A randomised, adaptive phase 3 trial to evaluate host-directed therapeutics in patients hospitalised with moderate or severe dengue. (360G-Wellcome-323061_Z_24_Z)

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.