INBUILD

NEJM 2019

the coarse crackle

INBUILD was a randomized, double-blind, placebo-controlled phase 3 trial across 15 countries that evaluated nintedanib (150 mg twice daily) versus placebo in 663 adults with progressive fibrosing interstitial lung diseases (PF-ILD). Nintedanib slowed the annual rate of decline in FVC over 52 weeks in the overall population (between group difference ~110.0 ml/yr) with benefit in both UIP-like and non-UIP-like subgroups.

fine crackles

  • A progressive fibrosing ILD phenotype behaves similarly across diagnostic labels; nintedanib slowed FVC decline consistently in UIP-like and non–UIP-like patterns.

  • The INBUILD trial provided insights into the natural history of progressive fibrosing interstitial lung diseases. In placebo-treated patients, annual FVC decline in the overall cohort and in those with a UIP-like pattern was similar to pooled INPULSIS data in IPF (−187.8, −211.1, and −223.5 ml/year, respectively). In those with non-UIP-like patterns, decline was only slightly less (−154.2 ml/year) yet remained clinically meaningful, consistent with prior observations.

  • Diarrhea and reversible liver enzyme elevations are the main treatment-limiting toxicities of nintedanib; dose interruption and reduction to 100 mg twice daily are effective management strategies. More patients stopped nintedanib than stopped placebo because of adverse effects, with diarrhea being the most common adverse event.

  • Background

    Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.

    Methods

    In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern.

    Results

    A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was −80.8 ml per year with nintedanib and −187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was −82.9 ml per year with nintedanib and −211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group.

    Conclusions

    In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.)

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