Metformin as adjunctive therapy for dengue in overweight and obese patients: a protocol for an open-label clinical trial (MeDO)

Abstract

<ns4:p><ns4:bold>Background:</ns4:bold> Dengue 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. In 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 <ns4:italic>in vitro</ns4:italic> and in a retrospective observational study of adult dengue patients with type 2 diabetes. This 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.</ns4:p><ns4:p> <ns4:bold>Methods:</ns4:bold> 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. 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.</ns4:p><ns4:p> <ns4:bold>Discussion:</ns4:bold> Previously 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. </ns4:p><ns4:p> <ns4:bold>Trial registration:</ns4:bold> ClinicalTrials.gov:<ns4:ext-link xmlns:ns3="http://www.w3.org/1999/xlink" ext-link-type="uri" ns3:href="https://clinicaltrials.gov/ct2/show/NCT04377451"> NCT04377451</ns4:ext-link> (May 6<ns4:sup>th</ns4:sup> 2020).</ns4:p>

Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines

“…A randomized, double-blind, placebo controlled, superiority trial (NCT04673422) to test efficacy of montelukast is currently on-going Rupatadine Dual PAF and histamine-1-receptor antagonist Reduced vascular leakage in mouse model of DENV infection [ 94 ] Randomized placebo-controlled trial ( n = 183) did not show reduction in leakage, but improved platelet counts and liver enzyme values (SLCTR/2014/023) [ 94 ] Metformin Oral anti-hyperglycemic agent, AMPK activator Antiviral effect in DENV infected cells in vitro [ 101 ] A retrospective study ( n = 223) showed decreased risk of severe dengue with metformin use in dengue patients with diabetes [ 103 •]. Clinical trial in progress (NCT04377451) [ 104 ] Carica papaya leaf extract Anti-inflammatory agent, augments megakaryocyte development and platelet formation Reduced production of proinflammatory cytokines [ 118 ] and increased platelet count in vivo [ 119 ] Three randomized controlled trials showed an improvement in platelet counts [ 106 – 108 ] Vitamin E Unclear mechanism. Can act as an antioxidant Nil Randomized placebo-controlled trials showed faster platelet recovery ( n = 66) [ 114 ] and reduced liver enzyme derangement ( n = 127) (SLCTR/2015/012) [ 113 ] Vitamin D Unclear mechanism.…”

“…However, it is unclear from this study whether the effects of metformin on diabetic control or on DENV replication may be linked to the use of this drug. Currently, an open-label, two-phase dose escalation trial (NCT04377451) of m etformin in d engue patients with o besity (MeDO) is on-going in Vietnam [ 104 ], which should clarify the therapeutic utility of metformin in dengue patients during acute disease.…”

“…So far, clinical trials with repurposed drugs with antiviral activity in pre-clinical studies like balapiravir [49], chloroquine [50], lovastatin [51], and celgosivir [52] did not show any efficacy in reducing viremia nor beneficial clinical outcomes. In this section, we describe both direct-acting and host factors-targeting antivirals that show the UV-4B Endogenous alpha glucosidase inhibitor Antiviral activity in vitro [70] and in vivo [71] Phase 1a clinical trial (NCT02061358) with healthy subjects indicated that a single dose up to 1000 mg of UV-4B was safe and well tolerated [72] Zanamivir Neuraminidase inhibitor to block desialylation on platelet membrane Reduction in DENV2 NS1-induced endothelial hyperpermeability and vascular leakage in vitro [73] Clinical trial to test efficacy against vascular leakage (NCT04597437) is currently on-going Clinical trial in progress (NCT04377451) [104] Carica papaya leaf extract Anti-inflammatory agent, augments megakaryocyte development and platelet formation Reduced production of proinflammatory cytokines [118] and increased platelet count in vivo [119] Three randomized controlled trials showed an improvement in platelet counts [106][107][108] Vitamin E Unclear mechanism. Can act as an antioxidant Nil Randomized placebo-controlled trials showed faster platelet recovery (n = 66) [114] and reduced liver enzyme derangement (n = 127) (SLCTR/2015/012) [113] Vitamin D Unclear mechanism.…”

Dengue Virus: Molecular Biology and Recent Developments in Control Strategies, Prevention, Management, and Therapeutics

“…In Vietnam, a clinical trial with metformin (NCT04377451) is currently ongoing in dengue patients who have obesity to identify the therapeutic potential of metformin against acute DENV infection. 138…”

Anti-flavivirus Properties of Lipid-Lowering Drugs

“…It has also been reported an association between the use of MET in diabetic patients and the lower risk of suffering a severe disease caused by DENV (Htun et al, 2018), suggesting that MET treatment could attenuate and/or prevent severe forms of DENV infection. Due to the anti-DENV potential of this drug, it is currently being tested as adjunctive therapy for dengue in overweight and obese patients (Nguyen et al, 2020).…”