Therapeutics for Moderate and Severe Dengue

Phase 3Not Yet RecruitingNCT07543458

Oxford University Clinical Research Unit, Vietnam8,800 enrolled

Overview

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.

This multi-site, factorial randomised, platform clinical trial will evaluate host-directed therapeutic agents in patients hospitalised with moderate and severe dengue virus infection. The 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. The trial will employ partial factorial randomization. Participants who provide informed consent will be entered into one or more randomisations, depending on eligibility for each intervention, clinician discretion, and availability of the treatment at the study site. For each intervention, eligible participants will be randomised in a 1:1 ratio to receive either the active intervention or the corresponding control (either matched placebo or usual care, depending on the intervention). Participants who are ineligible for a specific treatment comparison may still enter other treatment comparisons within the trial. Outcomes are described in more detail in the outcome section below. Participants will be followed up until death/day 30 after randomisation (whichever is sooner) to monitor for primary, secondary and safety outcomes. Participants who have been discharged from hospital alive before day 30 will have a final assessment conducted by telephone at least 30 days after randomisation. Patients will be additionally consented for collection of a blood sample, taken and stored as a dried blood spot, for analyses in genetic studies and other research.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

PlaceboDRUG

Placebo matched to baricitinib/dexamethasone in form, dose, frequency and duration.

DexamethasoneDRUG

Dexamethasone 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-AcetylcysteineDRUG

N-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 careOTHER

Standard of care as per local site guidelines

BaricitinibDRUG

Baricitinib 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.

Eligibility

Sex: ALLMin age: 5 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥5 years * Decision to hospitalise * Clinical diagnosis of dengue * Participants must also have at least one of the following: 1. Severe abdominal pain or tenderness 2. Vomiting more than 3 times in the past 24 hours 3. Pleural effusion or ascites on clinical or radiological examination 4. Absolute haematocrit \>50% 5. 15% increase in haematocrit compared with a baseline sample (defined as the first sample taken during the current illness) 6. Absolute platelet count \<50 × 10⁹/L 7. Absolute platelet count \<100 × 10⁹/L AND a drop \>50 × 10⁹/L in the past 32 hours 8. ALT or AST \>400 IU/L 9. Pulse pressure \<20mmHg or hypotension for age AND at least one of: peripheral capillary refill time \>2 seconds; urine output 0.5ml/kg/hr; cold/clammy peripheries; agitation or altered mental state 10. Bleeding leading to hypotension for age or requiring blood transfusion or medical intervention (e.g. surgery, endoscopy, or vasoactive drugs) 11. Symptomatic bleeding into a critical site (intracranial, intraspinal, intraocular with visual impairment, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome) 12. Requirement for organ support, including vasopressors or inotropes, assisted ventilation, dialysis or haemofiltration, or coma (unresponsive to pain without sedation) or requirement for intravenous antiseizure medications Exclusion Criteria: * 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.

Locations (18)

Chittagong Medical College Hospital

Chittagong, Bangladesh

Dhaka Medical College & Hospital

Dhaka, Bangladesh

Dhaka North City Corporation Hospital

Dhaka, Bangladesh

Instituto de Infectologia Emílio Ribas

São Paulo, Brazil

Centro de Atención y Diagnóstico de Enfermedades Infecciosas

Bucaramanga, Colombia

Fundación Valle del Lili

Cali, Colombia

Hospital Universitario Erasmo Meoz

Cúcuta, Colombia

Universitas Sumatera Utara

Medan, Indonesia

Hospital Queen Elizabeth II, Sabah

Kota Kinabalu, Malaysia

University Malaya Medical Centre

Kuala Lumpur, Malaysia

...and 8 more locations

Outcomes

Primary Outcomes

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.

Time frame: between randomization to hospital discharge (average of 5 days)

All-cause mortality within 30 days

All-cause mortality in any participant. Assessed as dead or alive

Time frame: Day 30

Secondary Outcomes

Length of hospital stay

Number of days from hospital admission to discharge

Time frame: At hospital discharge (average of 5 days)

Lowest recorded platelet count

Lowest recorded platelet count between randomisation and hospital discharge