A Randomised Platform Trial to Evaluate Therapeutics in Patients With Moderate or Severe Dengue (DEN-HOST)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 8,800
- 试验地点
- 18
- 主要终点
- Progression to severe dengue/critical dengue
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Comparison A: Baricitinib versus placebo
Participants eligible for baricitinib may be randomized to baricitinib or matched placebo.
干预措施: Placebo (Drug)
Comparison B: Dexamethasone versus Placebo
Participants eligible for dexamethasone may be randomized to dexamethasone or matched placebo.
干预措施: Placebo (Drug)
Comparison C: N-acetylcysteine versus standard of care
Patients with liver involvement (ALT or AST >400 IU/L) during hospital admission may be randomised to N-acetylcysteine or standard of care.
干预措施: Standard of care (Other)
Comparison A: Baricitinib versus placebo
Participants eligible for baricitinib may be randomized to baricitinib or matched placebo.
干预措施: Baricitinib (Drug)
Comparison B: Dexamethasone versus Placebo
Participants eligible for dexamethasone may be randomized to dexamethasone or matched placebo.
干预措施: Dexamethasone (Drug)
Comparison C: N-acetylcysteine versus standard of care
Patients with liver involvement (ALT or AST >400 IU/L) during hospital admission may be randomised to N-acetylcysteine or standard of care.
干预措施: N-Acetylcysteine (Drug)
结局指标
主要结局
Progression to severe dengue/critical dengue
时间窗: 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
时间窗: Day 30
All-cause mortality in any participant. Assessed as dead or alive
次要结局
- Length of hospital stay(At hospital discharge (average of 5 days))
- Lowest recorded platelet count(Between randomisation and hospital discharge (average of 5 days))
- Acute kidney injury(Between randomisation and hospital discharge (average of 5 days))
- Liver involvement(Between randomisation and hospital discharge (average of 5 days))
- Change in ALT/AST(at randomisation, day 2 (if feasible) and day 4 or hospital discharge (average on day 5) if sooner)
- Highest bilirubin(Between randomisation and hospital discharge (average of 5 days))
- Highest INR(Between randomisation and hospital discharge (average of 5 days))
- Safety reporting: Suspected Severe Adverse Reactions(During hospital stay (average of 5 days) and at day 30 follow up)
- Quality of live assessment using EQ-5D-5L value index(at day 30 follow up)
- Quality of live assessment using EQ-Visual Analogue Scale (VAS)(at day 30 follow up)