Metformin in Dengue With Obesity

Study Overview
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Brief Summary
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This study aims to investigate the effect of metformin as host-directed therapy in obese/overweight patients with dengue Primary Objective To evaluate the safety and tolerability of metformin in obese/overweight young adults and children with dengue Secondary Objectives To assess the effect of metformin therapy in obese/overweight patients with dengue on physiological, clinical and virological parameters To assess the immunomodulation effects of metformin therapy in obese/overweight patients with dengue To assess difference in gene expression between treatment group compared to non-treatment population

Detailed Description
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This is an open-label safety and tolerability study investigating the effects of five days of metformin treatment. The metformin therapy will be given to eligible participants admitted to the Hospital for Tropical Diseases (HTD) in Ho Chi Minh City, Vietnam. The 60 patients receiving metformin intervention will be compared to 60 age-matched overweight or obese controls, who get the standard supportive treatment only. The intervention will be conducted in two phases, with a dose escalation. In the initial phase (cohort 1), five young adults (16-30 years) and five children (age 10-16 years) with body mass index (BMI) >25 kg/m2 (BMI-for-age >1 standard deviation - SD) will be provided with a low dose of metformin once daily at 850mg and 500mg respectively. 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 five-day safety and clinical data of cohort 1 show no safety concerns, the study will progress to the second phase (cohort 2). This will include 25 adults and 25 children, who will be given a weight-based dose of metformin; 1000mg (500mg twice daily) for participants with weight < 60kg, and 1500mg (1000mg mane, 500mg nocte) for those ≥ 60kg. Patients that are admitted to the HTD within 72 hours of fever, with clinical suspicion of dengue, will be invited to participate in the trial. After giving consent, patients will be screened for their eligibility to commence treatment with the trial drug. Blood samples will be collected to test for NS1, pregnancy (in all female patients), and AST, ALT and creatinine levels. Glucose and lactate levels will be measured using point-of-care (POC) tests. All patients will be asked to come back for a final FU visit at around 21-28 days after the onset of fever. 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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Metformin as Adjunctive Therapy in Overweight and Obese Patients With Dengue: an Open-label Safety and Tolerability Trial

Conditions
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Obesity, Dengue, Viral Infection, Metformin, Anti-inflammatory Agents, Overweight

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 10 years to ≤ 30 years of age, Clinical diagnosis of dengue (based on WHO 2009 Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control/Vietnam Ministry of Health 2019: Guidelines for Dengue Diagnosis, treatment and prevention) Positive NS1 rapid test ≤ 3 days (≤ 72 hours) of fever BMI > 25 Kg/m2 (or BMI-for-age > 1 SD); Written informed consent or assent to participate in the study Agree to come back for follow up visit around day 21-28 of illness (maximum 1 month) Exclusion Criteria: In all female patients: Pregnancy Localizing features suggesting an alternative diagnosis, e.g. pneumonia, otitis etc. History of hypersensitivity to metformin Severe infection, including: (1) severe dengue (dengue shock syndrome, severe haemorrhage, severe organ impairment) (2) central nervous system infection, or (3) septicaemia etc… Baseline lactate level > 2.0 mmol/L Baseline glucose level < 3.9 mmol/L OR < 70 mg/dL Already taking metformin or any other regular hypoglycaemic agents, eg. insulin Significant diarrhoea and/or vomiting (> 3 episodes in 24 hours) Have acute or chronic renal impairment (baseline GFR < 30ml/min) Liver impairment (baseline AST and ALT > 250 U/L) Being treated for heart failure or have had a recent heart attack (in the last year) Taking any drug with significant interaction with metformin 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: 10 Years
Maximum Age: 30 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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is an open-label, two-phase dose escalation trial of metformin in overweight/obese patients with dengue compared to standard of care
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control arm<br>The control group will be formed of 60 overweight or obese dengue patients receiving standard of care | |
| Experimental: Intervention arm<br>Two cohorts receive a 5-day course of metformin treatment. In the initial phase (cohort 1), 5 young adults and 5 children (age <16) will receive a low dose of metformin. In the second phase (cohort 2), 25 adult and 25 paediatric patients will receive a weight-based dose of metformin. | Drug: Metformin<br>* The trial will be conducted in two phases, with a dose escalation of metformin. Metformin dosing will begin at 500mg (children) and 850mg (adults) once daily for 5 days in cohort 1. Cohort 2 will be received weight-based doses; 5 days of 1000mg (500mg twice daily) for those weighing <60kg and 5 days of 1500mg (1000mg mane, 500mg nocte) for those weighing ≥60kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events | Number of severe clinical symptoms and signs, including severe diarrhoea (defined as >5 episodes watery stool/day), severe vomiting (>=3 episodes separated by 15 minutes/24 hours), severe abdominal pain and laboratory markers of severity including -Hypoglycaemia defined as glucose <3.9 mmol/l, Hyperlactatemia (lactate >3 mmol/l), ALT/AST >400 U/l | Up to 30 days after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fever clearance time | Time to temperature <37.5 for 2 consecutive days | Up to 7 days after enrollment | 
| Platelet nadir | Lowest platelet count recorded during admission | Up to 7 days after enrollment | 
| Percentage increase in hematocrit from baseline | Percentage increase will be calculated from peak result to baseline (baseline is follow-up time-point) | Up to 30 days after enrollment | 
| Percentage change in endothelial and lipid-inflammatory parameters | Percentage change in parameters such as: VCAM1, ICAM1, leptin, adiponectin, LDL, AMPK levels will be calculated from peak result to baseline (follow-up time-point) | Up to 30 days after enrollment | 
| Changes in virological parameters | Area under the curve (AUC) of the serial measurements during days 3 - 6 (log10-transformed), time from enrollment to the first undetectable viraemia, or the first negative NS1 measurement will be compared | Up to 7 days after enrollment | 
| Changes in number of immune cells | Phenotyping CD8/4+T cell and NK cell and T cell exhaustion markers will be assessed | Up to 30 days after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, Dengue, Obesity, Vietnam