Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial.

The efficacy of nintedanib in progressive fibrosing interstitial lung diseases (ILDs) was demonstrated in the randomised, double-blind, placebo-controlled INBUILD trial. This subgroup analysis evaluated the efficacy and safety of nintedanib in the Japanese population. Patients with progressive fibrosing ILDs (evaluated by physicians within 24 months of screening) were randomised (1:1) to twice-daily 150-mg nintedanib or placebo; treatment continued until the last patient completed 52 weeks. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Time-to-first acute ILD exacerbation or death and time-to-death up until the last patient had completed the week 52 visit were evaluated. This subgroup analysis included 108 Japanese patients. The adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were -148.31 (nintedanib) and -240.36 (placebo), adjusted difference: 92.05 (95% CI: -10.69-194.80) and for non-Japanese patients were -67.41 (nintedanib) and -177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97-155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of "acute exacerbation or death" (hazard ratio, 0.30 [95% CI: 0.10-0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14-2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings. In Japanese patients, nintedanib slowed ILD progression, evidenced by a reduction in the annual rate of decline in FVC vs placebo. The efficacy and safety of nintedanib in Japanese patients were consistent with the overall INBUILD population. CLINICALTRIALS.GOV: NCT02999178 (21-Dec-2016).

Inoue Y ，Suda T ，Kitamura H ，Okamoto M ，Azuma A ，Inase N ，Kuwana M ，Makino S ，Nishioka Y ，Ogura T ，Takizawa A ，Ugai H ，Stowasser S ，Schlenker-Herceg R ，Takeuchi T ... -  《-》

Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Boehringer Ingelheim.

Wells AU ，Flaherty KR ，Brown KK ，Inoue Y ，Devaraj A ，Richeldi L ，Moua T ，Crestani B ，Wuyts WA ，Stowasser S ，Quaresma M ，Goeldner RG ，Schlenker-Herceg R ，Kolb M ，INBUILD trial investigators ... -  《-》

Effects of nintedanib on disease progression and safety in Japanese patients with progressive fibrosing interstitial lung diseases: Further subset analysis from the whole INBUILD trial.

A previous subgroup analysis of data from the INBUILD trial showed that nintedanib reduced the annual rate of decline in forced vital capacity (FVC) in Japanese patients with progressive fibrosing interstitial lung diseases (PF-ILDs). The safety profile of nintedanib over 52 weeks in Japanese patients was similar to that of the overall population. Using data from 108 Japanese patients with PF-ILDs who had received at least 1 dose of study medication in the INBUILD trial, we evaluated the effect of nintedanib on disease progression and assessed the safety profile over the whole trial period (i.e., a longer duration than the prior analysis) compared with placebo. ILD progression was defined as an absolute decline in FVC ≥10% predicted vs baseline. Over the whole trial, in Japanese patients with PF-ILDs, nintedanib numerically lowered the risk of progression of ILD or death (hazard ratio [HR], 0.66; 95% confidence intervals [CI]: 0.37, 1.16), acute exacerbation of ILD or death (HR, 0.28; 95% CI: 0.09, 0.83), and death (HR, 0.41; 95% CI: 0.11, 1.51). The most common adverse event over the whole trial in nintedanib-treated Japanese patients was diarrhea, which was manageable for most patients by dose reduction and interruption. The safety profile of nintedanib in this longer duration analysis was consistent with that previously reported. In this analysis of data from Japanese patients with PF-ILDs, nintedanib nominally reduced the risk of clinically meaningful outcomes reflecting disease progression, including death, over the whole trial, and no new safety concerns were observed. ClinicalTrials.gov NCT02999178.

Ogura T ，Suda T ，Inase N ，Nishioka Y ，Azuma A ，Okamoto M ，Takizawa A ，Ito T ，Rohr KB ，Inoue Y ... -  《-》

The effect of nintedanib on health-related quality of life in Japanese patients with progressive fibrosing interstitial lung diseases: A subset analysis of the INBUILD trial.

In previous Japanese subgroup/subset analyses of the global INBUILD trial, nintedanib reduced the annual rate of forced vital capacity (FVC) decline and the risk of disease progression in patients with progressive fibrosing interstitial lung diseases (PF-ILDs). This exploratory subset analysis assessed the effect of nintedanib on symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs, including those with usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT). This analysis included Japanese patients who received at least one dose of study treatment in the randomized, double-blind, placebo-controlled INBUILD trial. The Living with Pulmonary Fibrosis (L-PF) questionnaire was used to assess pulmonary fibrosis symptoms and impacts (higher scores indicated greater impairment) at baseline and weeks 12-52. In total, 108 Japanese patients (nintedanib: n = 52; placebo: n = 56) were included; 84 patients had UIP-like fibrotic pattern on HRCT. In the total Japanese subgroup and in those with UIP-like fibrotic pattern, numerically greater increases in L-PF total, symptoms total, symptoms fatigue domain, and impacts scores were observed in the placebo group than in the nintedanib group at all timepoints, starting from week 12. A numerically greater increase in the symptoms dyspnea domain score was observed with placebo versus nintedanib starting from week 36. Throughout the study, the symptoms cough domain score increased in the placebo group but decreased in the nintedanib group. Our findings demonstrate that nintedanib has the potential to reduce the worsening of symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs.

Inoue Y ，Kitamura H ，Okamoto M ，Ogura T ，Nishioka Y ，Kuwana M ，Taniguchi A ，Ito T ，Rohr KB ，Suda T ... -  《-》

Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases.

Cottin V ，Richeldi L ，Rosas I ，Otaola M ，Song JW ，Tomassetti S ，Wijsenbeek M ，Schmitz M ，Coeck C ，Stowasser S ，Schlenker-Herceg R ，Kolb M ，INBUILD Trial Investigators ... -  《RESPIRATORY RESEARCH》