ABSTRACT
Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.
Subject(s)
COVID-19 , Diabetes Mellitus , Severe Acute Respiratory SyndromeABSTRACT
Background: The SARS-CoV-2 pandemic is a public health emergency. Safe and effective therapies are urgently needed. Methods: Therapeutics for Inpatients with COVID-19 (TICO), is a global multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. The protocol design allows multiple therapeutic agents to be evaluated in an efficient and scientifically rigorous manner, with efficiencies delivered by the MAMS design, and began by studying neutralizing monoclonal antibodies. TICO employs an agile and robust approach to futility and safety evaluation at 300 patients enrolled (Stage 1), with subsequent expansion to full sample size and an expanded target population (Stage 2) if the agent shows an acceptable safety profile and evidence of efficacy. Two ordinal outcomes applied early (Day 5) determine the efficacy signals of the investigational agents(s) and progression to Stage 2. These ordinal outcomes assess both respiratory and other organ failure events, recognizing the broad range of COVID-19 morbidity. In Stage 2, overall efficacy is assessed using the primary outcome of time to sustained recovery, assessed over 90 days. This approach to early futility assessment using an early intermediate outcome and a primary endpoint out to 90 days allows the study team to make rapid decisions on safety and potential efficacy of novel agents while ultimately focusing on patient-centered, longer-term outcomes. The implementation of TICO across a global network allows for continued enrollment despite variations in geographic epidemiology. Study Status: The TICO master protocol moved from conception to first patient enrolled in approximately 9 weeks, a testament to the expedited regulatory and ethics review, coupled with flexible and responsive study operations. The first agent to be tested using this protocol, LY-CoV-555, enrolled N=326 participants before undergoing Stage 1 futility and safety assessment. Two additional agents will enter the study in November 2020, with other agents planned. Conclusion: The TICO MAMS platform trial has been implemented efficiently across a global network of sites and several trial networks. It will generate results rapidly for multiple novel neutralizing monoclonal antibodies and other therapeutics agents.