Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

“…Although celgosivir, an α-glucosidase inhibitor, was protective against DENV in AG129 mice (21,22,27), a phase Ib randomized placebo-controlled clinical trial in Singapore failed to show significant reduction of viremia (10,12). Our follow-up preclinical study reveals the challenges in lowering viral load when drug treatment is initiated near peak viremia, comparable to how most patients present clinically (11).…”

“…The use of the reduction of serum viremia as the primary laboratory endpoint for evaluating therapeutics against DF failed to show any significant efficacy, as recent clinical trials of repurposed drugs have demonstrated (10,(39)(40)(41)(42). Moreover, the potency of the tested drugs has been significantly questioned, since analysis showed an almost 4-log reduction in viral load during the acute phase for both the treated and untreated arms (10,(39)(40)(41)(42).…”

“…Moreover, the potency of the tested drugs has been significantly questioned, since analysis showed an almost 4-log reduction in viral load during the acute phase for both the treated and untreated arms (10,(39)(40)(41)(42). Viremia clearance is associated with the immune status of the patients and virus serotype (39,43).…”

“…Viremia clearance is associated with the immune status of the patients and virus serotype (39,43). In the case of adult patients, viremia reduction during secondary infection is significantly faster than that for primary infection (10,12,39), most probably due to the rapid reactivation of the acquired immune system. Overall, the wide variation of the viremia reduction rate, coupled with the short window given to observe these changes in patients, hampers the assessment of statistical difference among drug-treated and drug-naive cases.…”

“…Serum viral load (viremia), the current clinical diagnostic gold standard, does not always correlate with disease severity, nor does it robustly inform to anti-dengue therapy response under strict clinical trial conditions (10)(11)(12). However, DENV infection is consistently associated with cells of the mononuclear phagocyte lineage, and their increased proinflammatory cytokine production is believed to enhance disease severity by disrupting the integrity of vascular endothelial lining and causing increased vascular permeability (13,14).…”