Early Nintedanib Deployment in COVID-19 Interstitial Lung Disease (ENDCOV-I): A Randomized, Double Blind, Placebo-controlled Trial

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Abstract RATIONALE: The outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 sparked a global pandemic, leading to an estimated three million deaths worldwide in the first year alone. Millions of survivors live with the sequelae of their acute illness, including a subset of patients who developed parenchymal lung abnormalities resembling interstitial lung disease (ILD) as a consequence of injury from COVID-19 pneumonia. The tyrosine-kinase inhibitor nintedanib has been shown to slow the rate of decline of forced vital capacity (FVC) in patients with a range of progressive fibrosing lung diseases. The role of nintedanib in mediating post-COVID ILD has not been studied in a prospective randomized trial. METHODS: In this multicenter, double-blind, randomized controlled trial, 103 participants with a history of COVID-19 lung injury complicated by respiratory failure requiring oxygen support, and with radiologic evidence of ILD, were randomized in a 1:1 ratio to receive oral nintedanib or placebo. Patients with ILD diagnosed prior to COVID-19 infection were excluded. The primary endpoint was change in baseline forced vital capacity (FVC, mL) at 180 days. Secondary endpoints included change in diffusing capacity for carbon monoxide (DLCO, percent predicted) and six-minute walk test (6MWT, feet) at 180 days. Serious adverse events were assessed. RESULTS: Of the 103 patients randomized, 51 received nintedanib and 52 received placebo. The mean FVC change was 147.55 mL with nintedanib and 167.72 mL with placebo. There was no significant between-group difference in the primary endpoint (mean difference, -20.17; 95% CI, -138.54 to 98.20; P=0.74). Mean change in DLCO did not differ between nintedanib and placebo (0.54% predicted vs. 2.12% predicted, respectively; mean difference, -1.58; 95% CI, -6.10 to 2.94) nor did mean change in the six-minute walk distance (79.98 feet vs. 42.58 feet; mean difference, 37.40; 95% CI, -84.31 to 159.12). The incidence of serious adverse events was similar in the two groups (11.8% for nintedanib vs. 13.5% for placebo). CONCLUSIONS: Administration of nintedanib to subjects with ILD findings following COVID-19-related lung injury did not improve FVC at 180 days when compared with placebo. Participants in both groups demonstrated improvement in FVC over the study period. There was no difference in incidence of serious adverse events between the two groups.

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