A randomised, adaptive phase 3 trial to evaluate host-directed therapeutics in patients hospitalised with moderate or severe dengue

Dengue is the most abundant and rapidly spreading arboviral infection globally, with more than 100 million estimated symptomatic infections per year. In endemic countries, dengue is a leading cause of hospital admission during rainy season, and outbreaks can rapidly overwhelm healthcare facilities. Despite this, there are no licensed antiviral or host-directed treatments to prevent progression to severe disease or death, which is often caused by multi-organ failure in the context of hyperinflammation. We plan to conduct a multi-site, multi-country, randomised, placebo-controlled clinical trial to evaluate host-directed and adjuvant therapeutic agents for patients over 5 years of age who are hospitalised with moderate or severe dengue virus infection. Within the trial, we will evaluate the safety and efficacy of immunomodulation with baricitinib and/or corticosteroids. The primary endpoint is a composite outcome of progression to severe dengue and all-cause mortality within 30 days. We will also evaluate the safety and efficacy of N-acetylcysteine to improve liver impairment in a sub-group of patients with moderate or severe dengue-induced liver injury. Randomisation will be factorial and the total sample size will be adaptive (estimated 7500-8500 participants), with multiple planned interim analyses and stopping rules for success.