{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:10:43Z","timestamp":1772169043882,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.16053.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000}}],"reference-count":47,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["106680"],"award-info":[{"award-number":["106680"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"\n Background:<\/ns4:bold>\n \u00a0Dengue is a disease of major global importance. While most symptomatic infections are mild, a small proportion of patients progress to severe disease with risk of hypovolaemic shock, organ dysfunction and death. \u00a0In the absence of effective antiviral or disease modifying drugs, clinical management is solely reliant on supportive measures. Obesity is a growing problem among young people in Vietnam and is increasingly recognised as an important risk factor for severe dengue, likely due to alterations in host immune and inflammatory pathways. Metformin, a widely used anti-hyperglycaemic agent with excellent safety profile, has demonstrated potential as a dengue therapeutic\n in vitro<\/ns4:italic>\n and in a retrospective observational study of adult dengue patients with type 2 diabetes. \u00a0This study aims to assess the safety and tolerability of metformin treatment in overweight and obese dengue patients, and investigate its effects on several clinical, immunological and virological markers of disease severity.\n <\/ns4:p>\n \n Methods:<\/ns4:bold>\n This open label trial of 120 obese\/overweight dengue patients will be performed in two phases, with a metformin dose escalation if no safety concerns arise in phase one. The primary endpoint is identification of clinical and laboratory adverse events.\u00a0 Sixty overweight and obese dengue patients aged 10-30 years will be enrolled at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. Participants will complete a 5-day course of metformin therapy and be compared to a non-treated group of 60 age-matched overweight and obese dengue patients.\n <\/ns4:p>\n \n Discussion:<\/ns4:bold>\n \u00a0Previously observed antiviral and immunomodulatory effects of metformin make it a promising dengue therapeutic candidate in appropriately selected patients. This study will assess the safety and tolerability of adjunctive metformin in the management of overweight and obese young dengue patients, as well as its effects on markers of viral replication, endothelial dysfunction and host immune responses.\u00a0\n <\/ns4:p>\n \n Trial registration:<\/ns4:bold>\n ClinicalTrials.gov:\n NCT04377451<\/ns4:ext-link>\n (May 6\n th<\/ns4:sup>\n 2020).\n <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.16053.2","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T17:12:59Z","timestamp":1612804379000},"page":"160","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Metformin as adjunctive therapy for dengue in overweight and obese patients: a protocol for an open-label clinical trial (MeDO)"],"prefix":"10.12688","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5960-7849","authenticated-orcid":false,"given":"Nguyet 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Thi Thanh","family":"Van","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5417-2738","authenticated-orcid":false,"given":"Quyen","family":"Nguyen Than Ha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Rivino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4475-7761","authenticated-orcid":false,"given":"Nick K.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2740-3155","authenticated-orcid":false,"given":"Ronald 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reduced resources.","volume":"369","author":"S Yacoub","year":"2011","journal-title":"Philos Trans A Math Phys Eng Sci."}],"container-title":["Wellcome Open 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.17609.r39444, Eng Eong Ooi, Emerging Infectious Diseases Program, Duke NUS Graduate Medical School, Singapore, Singapore, 28 Jul 2020, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-160\/v1#referee-response-39444","order":0,"name":"referee-response-39444","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Nguyet Nguyen<\/b>; \nPosted: 02 Nov 2020<\/i>; Comment #1: Thank you for this suggestion, we also acknowledge that there is a narrow therapeutic window, in all dengue therapeutic trials. We are therefore aiming to give the drug within the first 48 hours of fever (latest 72 hours). Metformin is rapidly absorbed and eliminated as an oral formulation and steady state is usually achieved within 24 hours. In obese\/overweight adolescents, time to peak concentration and absorption, appears to be faster than non-obese children {van Rongen A. et al. 2018. \nPaediatr Drugs<\/i>}.   