Metformin in Dengue With Obesity

Obesity Clinical Trial

— MeDO  

Official title:

Metformin as Adjunctive Therapy in Overweight and Obese Patients With Dengue: an Open-label Safety and Tolerability Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04377451
• Other study ID #: 56DX
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 27, 2020
• Est. completion date: August 1, 2023

Study information

• Verified date: August 2023
• Source: Oxford University Clinical Research Unit, Vietnam
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: August 1, 2023
• Est. primary completion date: June 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Anti-inflammatory Agents
• Dengue
• Metformin
• Obesity
• Overweight
• Viral Infection
• Virus Diseases

Intervention

Drug:
• Metformin
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

Locations

Country	Name	City	State
Vietnam	Hospital for Tropical Diseases	Ho Chi Minh City

Sponsors (2)

Lead Sponsor	Collaborator
Oxford University Clinical Research Unit, Vietnam	Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

Country where clinical trial is conducted

Vietnam, 

References & Publications (12)

Dieu HT, Dibley MJ, Sibbritt DW, Hanh TT. Trends in overweight and obesity in pre-school children in urban areas of Ho Chi Minh City, Vietnam, from 2002 to 2005. Public Health Nutr. 2009 May;12(5):702-9. doi: 10.1017/S1368980008003017. Epub 2008 Jul 29. — View Citation

Do LM, Tran TK, Eriksson B, Petzold M, Nguyen CT, Ascher H. Preschool overweight and obesity in urban and rural Vietnam: differences in prevalence and associated factors. Glob Health Action. 2015 Oct 8;8:28615. doi: 10.3402/gha.v8.28615. eCollection 2015. — View Citation

Doyle MA, Singer J, Lee T, Muir M, Cooper C. Improving treatment and liver fibrosis outcomes with metformin in HCV-HIV co-infected and HCV mono-infected patients with insulin resistance: study protocol for a randomized controlled trial. Trials. 2016 Jul 20;17(1):331. doi: 10.1186/s13063-016-1454-6. — View Citation

Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother. 2013 Oct;47(10):1348-52. doi: 10.1177/1060028013503108. — View Citation

Htun HL, Yeo TW, Tam CC, Pang J, Leo YS, Lye DC. Metformin Use and Severe Dengue in Diabetic Adults. Sci Rep. 2018 Feb 20;8(1):3344. doi: 10.1038/s41598-018-21612-6. — View Citation

Kay JP, Alemzadeh R, Langley G, D'Angelo L, Smith P, Holshouser S. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism. 2001 Dec;50(12):1457-61. doi: 10.1053/meta.2001.28078. — View Citation

Khan IM, Malik BR, Randhawa FA, Butt NF, Malik U, Hamid S. Comparison of metformin and pioglitazone in achieving sustained virological response in chronic hepatitis C patients with insulin resistance: A quasi-experimental study. J Pak Med Assoc. 2017 Dec;67(12):1848-1852. — View Citation

Nguyen PV, Hong TK, Hoang T, Nguyen DT, Robert AR. High prevalence of overweight among adolescents in Ho Chi Minh City, Vietnam. BMC Public Health. 2013 Feb 15;13:141. doi: 10.1186/1471-2458-13-141. — View Citation

Padmapriyadarsini C, Bhavani PK, Natrajan M, Ponnuraja C, Kumar H, Gomathy SN, Guleria R, Jawahar SM, Singh M, Balganesh T, Swaminathan S. Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial. BMJ Open. 2019 Mar 1;9(3):e024363. doi: 10.1136/bmjopen-2018-024363. — View Citation

Pastor-Villaescusa B, Canete MD, Villarraso-Caballero J, et al. Metformin for Obesity in Prepubertal and Pubertal Children: A Randomized Controlled Trial. Pediatrics. 2017;140 (1):e20164285. Pediatrics. 2017 Nov;140(5):e20172555. doi: 10.1542/peds.2017-2555. No abstract available. — View Citation

Soto-Acosta R, Bautista-Carbajal P, Cervantes-Salazar M, Angel-Ambrocio AH, Del Angel RM. DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target. PLoS Pathog. 2017 Apr 6;13(4):e1006257. doi: 10.1371/journal.ppat.1006257. eCollection 2017 Apr. — View Citation

Zulkipli MS, Dahlui M, Jamil N, Peramalah D, Wai HVC, Bulgiba A, Rampal S. The association between obesity and dengue severity among pediatric patients: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2018 Feb 7;12(2):e0006263. doi: 10.1371/journal.pntd.0006263. eCollection 2018 Feb. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Fever clearance time	Time to temperature <37.5 for 2 consecutive days	Up to 7 days after enrollment
Secondary	Platelet nadir	Lowest platelet count recorded during admission	Up to 7 days after enrollment
Secondary	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
Secondary	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
Secondary	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
Secondary	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