Anakinra in Dengue With Hyperinflammation ( AnaDen )
Study Details
Study Description
Brief Summary
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:
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To assess the safety of anakinra therapy in dengue with hyperinflammation
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To assess the effect of anakinra therapy in patients with dengue on physiological, clinical and virological parameters
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To assess the immunomodulation effects of anakinra in dengue
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Immune cell signatures in dengue with and without anakinra
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To assess difference in gene expression between treatment group compared to non-treatment population
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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.
There will be two phases of consent. Firstly, the 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).
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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.
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If ferritin level is between 1000 and 2000ng/mL, their ferritin level measurement will be repeated daily for up to three days. If after three days, ferritin level exceeds 2000ng/mL, patients will be invited to participate in the randomization as describes above. However, if their ferritin level remains below 2000ng/mL after three days of screening, they will be excluded from this trial.
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If ferritin level is less than 1000ng/mL, patients will be excluded from the trial. All procedures will be stopped and patients will not take any study drug.
The intervention will be conducted in two phases. In the initial phase (cohort 1), ten adults (≥16 years) will be enrolled and be provided with anakinra 200mg bid via IV route for 4 days. A Data Monitoring Committee (DMC) review will take place after day 5 data is fully available for the first ten patients enrolled in cohort 1.
If the safety and clinical data of cohort 1 show no safety concerns, the study will progress to the second phase (cohort 2), which will include 150 patients (adults and children), who will be given a weight-based dose of IV anakinra:-
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(i) 200mg bid for four days in adults participants (≥ 16 years) or in children (12-16 years), with weight > 50kg; and
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(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. Blood samples will be collected daily for 5 days, for:- (i) full blood cell counts; (ii) biochemistry tests (creatinine, transaminases, albumin, bilirubin, ferritin, CRP,…); (iii) measuring the kinetics of viremia; (iv) analyzing the host genetic factors using the RNA extraction samples; and (v) investigating the immune responses. Ultrasound scans will be performed on alternate day to assess vascular leakage. After discharge, all patients will be asked to come back for a final FU visit at around day 30 of illness (25 days-35 days) and also at 3 months. Patients' quality of life will be explored using the EQ-5D questionnaire score at hospital discharge and day 30.
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo The control group will be formed of 80 dengue patients with warning signs or severe dengue receiving placebo. |
Drug: Placebo
Drug: Placebo, with visually matched clear syringes containing 0.67mL NaCl 0.9%
Cohort 1: 5 adults patients (≥16 years) will receive 2 syringes of placebo via IV route twice daily for 4 days
Cohort 2: 75 patients
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
|
| Experimental: Anakinra The intervention group will include 80 dengue patients with warning signs or severe dengue receiving anakinra. |
Drug: Anakinra
Drug: Anakinra
Cohort 1: 5 adults patients (≥16 years) will receive 200mg of anakinra (2 syringes) via IV route twice daily for 4 days
Cohort 2: 75 patients
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)
|
Outcome Measures
Primary Outcome Measures
- Change in modified Sequential Organ Failure Assessment score (mSOFA core, modified for limited resource settings and dengue) within 4 days [baseline, up to day 4]
Change in mSOFA score over 4 days after randomization (min score= 0, max score = 24, higher scores mean worse outcomes)
Secondary Outcome Measures
- Mortality [Up to day 30]
Number of death up to day 30
- Change in modified Sequential Organ Failure Assessment score (mSOFA core, modified for limited resource settings and dengue) at day 7 [baseline, day 7]
Change in mSOFA score at day 7 post randomization (min score= 0, max score = 24, higher scores mean worse outcomes)
- Number of days treated in Intensive care unit (ICU) [Up to day 30]
Number of days treated in ICU
- Number of days treated in hospital [Up to day 30]
Number of days treated in hospital
- Number of participants with Serious Adverse Events (SAEs) [Day 1-5 and Day 6-30]
Number of participants having SAEs within 2 time-periods, 1- 5 days and 6-30 days
- Number of Adverse Events (AEs) per participant [Up to day 30]
Number of AEs per individual
- Change in Platelets count [Up to day 5, at day 30]
Change in blood levels (Platelets) over 5 days following randomization and at day 30
- Change in neutrophils count [Up to day 5, at day 30]
Change in blood levels (neutrophils) over 5 days following randomization and at day 30
- Change of ALT levels [Up to day 5, at day 30]
Change in blood levels (ALT) over 5 days following randomization and at day 30
- Change of Ferritin levels [Up to day 5, at day 30]
Change in blood levels (Ferritin) over 5 days following randomization and at day 30
- Change of CRP levels [Up to day 5, at day 30]
Change in blood levels (CRP) over 5 days following randomization and at day 30
- Time to normalization of blood levels [Up to day 30]
Time to normalization of platelets (defined as >150 x109/l) and neutrophils (>2 x109/l)
- Platelet nadir [Up to day 30]
Lowest platelet count recorded during admission
- Fever clearance time [Up to day 30]
Time to temperature <37.5 for at least 48 hours
- Duration of viraemia [Up to day 30]
Number of days from enrollment to the first undetectable viraemia (negative in qPCR and NS1)
- Area under the curve (AUC) of the serial viral load measurements during hospital stay [at discharge (assessed up to day 8)]
AUC of viral load measurements during hospital stay will be reported
- Patients' quality of life questionnaire score [at discharge (assessed up to day 8) and at day 30]
Patients' quality of life during their hospitalisation will be explored at discharge and day 30 using the EQ-5D questionnaire.
Other Outcome Measures
- Change in immune cells [Up to day 90]
Phenotyping CD8/4+T and NK cells will be assessed
Eligibility Criteria
Criteria
Inclusion Criteria:
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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),
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Ferritin levels > 2000ng/mL
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≥ 12 years of age
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Written informed consent or assent to participate in the study
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Agree to come back for 2 follow up visits around day 30 of illness (maximum 5 weeks) and at 3 months
Exclusion Criteria:
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Pregnancy
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Localizing features suggesting an alternative/additional diagnosis, e.g. pneumonia, sepsis
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Patients taking immunosuppressive drugs or other biologics in last 1 month
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Patients with underlying malignancy or immunosuppression
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Children <12 years
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Have end-stage renal failure (baseline GFR < 30ml/min)
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Being treated for TB
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Taking any drug with significant interaction with anakinra
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hospital for Tropical Diseases | Ho Chi Minh | Vietnam |
Sponsors and Collaborators
- Oxford University Clinical Research Unit, Vietnam
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Investigators
- Principal Investigator: Sophie Yacoub, University of Oxford, UK
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 60DX