Evaluating Emetine for Viral Outbreaks (EVOLVE)

Study Overview
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Brief Summary
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The goal of this clinical trial (phase 2/phase 3) is to evaluate the efficacy and safety of emetine administered orally for symptomatic Covid-19 patients in patients ages 30 years and above. Participants will be asked to: Take Emetine 6mg orally for 10 consecutive days Be monitored by healthcare staff or self-monitor for daily vital signs and symptoms Undergo blood draws Researchers will compare the control group given placebo medicine to assess if emetine improved the symptoms of Covid-19.

Detailed Description
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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.

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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Emetine Hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 30 years of age or older at time of randomization RT-PCR positive for SARS-CoV-2 infection within ≤ 10 days of the screening visit. In addition to confirmed RT-PCR, symptomatic Covid-19 patients with at least two or more symptoms within 7 days of the screening visit: Cough, shortness of breath, fever/chills, sore throat, nausea, vomiting, diarrhea, fatigue, body aches, headache Ability to give informed consent (administered in local language) Exclusion Criteria Asymptomatic Covid-19 patients Pregnant or breastfeeding woman Current or recent use of the study drug Known allergy to study drug Current or planned participation in another interventional trial in next 10 days. Critical Covid-19 patients (ARDS) at the time of screening. Patients needing intubation, mechanical ventilation, or ICU care at screening Patients with prior cardiac disease including cardiac dysrhythmias, heart failure, ischemic heart disease or cardiomyopathies.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blinded randomized controlled clinical trial (RCT) with placebo and intervention group
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Emetine<br>Participant takes Emetine 6mg for 10 consecutive days | Drug: Emetine Hydrochloride<br>* To administer Emetine Hydrochloride 6mg orally for 10 consecutive days to evaluate the efficacy and safety of emetine for symptomatic Covid-19 patients.<br>|
| Placebo Comparator: Placebo<br>Participant takes a placebo for 10 consecutive days | Drug: Placebo<br>* Participant takes a placebo for 10 consecutive days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate effectiveness of emetine in symptomatic Covid-19 patients | Effectiveness of emetine will be assessed by a 1) composite outcome of Hospitalization, ICU admission, mechanical ventilation, death | After medication administration up to 30 days | 
| Evaluate effectiveness of emetine in symptomatic Covid-19 patients | Recovery without symptoms (≥3 days without symptoms) will be assessed. | After medication administration up to 30 days | 
| Evaluate safety of emetine in symptomatic Covid-19 patients | All serious adverse events (SAEs), adverse events (AEs) will be documented and described using descriptive statistics. Adverse events will be per the Medical Dictionary for Regulatory Activities (MedDRA) and categorized by system organ class, accompanied by duration (in days), and start and stop dates. | Duration of the intervention and for up to 30 days post intervention | 
| Evaluate safety of emetine in symptomatic Covid-19 patients | Record rates of drug discontinuation. | Duration of intervention up to 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virologic conversion as assessed by SARS-CoV-2 real time polymerase chain reaction (RT-PCR) | We will measure the time to virologic conversion as a single outcome. Qualitative SARS-CoV-2 RT-PCR result from nasopharyngeal swabs with cycle threshold (ct) value. | Day 0 and then at days 3, 5 and 10 | 
| Anti-inflammatory effect of emetine | Measure interleukin-6 (IL-6) in picograms per milliliter (pg/ml) for in-patients. | Days 0 (baseline), 3 and 7 for up to 10 days after intervention | 
| Anti-inflammatory effect of emetine | Measure c-reactive protein (CRP) measure in milligrams per liter (mg/L) for in-patients | Days 0 (baseline), 3 and 7 for up to 10 days after intervention | 
| Anti-inflammatory effect of emetine | Measure serum ferritin for in-patients measured in nanograms per milliliter (ng/mL) | Days 0 (baseline), 3 and 7 for up to 10 days after intervention | 
| Anti-inflammatory effect of emetine | Measure d-dimer for in-patients in milligrams/liter (mg/L) | Days 0 (baseline) 3 and 7 for up to 10 days after intervention. | 
| Anti-inflammatory effect of emetine | Measure white blood cell (WBC) for in-patients measured per microliter (mcL) | Days 0 (baseline), 3 and 7 for up to 10 days after intervention. | 
| Anti-inflammatory effect of emetine | Measure Platelet count for in-patients measured per microliter (mcL) | Days 0 (baseline), 3 and 7 for up to 10 days after intervention. |