Clinical trial NCT04377451: Metformin in Dengue With Obesity
Official title: Metformin as Adjunctive Therapy in Overweight and Obese Patients With Dengue: an Open-label Safety and Tolerability Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Dengue
Viral Infection
Metformin
Anti-inflammatory Agents
Obesity
Overweight
Keywords: Dengue
Obesity
Metformin
Vietnam
Lead sponsor: Oxford University Clinical Research Unit, Vietnam
Sponsor class: OTHER
Collaborators: name: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
First posted: 2020-05-06
Enrollment: 120
Sex: ALL
Minimum age (years): 10
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of adverse events
timeFrame: Up to 30 days after enrollment
Secondary outcomes:
measure: Fever clearance time
timeFrame: Up to 7 days after enrollment
measure: Platelet nadir
timeFrame: Up to 7 days after enrollment
measure: Percentage increase in hematocrit from baseline
timeFrame: Up to 30 days after enrollment
measure: Percentage change in endothelial and lipid-inflammatory parameters
timeFrame: Up to 30 days after enrollment
measure: Changes in virological parameters
timeFrame: Up to 7 days after enrollment
measure: Changes in number of immune cells
timeFrame: Up to 30 days after enrollment
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Hospital for Tropical Diseases
Study officials:
affiliation: University of Oxford, UK
name: Sophie Yacoub, PhD. MD
role: PRINCIPAL_INVESTIGATOR
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