebo in INPULSIS. Confirmed or suspected idiopathic acute exacerbations were reported in 0.6 and 3.7% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 2.1% of patients treated with placebo in INPULSIS. Deaths occurred in 2.0, 11.0 and 1.9% of patients in these groups, respectively. Diarrhoea adverse events were reported in 52.5 and 48.5% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 16.1% of patients treated with placebo in INPULSIS.Conclusions: Based on data from the INSTAGE and INPULSIS trials, nintedanib had a similar effect on FVC decline over 24 weeks, and a similar safety and tolerability profile, in patients with IPF and more versus less severe impairment in gas exchange. These data support the use of nintedanib in patients with IPF who have advanced disease.Trial registration: INPULSIS (NCT01335464 and NCT01335477); INSTAGE (NCT02802345).

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“…Collard et al . have previously published a risk factor analysis on time to first acute exacerbation also using data from the INPULSIS trials.…”

Section: Discussionmentioning

confidence: 99%

“…9 Nonetheless, our analysis indirectly supports an effect of nintedanib treatment on the exacerbation risk as nintedanib has been shown to reduce the annual rate of FVC decline significantly. 5 Collard et al 25 have previously published a risk factor analysis on time to first acute exacerbation also using data from the INPULSIS trials. Their final Cox proportional hazard model included baseline %pFVC, supplemental oxygen, use of antacid medications, and randomization to nintedanib as risk factors for investigator-reported acute exacerbations.…”

Section: Time-to-event Model For Ipf Exacerbationsmentioning

confidence: 99%

Parametric Time‐to‐Event Model for Acute Exacerbations in Idiopathic Pulmonary Fibrosis

Tang

Weber

Stowasser

et al. 2020

CPT Pharmacom & Syst Pharma

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We describe a parametric time‐to‐event model for idiopathic pulmonary fibrosis (IPF) exacerbations and identify predictors of exacerbation risk using data obtained for the tyrosine‐kinase inhibitor nintedanib in two phase III studies (INPULSIS‐1/2). Parametric survival analysis was performed on time to first exacerbation (censoring on day 372), with univariate analysis to select statistically significant covariates (P = 0.05). Multivariate covariate models were developed using stepwise covariate modeling with forward inclusion (P = 0.05) and backward elimination (P = 0.01). Sixty‐three first exacerbation events were reported across 1,061 subjects in the INPULSIS studies. Baseline and decline of forced vital capacity (FVC)/percent‐predicted FVC (%pFVC), supplemental oxygen use, baseline CO diffusing capacity and age were statistically significant in the univariate analysis. The final covariate model included decline in FVC to week 52, baseline %pFVC, supplemental oxygen use, and age. The developed model may be used to identify patients at high risk of IPF exacerbations and accelerate development of novel treatments.

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

Cited by 117 publications

References 23 publications

Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years

Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years

Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis

Parametric Time‐to‐Event Model for Acute Exacerbations in Idiopathic Pulmonary Fibrosis

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