Anakinra in Dengue With Hyperinflammation ( AnaDen )

Study Overview
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Brief Summary
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This study aims to evaluate the effect of anakinra in dengue patients with hyperinflammation as compared to placebo Primary Objective: To evaluate the efficacy of Anakinra in moderate-severe dengue patients with hyperinflammation. Secondary Objectives: To assess the safety of anakinra therapy in dengue with hyperinflammation To assess the effect of anakinra therapy in patients with dengue on physiological, clinical and virological parameters To assess the immunomodulation effects of anakinra in dengue Immune cell signatures in dengue with and without anakinra To assess difference in gene expression between treatment group compared to non-treatment population

Detailed Description
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This is a randomized double blinded placebo controlled trial investigating the effects of four days of anakinra treatment on dengue patients with hyperinflammatory syndrome. The anakinra/placebo will be given to eligible participants admitted to the Hospital for Tropical Diseases (HTD) in Ho Chi Minh City, Vietnam. 160 dengue patients will be randomly assigned to either anakinra or placebo intervention group to receive treatment for 4 days. Patients admitted to the HTD with a clinical diagnosis of dengue and at least 1 warning sign(s) or severe dengue to Emergency department / inpatient wards / Intensive Care Units (ICU), will be invited to participate in the trial. Eligible patients will be invited to participate in the screening phase during which, the collection of clinical information about this acute illness episode as well as some screening tests will be performed, including measurement ferritin, creatinine, pregnancy test (for all females). - If ferritin level is greater than 2000ng/mL and meet all other inclusion/exclusion criteria, patients will be invited to participate in the randomization phase (second consent), which they will be randomly given either anakinra or placebo intravenous (IV) for four days. The intervention: (i) 200mg bid for four days in adults participants (≥ 16 years) or in children (12-16 years), with weight > 50kg; and (ii) 2mg/kg bid for four days in children (12-16 years), with weight < 50Kg. All patients will be followed up daily at the clinical wards until discharge. Details of all AEs and SAEs will be recorded on specific forms, together with an assessment as to whether the events are likely to have been related to any treatment received. All SAEs will be reported promptly to the DMC and ECs according to policy. In cases of discontinuation due to AEs, participants will be followed up until the events have resolved or stabilized.

Official Title
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Anakinra for Dengue Patients With Hyperinflammation - a Randomized Double-blind Placebo-controlled Trial

Conditions
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Dengue, Dengue With Warning Signs, Severe Dengue, Anakinra, Immuno-modulation, Anti-inflammatory Agents, Macrophage Activation Syndrome, Hyperinflammatory Syndrome, Cytokine Storm

Intervention / Treatment
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* Drug: Placebo
* Drug: Anakinra


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients hospitalised with a clinical diagnosis of dengue and at least 1 warning sign(s) (see appendix) or severe dengue to Emergency department/inpatient wards/Intensive Care wards (ICU), Ferritin levels > 2000ng/mL ≥ 12 years of age Written informed consent or assent to participate in the study Agree to come back for 2 follow up visits around day 30 of illness (maximum 5 weeks) and at 3 months Exclusion Criteria: Pregnancy Localizing features suggesting an alternative/additional diagnosis, e.g. pneumonia, sepsis Patients taking immunosuppressive drugs or other biologics in last 1 month Patients with underlying malignancy or immunosuppression Children <12 years Have end-stage renal failure (baseline GFR < 30ml/min) Being treated for TB Taking any drug with significant interaction with anakinra The study physician judges that the patient is unlikely to attend follow up visit at around 3-4 weeks after fever onset - e.g. due to long travelling distance from the clinic

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a randomized, double blinded, placebo controlled trial of anakinra in patients with dengue with warning signs or severe dengue
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>The control group will be formed of 80 dengue patients with warning signs or severe dengue receiving placebo. | Drug: Placebo<br>* Drug: Placebo, with visually matched clear syringes Adults (≥16 years) and children (12-16 years, > 50Kg) will receive 2 syringes of placebo via IV route, twice daily for 4 days Children (12-16 years, < 50Kg) will receive no more than 1 syringe of placebo via IV route, twice daily for 4 days<br>|
| Experimental: Anakinra<br>The intervention group will include 80 dengue patients with warning signs or severe dengue receiving anakinra. | Drug: Anakinra<br>* Drug: Anakinra Adults (≥16 years) and children (12-16 years, > 50Kg) will receive 200mg of anakinra (2 syringes) via IV route, twice daily for 4 days Children (12-16 years, < 50Kg) will receive 2mg/Kg of anakinra via IV route, twice daily for 4 days (no more than 1 syringe of anakinra, twice daily for 4 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in modified Sequential Organ Failure Assessment score (mSOFA core, modified for limited resource settings and dengue) within 4 days | Change in mSOFA score over 4 days after randomization (min score= 0, max score = 24, higher scores mean worse outcomes) | baseline, up to day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Number of death up to day 30 | Up to day 30 | 
| Change in modified Sequential Organ Failure Assessment score (mSOFA core, modified for limited resource settings and dengue) at day 7 | Change in mSOFA score at day 7 post randomization (min score= 0, max score = 24, higher scores mean worse outcomes) | baseline, day 7 | 
| Number of days treated in Intensive care unit (ICU) | Number of days treated in ICU | Up to day 30 | 
| Number of days treated in hospital | Number of days treated in hospital | Up to day 30 | 
| Number of participants with Serious Adverse Events (SAEs) | Number of participants having SAEs within 2 time-periods, 1- 5 days and 6-30 days | Day 1-5 and Day 6-30 | 
| Number of Adverse Events (AEs) per participant | Number of AEs per individual | Up to day 30 | 
| Change in Platelets count | Change in blood levels (Platelets) over 5 days following randomization and at day 30 | Up to day 5, at day 30 | 
| Change in neutrophils count | Change in blood levels (neutrophils) over 5 days following randomization and at day 30 | Up to day 5, at day 30 | 
| Change of ALT levels | Change in blood levels (ALT) over 5 days following randomization and at day 30 | Up to day 5, at day 30 | 
| Change of Ferritin levels | Change in blood levels (Ferritin) over 5 days following randomization and at day 30 | Up to day 5, at day 30 | 
| Change of CRP levels | Change in blood levels (CRP) over 5 days following randomization and at day 30 | Up to day 5, at day 30 | 
| Time to normalization of blood levels | Time to normalization of platelets (defined as >150 x109/l) and neutrophils (>2 x109/l) | Up to day 30 | 
| Platelet nadir | Lowest platelet count recorded during admission | Up to day 30 | 
| Fever clearance time | Time to temperature <37.5 for at least 48 hours | Up to day 30 | 
| Duration of viraemia | Number of days from enrollment to the first undetectable viraemia (negative in qPCR and NS1) | Up to day 30 | 
| Area under the curve (AUC) of the serial viral load measurements during hospital stay | AUC of viral load measurements during hospital stay will be reported | at discharge (assessed up to day 8) | 
| Patients' quality of life questionnaire score | Patients' quality of life during their hospitalisation will be explored at discharge and day 30 using the EQ-5D questionnaire. | at discharge (assessed up to day 8) and at day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue, Hyperinflammatory syndrome, Anakinra, Vietnam