The purpose of this multi-site, factorial randomised, platform trial is to evaluate host-directed therapeutic agents in patients hospitalised with moderate and severe dengue virus infection. Our primary aim is to find safe and affordable therapeutics which prevent disease progression among those at high risk for severe dengue, and improve outcomes for those with established severe disease, thereby also reducing the substantial burden placed on health systems in dengue endemic regions.
Age ≥5 years
Decision to hospitalise
Clinical diagnosis of dengue
Severe abdominal pain or tenderness
Patients on ≥ day 10 of illness or who are clinically improving in the opinion of the managing doctor (the 'recovery phase') will be excluded from recruitment. Other exclusion criteria are specific to individual treatment comparisons, and do not preclude randomisation to other arms of the study.
A participant may not enter a specific treatment comparison if that treatment is considered to be indicated or contraindicated by the responsible clinician.
Factorial
Placebo
DrugPlacebo matched to baricitinib/dexamethasone in form, dose, frequency and duration.
Dexamethasone
DrugDexamethasone is a corticosteroid. Form: tablet or intravenous preparation. Dose: Aged ≥ 12 years: 6mg once daily. Aged 5 - 11 years by weight: * 10kg to \<20 kg: 2mg once daily, * 20kg to \<30 kg: 4mg once daily, * 30kg: 6mg once daily. Duration: 4 days, or until discharge if this happens before.
N-Acetylcysteine
DrugN-acetylcysteine acts to protect the liver. It functions as a glutathione precursor and antioxidant. Dose: 100mg/kg/day, by continuous infusion over 24 hours in glucose 5% (preferred) or sodium chloride 0.9%. Duration: 4 days, or until hospital discharge if sooner.
Standard of care
Other interventionStandard of care as per local site guidelines
Baricitinib
DrugBaricitinib is an inhibitor of Janus Kinase (JAK) 1 \& 2, and Numb associated kinase (NAK). Form: tablet. Dose: Aged ≥ 12 years: 4mg once daily, Aged 5 - 11 years: 2mg once daily. - Renal adjustment of dose: Adults: eGFR ≥30 and \<60 mL/min/1.73m2: 2mg once daily, eGFR ≥15 and \<30 mL/min/1.73m2: 2mg on alternate days. Children: eGFR ≥30 and \<60mL/min/1.73m2: 2mg on alternate days \- Dose should be halved in patients also taking probenecid Duration: 4 days, or less if the patient is discharged before this time.
Progression to severe dengue/critical dengue
In the trial, baseline severity of dengue will be assessed at the start of study participation. Participants will be defined in accordance with our case definitions as having moderate, severe or critical dengue, based on clinical signs and symptoms, laboratory parameters, and if they have evidence of organ failure with or without need for organ support. At hospital discharge or following death, we will capture if the participant had evidence of at least one of: * Progression to Severe dengue, in a participant with moderate dengue at enrolment, * Progression to Critical dengue, in a participant with moderate or severe dengue at enrolment.
All-cause mortality within 30 days
All-cause mortality in any participant. Assessed as dead or alive
Length of hospital stay
Number of days from hospital admission to discharge
Lowest recorded platelet count
Lowest recorded platelet count between randomisation and hospital discharge
Acute kidney injury
Serum creatinine \> 3.5 mg/dL or more than double baseline
Liver involvement
Highest recorded ALT or AST
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Oxford University Clinical Research Unit, Vietnam
Lead sponsor
University of Oxford
Collaborator
The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Collaborator
Number 2 Children's Hospital, Ho Chi Minh City
Collaborator
Sukraraj Tropical and Infectious Disease Hospital, Kathmandu, Nepal
Collaborator
National Academy of Medical Sciences/Bir Hospital, Kathmandu, Nepal
Collaborator
Siriraj Hospital
Collaborator
Prince of Songkla University in Southern Thailand, Thailand
Collaborator
Dhaka Medical College
Collaborator
Chittagong Medical College Hospital, Chittagong, Bangladesh
Collaborator
Centro de Atención y Diagnóstico de Enfermedades Infecciosas, Bucaramanga, Colombia
Collaborator
Hospital Universitario Erasmo Meoz, Cucuta, Colombia
Collaborator
Fundación Valle del Lili, Cali, Colombia
Collaborator
Hospital Regional de Loreto, Iquitos, Peru
Collaborator
Instituto de Infectologia Emílio Ribas, São Paulo, Brazil
Collaborator
Universitas Sumatera Utara, Medan, Indonesia
Collaborator
Airlangga University (UNAIR), Indonesia
Collaborator
University Malaya Medical Centre, Malaysia
Collaborator
Hospital Queen Elizabeth II, Malaysia
Collaborator
San Lazaro Hospital (SLH-NU), Manila, Philippines
Collaborator
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