Arbovirus Infections, Dengue, Flavivirus Infections, Hemorrhagic Fever, Mosquito-Borne Diseases, RNA Virus Infections, Severe Dengue, Vector Borne Diseases
Conditions
Keywords
dengue treatment, host-directed therapy, host-targeted therapeutics
Brief summary
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
DRUGPlacebo
Placebo matched to baricitinib/dexamethasone in form, dose, frequency and duration.
DRUGDexamethasone
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.
DRUGN-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.
OTHERStandard of care
Standard of care as per local site guidelines
DRUGBaricitinib
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.
Sponsors
Oxford University Clinical Research Unit, Vietnam
University of Oxford
The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Number 2 Children's Hospital, Ho Chi Minh City
Sukraraj Tropical and Infectious Disease Hospital, Kathmandu, Nepal
National Academy of Medical Sciences/Bir Hospital, Kathmandu, Nepal
Siriraj Hospital
Prince of Songkla University in Southern Thailand, Thailand
Dhaka Medical College & Hospital, Dhaka, Bangladesh
Chittagong Medical College Hospital, Chittagong, Bangladesh
Centro de Atención y Diagnóstico de Enfermedades Infecciosas, Bucaramanga, Colombia
Hospital Universitario Erasmo Meoz, Cucuta, Colombia
Fundación Valle del Lili, Cali, Colombia
Hospital Regional de Loreto, Iquitos, Peru
Instituto de Infectologia Emílio Ribas, São Paulo, Brazil
Universitas Sumatera Utara, Medan, Indonesia
Airlangga University (UNAIR), Indonesia
University Malaya Medical Centre, Malaysia
Hospital Queen Elizabeth II, Malaysia
San Lazaro Hospital (SLH-NU), Manila, Philippines
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
For placebo-matched agents, the participant, care provider, investigator and outcomes assessor will all be masked. Currently, this includes baricitinib and dexamethasone. The N-acetylcysteine arm is open-label with no masking; there will be no matched placebo. Treatment with N-acetylcysteine will be compared to standard care.
Intervention model description
This multi-site, phase 3, randomised, clinical trial will evaluate therapeutic agents in patients hospitalised with moderate or severe dengue virus infection. The trial will employ partial factorial randomisation. 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. Patients are randomised to Baricitinib versus placebo (Comparison A) and/or Dexamethasone versus placebo (Comparison B) depending on eligibility. Participants who are ineligible for one intervention are randomized only to the other intervention. In addition, participants with evidence of liver involvement undergo a second, independent randomisation to receive N-acetylcysteine or standard of care (Comparison C). This second randomisation may occur at any time during admission, when the patient is first noted to fulfil the eligibility criteria during the main trial.
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression to severe dengue/critical dengue | between randomization to hospital discharge (average of 5 days) | 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 | Day 30 | All-cause mortality in any participant. Assessed as dead or alive |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of hospital stay | At hospital discharge (average of 5 days) | Number of days from hospital admission to discharge |
| Lowest recorded platelet count | Between randomisation and hospital discharge (average of 5 days) | Lowest recorded platelet count between randomisation and hospital discharge |
| Acute kidney injury | Between randomisation and hospital discharge (average of 5 days) | Serum creatinine \> 3.5 mg/dL or more than double baseline |
| Liver involvement | Between randomisation and hospital discharge (average of 5 days) | Highest recorded ALT or AST |
| Change in ALT/AST | at randomisation, day 2 (if feasible) and day 4 or hospital discharge (average on day 5) if sooner | N-acetylcysteine treatment comparison only. Fold change in ALT or AST |
| Highest bilirubin | Between randomisation and hospital discharge (average of 5 days) | N-acetylcysteine treatment comparison only. Highest recorded bilirubin |
| Highest INR | Between randomisation and hospital discharge (average of 5 days) | N-acetylcysteine treatment comparison only. Highest recorded INR |
| Safety reporting: Suspected Severe Adverse Reactions | During hospital stay (average of 5 days) and at day 30 follow up | Suspected serious adverse reactions (SSARs) excluding primary outcomes |
| Quality of live assessment using EQ-5D-5L value index | at day 30 follow up | The EQ-5D-5L (EuroQoL \[European Quality of Life\] 5-Dimension 5-Level) is a standardized measure of health-related quality of life assessing five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain is self-reported by the respondent and rated on five levels of severity, ranging from "no problems" (level 1) to "extreme problems/unable" (level 5). Responses across the five domains define a health state, which is converted into a single index (utility) score using population-based value sets. This index score typically ranges from values below 0 (health states considered worse than death) to 1 (perfect health). |
| Quality of live assessment using EQ-Visual Analogue Scale (VAS) | at day 30 follow up | This is a self-rated measure of overall health. Respondent indicate their current health status on a vertical scale from 0 to 100. A score of 0 represents "the worst health you can imagine" and 100 represents "the best health you can imagine". This measure captures the respondent's subjective assessment of their overall health on the day of evaluation. When this assessment done remotely by telephone, the rating is approximated verbally by the respondent using the 0 to 100 numeric scale. |
Countries
Bangladesh, Brazil, Colombia, Indonesia, Malaysia, Nepal, Peru, Philippines, Thailand, Vietnam
Contacts
CONTACTMr. Samuel Paul
CONTACTOUCRU-CTU
PRINCIPAL_INVESTIGATORSophie Yacoub, MD., PhD.
University of Oxford, UK
Outcome results
None listed