Therapeutics for Moderate and Severe Dengue

Official title

A Randomised Platform Trial to Evaluate Therapeutics in Patients With Moderate or Severe Dengue (DEN-HOST)

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.

Detailed description

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.

Interventions

• Drug Placebo
  Placebo matched to baricitinib/dexamethasone in form, dose, frequency and duration.
• Drug Dexamethasone
  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.
• Drug N-Acetylcysteine
  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.
• Other Standard of care
  Standard of care as per local site guidelines
• Drug Baricitinib
  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 dis

Primary outcome measures

• Progression to severe dengue/critical dengue [Time frame: between randomization to hospital discharge (average of 5 days)]
• All-cause mortality within 30 days [Time frame: Day 30]

Secondary outcome measures (10)

• Length of hospital stay [Time frame: At hospital discharge (average of 5 days)]
• Lowest recorded platelet count [Time frame: Between randomisation and hospital discharge (average of 5 days)]
• Acute kidney injury [Time frame: Between randomisation and hospital discharge (average of 5 days)]
• Liver involvement [Time frame: Between randomisation and hospital discharge (average of 5 days)]
• Change in ALT/AST [Time frame: at randomisation, day 2 (if feasible) and day 4 or hospital discharge (average on day 5) if sooner]
• Highest bilirubin [Time frame: Between randomisation and hospital discharge (average of 5 days)]
• Highest INR [Time frame: Between randomisation and hospital discharge (average of 5 days)]
• Safety reporting: Suspected Severe Adverse Reactions [Time frame: During hospital stay (average of 5 days) and at day 30 follow up]
• Quality of live assessment using EQ-5D-5L value index [Time frame: at day 30 follow up]
• Quality of live assessment using EQ-Visual Analogue Scale (VAS) [Time frame: at day 30 follow up]

Eligibility criteria

Inclusion criteria

• Age ≥5 years
• Decision to hospitalise
• Clinical diagnosis of dengue
• Participants must also have at least one of the following:

• Severe abdominal pain or tenderness
• Vomiting more than 3 times in the past 24 hours
• Pleural effusion or ascites on clinical or radiological examination
• Absolute haematocrit >50%
• 15% increase in haematocrit compared with a baseline sample (defined as the first sample taken during the current illness)
• Absolute platelet count <50 × 10⁹/L
• Absolute platelet count <100 × 10⁹/L AND a drop >50 × 10⁹/L in the past 32 hours
• ALT or AST >400 IU/L
• 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
• Bleeding leading to hypotension for age or requiring blood transfusion or medical intervention (e.g. surgery, endoscopy, or vasoactive drugs)
• Symptomatic bleeding into a critical site (intracranial, intraspinal, intraocular with visual impairment, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome)
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Bangladesh · 3 centers

• Chittagong Medical College Hospital — Chittagong
• Dhaka Medical College & Hospital — Dhaka
• Dhaka North City Corporation Hospital — Dhaka

Colombia · 3 centers

• Centro de Atención y Diagnóstico de Enfermedades Infecciosas — Bucaramanga
• Fundación Valle del Lili — Cali
• Hospital Universitario Erasmo Meoz — Cúcuta

Malaysia · 2 centers

• Hospital Queen Elizabeth II, Sabah — Kota Kinabalu
• University Malaya Medical Centre — Kuala Lumpur

Nepal · 2 centers

• National Academy of Medical Sciences/Bir Hospital — Kathmandu
• Sukraraj Tropical and Infectious Disease Hospital — Kathmandu

Thailand · 2 centers

• Siriraj Hospital, Mahidol University — Bangkok
• Prince of Songkla University in Southern Thailand — Songkhla

Vietnam · 2 centers

• Hospital for Tropical Diseases — Ho Chi Minh City
• Number 2 Children's Hospital — Ho Chi Minh City

Brazil · 1 center

• Instituto de Infectologia Emílio Ribas — São Paulo

Indonesia · 1 center

• Universitas Sumatera Utara — Medan

Peru · 1 center

• Hospital Regional de Loreto — Iquitos

Philippines · 1 center

• San Lazaro Hospital — Manila

Identifiers

NCT: NCT07543458 · OxTREC 3271082 · 323061/Z/24/Z

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