Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS(®) trials.

The Phase II TOMORROW trial and two Phase III INPULSIS(®) trials investigated the efficacy and safety of nintedanib versus placebo in patients with idiopathic pulmonary fibrosis (IPF). To obtain an overall estimate of the treatment effect of nintedanib 150 mg twice daily (bid), pooled and meta-analyses of data from these three trials were conducted. Pooled and meta-analyses were conducted for annual rate of decline in forced vital capacity (FVC), time to first acute exacerbation, change from baseline in St George's Respiratory Questionnaire (SGRQ) total score and mortality over 52 weeks. 1231 patients (nintedanib n = 723, placebo n = 508) were included in the pooled analysis. Adjusted annual rate of decline in FVC was -112.4 mL/year with nintedanib and -223.3 mL/year with placebo (difference: 110.9 mL/year [95% CI: 78.5, 143.3]; p < 0.0001). The hazard ratio for time to first acute exacerbation was 0.53 (95% CI: 0.34, 0.83; p = 0.0047). Adjusted mean change from baseline in SGRQ score at week 52 was 2.92 with nintedanib and 4.97 with placebo (difference: -2.05 [95% CI: -3.59, -0.50]; p = 0.0095). Hazard ratios for time to all-cause and on-treatment mortality were 0.70 (95% CI: 0.46, 1.08; p = 0.0954) and 0.57 (95% CI: 0.34, 0.97; p = 0.0274), respectively, in favour of nintedanib. The meta-analysis was generally consistent with the pooled analysis. Diarrhoea was the most frequent adverse event in the nintedanib group (61.5% of patients treated with nintedanib versus 17.9% of patients treated with placebo). Nintedanib has a beneficial effect on slowing disease progression in patients with IPF.

Richeldi L ，Cottin V ，du Bois RM ，Selman M ，Kimura T ，Bailes Z ，Schlenker-Herceg R ，Stowasser S ，Brown KK ... -  《-》

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

Richeldi L ，du Bois RM ，Raghu G ，Azuma A ，Brown KK ，Costabel U ，Cottin V ，Flaherty KR ，Hansell DM ，Inoue Y ，Kim DS ，Kolb M ，Nicholson AG ，Noble PW ，Selman M ，Taniguchi H ，Brun M ，Le Maulf F ，Girard M ，Stowasser S ，Schlenker-Herceg R ，Disse B ，Collard HR ，INPULSIS Trial Investigators ... -  《-》

Design of the INPULSIS™ trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis.

Nintedanib is in clinical development as a treatment for idiopathic pulmonary fibrosis (IPF). Data from the Phase II TOMORROW study suggested that nintedanib 150 mg twice daily had clinical benefits with an acceptable safety profile. The INPULSIS™ trials are replicate Phase III, randomized, double-blind, studies comparing the efficacy and safety of nintedanib 150 mg twice daily with placebo in patients with IPF. Eligible patients were aged ≥40 years with a diagnosis of IPF within 5 years before randomization who had undergone a chest high-resolution computed tomography (HRCT) scan within 1-year before screening, and who had a forced vital capacity (FVC) of ≥50% predicted and a diffusing capacity for carbon monoxide of 30-79% predicted. Participants were randomized 3:2 to receive nintedanib or placebo for 52 weeks. The primary endpoint is the annual rate of decline in FVC. The key secondary endpoints are change from baseline in the total score on the St. George's Respiratory Questionnaire (a measure of health-related quality of life) over 52 weeks and time to first acute exacerbation. Enrolment of 1066 patients in 24 countries was completed in September 2012. Results will be reported in the first half of 2014. The INPULSIS™ trials will determine the efficacy of nintedanib in patients with IPF, including its impact on disease progression as defined by decline in FVC, acute exacerbations and health-related quality of life. In addition, they will characterise the adverse event profile of nintedanib in this patient population. Registered at ClinicalTrials.gov (identifiers: NCT01335464 and NCT01335477).

Richeldi L ，Cottin V ，Flaherty KR ，Kolb M ，Inoue Y ，Raghu G ，Taniguchi H ，Hansell DM ，Nicholson AG ，Le Maulf F ，Stowasser S ，Collard HR ... -  《-》

Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis across Prespecified Subgroups in INPULSIS.

Costabel U ，Inoue Y ，Richeldi L ，Collard HR ，Tschoepe I ，Stowasser S ，Azuma A ... -  《-》

Subgroup analysis of Asian patients in the INPULSIS(®) trials of nintedanib in idiopathic pulmonary fibrosis.

In the two-replicate randomized Phase III INPULSIS® trials in patients with idiopathic pulmonary fibrosis (IPF), nintedanib 150 mg bd significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo. The key secondary endpoints were time to first investigator-reported acute exacerbation and change from baseline in St George's Respiratory Questionnaire total score, both over 52 weeks. Here, we assessed the effect of nintedanib in Asian patients. Pre-specified subgroup analyses of the effect of nintedanib on the primary and key secondary endpoints in Asian versus White patients were undertaken based on pooled data from the two INPULSIS® trials. Safety data were analyzed descriptively. Of the treated patients, 322 were Asian (nintedanib n = 194; placebo n = 128) and 608 were White (nintedanib n = 360; placebo n = 248). In Asian patients, the nintedanib versus placebo difference in the adjusted annual rate of decline in FVC was 94.1 mL/year (95% CI: 33.7, 154.6). The treatment effect of nintedanib on the annual rate of decline in FVC in Asian and White patients was similar (treatment-by-subgroup interaction P = 0.72) and consistent with the overall population. No significant treatment-by-subgroup interaction was observed for the key secondary endpoints between Asian and White patients. In Asian patients, the most common adverse event in the nintedanib group was diarrhoea (56.2% of patients vs 15.6% for placebo). In pre-specified subgroup analyses of Asian versus White patients with IPF in the INPULSIS® trials, race did not influence the effect of nintedanib on disease progression.

Taniguchi H ，Xu Z ，Azuma A ，Inoue Y ，Li H ，Fujimoto T ，Bailes Z ，Schlenker-Herceg R ，Kim DS ... -  《-》