Emetine for Viral Outbreaks: Randomized, Double-Blind, Placebo-Controlled, Clinical Trial to Evaluate Oral Emetine Against Covid-19 (EVOLVE)

More than 675 million cases of coronavirus disease-19 (COVID-19) have occurred in this ongoing pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). More than 6.8 million people have died so far, with case count and deaths cumulating every day. Despite the scale of the damage, there exists extremely limited antiviral treatment options for Covid-19. Emetine exhibits broad spectrum antiviral activity including inhibition of SARS-CoV-2 by inhibiting viral replication and protein biosynthesis. It has been have recently shown that by lowering the standard amoebicidal dose by a factor of 10, emetine can inhibit viral replication while avoiding cardiovascular toxicity. Therefore, the investigators plan to evaluate emetine's efficacy and safety for treatment of symptomatic Covid-19 in a randomized, clinical trial. Emetine, an alkaloid extracted from ipecacuanha roots, was widely used for the treatment of amoebic dysentery. Because of cardiotoxicity (cardiac dysrhythmias), emetine was replaced by metronidazole. The toxicity was unequivocally associated with high-dose emetine (60 mg/day for 10 days to achieve a minimum inhibitory concentration (MIC) of 25 µM against Entamoeba hystolytica); however, the cardiovascular side-effects were minimal or none when emetine was used for various indications in low dose (<20 mg/day). In a screening of 3000 potential compounds against SARS-CoV-2, emetine was found to have the lowest half maximal inhibitory concentration (IC50) of 4.0e-4 µM and a half maximum cytotoxicity concentration (CC50) >10 µM in Vero E6 cells providing it a high therapeutic index. Likewise, several in-vitro studies have demonstrated very low IC50 (~0.05µM) against SARS-CoV-2 for emetine. Based on this, a lower dose of emetine (6 mg/day for 10 days) has been calculated for the treatment of SARS-CoV-2. The investigators hypothesize that low dose emetine will be effective and safe in the treatment of Covid-19. Extensive use of the drug in the past has documented that low dose usage avoids the cardiovascular side-effects there were present at higher doses (>20 mg per day); however, the safety has not been systematically documented in a clinical trial, a key objective of this study. The primary objective of the trial would be to evaluate the safety and efficacy of oral formulation of emetine for patients diagnosed with Covid-19 in a phase 2 study to be followed up by a multicenter phase 3 study based on the preliminary results. Proven beneficial, this study has the potential to save millions of lives by providing a viable, convenient option for treatment of Covid-19. Preliminary results can provide the basis for additional research to evaluate added benefit to patients by combining emetine with other drugs. Emetine has also been shown in-vitro to have activity against Middle East Respiratory Syndrome (MERS), Zika, Cytomegalovirus and Ebola virus infections-this highlights a broader application for emetine beyond coronavirus infections.