Early nintedanib deployment in COVID-19 interstitial lung disease (ENDCOV-I): study protocol of a randomised, double-blind, placebo-controlled trial.

Introduction: In December 2019, the novel SARS-CoV-2 triggered a global pneumonia outbreak, leading to millions of deaths worldwide. A subset of survivors faces increased morbidity and mortality, particularly due to subacute lung injury evolving to chronic fibrosing interstitial lung disease. While nintedanib, a tyrosine-kinase inhibitor, shows promise in treating progressive fibrotic lung disease, limited randomised trial data exists for post-COVID-19-induced lung injury. We hypothesise that treatment with nintedanib may attenuate advancement to the fibrotic stages, offering a potential avenue for improving outcomes in this specific patient subset.

Methods and analysis: We describe the design of a multicentre, randomised, double-blind, placebo-controlled trial involving approximately 170 patients with subacute lung injury secondary to COVID-19, who required respiratory support with oxygen supplementation. Patients are randomised by site and disease phenotype (fibrotic vs non-fibrotic) in a 1:1 ratio to either oral nintedanib or placebo. Patients will be followed for 180 days. The primary endpoint is to assess change from baseline in forced vital capacity (FVC, mL) at 180 days. Secondary objectives include change in FVC (mL) at 90 days; diffusing capacity of carbon monoxide (% of predicted) and 6-min walk test (feet) at 180 days; and mortality at 90 and 180 days. Qualitative and quantitative changes in high-resolution computerised tomography (HRCT), change in patient-reported outcome measures (PROMs) and safety endpoints will also be assessed. Analysis will be performed according to the intention-to-treat principle.

Ethics and dissemination: The study is conducted in accordance with the Good Clinical Practices as outlined by the Food and Drug Administration and the Declaration of Helsinki 2008. This study received approval from participating sites' Institutional Review Boards and committees, including The Ethics Committee of the Medical Board at the Mount Sinai Hospital (ID: HS#20-01166). The Independent Oversight Committee oversees study conduct, data and patient safety for the duration of the study investigation. The trial details presented align with the trial protocol V.8. (April 2022). Results will be presented at national and international conferences, published in a peer-reviewed journal and disseminated to patients, funders and researchers on data analysis completion.

Trial registration number: NCT04619680. First posted 6 November 2020.