An in-vitro study showed metformin increased AMPK activity after 24 hours and reduced of dengue viral replication by one logarithm and up to 90% of NS1 secretion {Soto-Acosta R. et al. 2017. \nPLoS Pathog<\/i>}. In addition, anti-viral effects using a 5 day course of metformin has also been demonstrated in a mouse model of coxsackievirus B3 (CVB3) infection, through rapid action on AMPK activation {Xie W. et al. 2015. \nJ Mol Cell Cardiol<\/i>}. The effect of metformin on AMPK and reduction in viremia is just one mechanism why we hypothesize this drug will be beneficial in dengue patients, its other effects, including anti-inflammatory, immunomodulatory and endothelial stabilizing properties  are also likely to be important mechanisms in attenuating the disease outcome. A paragraph has been added to "Metformin and Dengue" section. Comment #2: Thank you - all patients will be followed up at day 28 and will have safety data recorded at that follow-up time-point. For cohort 1 the DSMB have agreed to review day-5 data for the first safety review and all 28-day data for further reviews. We do not anticipate any issues of drug accumulation, as in patients with normal renal function, the half life is short and the drug rapidly eliminated (a dose of 1000mg has a Tmax of 1.5 hours and a half-life of 2.3hrs {Chung H. et al. 2018. \nPLoS One<\/i>}). The drug will be stopped in any patient developing acute renal failure. Comment #3 and #4: While not an RCT, this trial was designed to enroll patients contemporaneously with an observational obesity trial, where patients received standard care, to minimize systematic differences between the intervention (metformin) and control group. I.e. patients have the same inclusion \/exclusion criteria, enrolled on same wards, with the same standard of care during the same dengue season (to avoid the issue of viral serotype shifts). To minimize selection bias, we have set up a system on the dengue wards, to ensure eligible patients are recruited into both studies in a systematic way. This involves only one study enrolling for a 2-week time block. During that time, if a patient fails screening assessment or declines enrollment into one of the trials, they are not eligible for the other. In addition, we will ensure the predefined inclusion\/exclusion criteria for all patients enrolled are strictly adhered to reduce investigator subjective assessment and will carefully document screen failures and all exclusions and withdrawals in the trial. And lastly, we plan to have an intention-to-treat analysis where independent study investigators will perform a blinded outcome assessment for all patients. We have added this to the \u2018Screening, enrollment and retention paragraph.\u2019 Comment #5: Thank you. The typo error has already been corrected","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-160\/v2#referee-comment-4407","order":1,"name":"referee-comment-4407","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.17609.r40522, Quirijin de Mast, Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands, 06 Oct 2020, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-160\/v1#referee-response-40522","order":2,"name":"referee-response-40522","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Nguyet Nguyen<\/b>; \nPosted: 02 Nov 2020<\/i>; Comment #1: This is a pilot study investigating the safety and tolerability of metformin in dengue patients. As metformin has not been used in acute dengue infections before, this trial was designed to establish safety first, as well as generate some clinical and viral efficacy data. A larger phase 3 RCT will be conducted if this trial shows a positive result. Comment #2: Thank you for this suggestion, we also acknowledge that there is a narrow therapeutic window, in all dengue therapeutic trials. We are therefore aiming to give the drug within the first 48 hours of fever (latest 72 hours). Metformin is rapidly absorbed and eliminated as an oral formulation and steady state is usually achieved within 24 hours. In obese\/overweight adolescents, time to peak concentration and absorption, appears to be faster than non-obese children {van Rongen A. et al. 2018. \nPaediatr Drugs<\/i>}.   