Efficacy and safety of nintedanib for pulmonary fibrosis in severe pneumonia induced by COVID-19: An interventional study

Umemura et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.05.055, jRCTs051200036, Jul 2021
Late treatmentRetrospective · 60 patients · Japan · Mar – Jul 2020
Nintedanib for COVID-19
Outcome
Improvement
Relative Risk · 95% CI
Study underpowered to detect differences
Analysis of 60 mechanically ventilated COVID-19 patients (30 nintedanib, 30 historical controls) showing no significant difference in 28-day mortality or the need for mechanical ventilation, but shorter mechanical ventilation duration (p=0.046) and lower CT high-attenuation areas after mechanical ventilation. Major limitations include the non-randomized historical control design and small size.
Standard of Care (SOC) for COVID-19 in the study country, Japan, is very poor with very low average efficacy for approved treatments1. Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments. This may explain in part the very high mortality seen in this study. Results may differ in countries with improved SOC.
OutcomeImprovementEffect · pTreatmentControl
risk of death 14.3% lower · RR 0.86 · p = 1.00 14.3% lowerRR 0.86p = 1.00 6 of 30 (20.0%) 7 of 30 (23.3%) treatment 6 of 30 (20.0%), control 7 of 30 (23.3%)NNT 30day 28
percentage of high-attenuation areas on CT at liberation from mechanical ventilation 33.6% lower · relative time 0.66 · p = 0.03* 33.6% lowerrelative time 0.66p = 0.03* median 25.7 IQR 25.2 n=30 median 38.7 IQR 24.7 n=30 median 25.7 IQR 25.2 n=30, median 38.7 IQR 24.7 n=30
ventilator-free days 29.4% lower · relative time 0.71 · p = 0.04* 29.4% lowerrelative time 0.71p = 0.04* median 17.0 IQR 21.0 n=30 median 12.0 IQR 17.0 n=30 median 17.0 IQR 21.0 n=30, median 12.0 IQR 17.0 n=30day 28

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates. * p < 0.05

Umemura et al., 31 Jul 2021, Japan, peer-reviewed, 9 authors, study period March 2020 - July 2020, trial jRCTs051200036. Contact: plum00022@gmail.com, goto8940@gmail.com, kensuke.min@gmail.com, tnishida.716@gmail.com, nabeatsushi0407@gmail.com, wggdilp@gmail.com, kyamakawa-osk@umin.ac.jp, nochioka@cardio.med.tohoku.ac.jp, sfujimi40@nifty.com.
$0 $500 $1,000+ Efficacy vs. cost for COVID-19 treatment protocols c19early.org November 2026 Japan Angola Colombia Kenya Mozambique Myanmar South Africa Peru Philippines USA Vietnam Iran Bangladesh Ethiopia Ghana Germany Mexico South Korea United Kingdom Saudi Arabia Algeria Morocco Yemen Poland Uzbekistan India China Venezuela DR Congo Madagascar Thailand Uganda Egypt Nigeria Taiwan Fiji Zambia Bosnia-Herzegovina Dominican Republic Bolivia Côte d'Ivoire Eritrea Togo Bulgaria Greece Slovakia Iceland New Zealand Trinidad and Tobago Mongolia Czechia Belarus Israel Haiti North Macedonia Hong Kong Qatar Panama Serbia Japan favored high-profit treatments.The average efficacy of treatments was very low.High-cost protocols reduce early treatment, andforgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
$0 $500 $1,000+ Efficacy vs. cost for COVID-19treatment protocols worldwide c19early.org November 2026 Japan Angola Colombia Kenya Mozambique Myanmar South Africa Peru Philippines USA Vietnam Iran Bangladesh Ethiopia Ghana Germany Mexico South Korea United Kingdom Saudi Arabia Algeria Morocco Yemen Poland Uzbekistan India China Venezuela DR Congo Madagascar Thailand Uganda Egypt Taiwan Fiji Zambia Dominican Rep. Bolivia Côte d'Ivoire Eritrea Togo Sri Lanka Bulgaria Greece Slovakia New Zealand Trinidad and Tobago Mongolia Czechia Belarus Israel North Macedonia Hong Kong Qatar Panama Serbia Japan favored high-profit treatments.The average efficacy was very low.High-cost protocols reduce early treatment,and forgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
Nintedanib is an orally administered small molecule tyrosine kinase inhibitor with antifibrotic activity, targeting PDGFR, FGFR, and VEGFR signaling, and investigated in COVID-19 for the prevention and treatment of SARS-CoV-2-induced pulmonary fibrosis.
Abstract: Contents lists available at ScienceDirect International Journal of Infectious Diseases j o u r n a l home page: www.elsevier.com/locat e/ijid Ef fi cacy and safety of nintedanib for pulmonary fi brosis in severe pneumonia induced by COVID-19: An interventional study Yutaka Umemura a,b, *, Yumi Mitsuyama a , Kensuke Minami a , Takeshi Nishida a , Atsushi Watanabe a , Naoki Okada c , Kazuma Yamakawa c , Kotaro Nochioka d , Satoshi Fujimi a - a Division of Trauma and Surgical Critical Care, Osaka General Medical Center, Osaka, Japan - b Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan - c Department of Emergency Medicine, Osaka Medical College, Osaka, Japan - d Clinical Research, Innovation and Education Center, Tohoku University Hospital, Miyagi, Japan A R T I C L E I N F O Article history: Received 12 April 2021 Received in revised form 17 May 2021 Accepted 21 May 2021 Keywords: COVID-19 Respiratory distress syndrome Pulmonary fi brosis Nintedanib Respiration Arti fi cial Intensive care units
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Late treatment
is less effective