An in-vitro study showed metformin increased AMPK activity after 24 hours and reduced of dengue viral replication by one logarithm and up to 90% of NS1 secretion {Soto-Acosta R. et al. 2017. \nPLoS Pathog<\/i>}. In addition, anti-viral effects using a 5 day course of metformin has also been demonstrated in a mouse model of coxsackievirus B3 (CVB3) infection, through rapid action on AMPK activation {Xie W. et al. 2015. \nJ Mol Cell Cardiol<\/i>}. The effect of metformin on AMPK and reduction in viremia is just one mechanism why we hypothesize this drug will be beneficial in dengue patients, its other effects, including anti-inflammatory, immunomodulatory and endothelial stabilizing properties  are also likely to be important mechanisms in attenuating the disease outcome. A paragraph has been added to "Metformin and Dengue" section.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-160\/v2#referee-comment-4408","order":3,"name":"referee-comment-4408","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.17609.r40457, Rosa Mar\u00eda Del \u00c1ngel, Juan Fidel Osuna-Ramos, Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico, 08 Oct 2020, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-160\/v1#referee-response-40457","order":4,"name":"referee-response-40457","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Nguyet Nguyen<\/b>; \nPosted: 02 Nov 2020<\/i>; Comment #1: Thank you for this suggestion, we also acknowledge that there is a narrow therapeutic window, in all dengue therapeutic trials. We are therefore aiming to give the drug within the first 48 hours of fever (latest 72 hours). Metformin is rapidly absorbed and eliminated as an oral formulation and steady state is usually achieved within 24 hours. In obese\/overweight adolescents, time to peak concentration and absorption, appears to be faster than non-obese children {van Rongen A. et al. 2018. \nPaediatr Drugs<\/i>}.   An in-vitro study showed metformin increased AMPK activity after 24 hours and reduced of dengue viral replication by one logarithm and up to 90% of NS1 secretion {Soto-Acosta R. et al. 2017. \nPLoS Pathog<\/i>}. In addition, anti-viral effects using a 5 day course of metformin has also been demonstrated in a mouse model of coxsackievirus B3 (CVB3) infection, through rapid action on AMPK activation {Xie W. et al. 2015. \nJ Mol Cell Cardiol<\/i>}. The effect of metformin on AMPK and reduction in viremia is just one mechanism why we hypothesize this drug will be beneficial in dengue patients, its other effects, including anti-inflammatory, immunomodulatory and endothelial stabilizing properties  are also likely to be important mechanisms in attenuating the disease outcome. A paragraph has been added to "Metformin and Dengue" section. Comment #2: We chose to focus on obese patients initially, as these patients have a higher risk of disease progression and therefore warrant an intervention. In addition, we hypothesize many of metformin actions, including anti-inflammatory, immunomodulatory, endothelial stabilizer and AMPK activation are already chronically impaired at baseline in obese individuals, thus maximizing the chance of demonstrating efficacy in this population. Comment #3: The follow-up time point of 28 days is to allow full recovery from the acute illness, and is in line with other clinical trials. Comment #4: This is a pilot study investigating the safety and tolerability of dengue obese patients to metformin. If the safety of this drug is established, we plan to move to a phase 3 RCT, with larger sample size to allow investigation of clinical endpoints. Comment #5: Other flaviviruses do circulate in Vietnam including Zika and Japanese encephalitis but these are rare and do not cause the same clinical syndrome as dengue {Quyen NTH et al. 2017. \nAm J Trop Med Hyg<\/i>}. The sensitivity of NS1 tests for dengue varies by immune status, illness day and serotype ranging from 62-89% , but are highly specific (around 100%) {Tricou V. et al. 2011. \nPLoS Negl Trop Dis<\/i>;\n <\/i>Hermann LL et al. 2014. \nPLoS Negl Trop Dis<\/i>} As RT-PCR is costly and time consuming, it is not ideal as a screening test- we are however confirming diagnosis at a later stage with RT-PCR and paired serology. Comment #6: VCAM1, CRP, leptin, adiponectin, low density lipoprotein (LDL), and AMPK phosphorylation will be measured using a luminex platform and commercially available ELISAs. This has been added to the laboratory evaluation section.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/5-160\/v2#referee-comment-4409","order":5,"name":"referee-comment-4409","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work is supported by the Wellcome Trust [106680]. The trial sponsor is the University of Oxford, Oxford, United Kingdom. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}