Novel Agents for Treatment of High-risk COVID-19 Positive Patients

Study Overview
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Brief Summary
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This is a multi-arm, phase II trial for rapid efficacy and toxicity assessment of multiple therapies immediately after COVID19 positive testing in high-risk individuals. Therapies include stand-alone or combination treatment with hydroxychloroquine, azithromycin, ivermectin, or camostat mesilate, artemesia annua. The hypothesis of this study is that the addition of agents that inhibit viral entry or replication of SARS-CoV-2 virus replication in will be devoid of additional moderate to severe toxicities, will prevent clinical deterioration, and will improve viral clearance in high risk individuals.

Detailed Description
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Coronavirus Disease 2019 (COVID-19) is a highly contagious disease, caused by a novel enveloped RNA beta-coronavirus, also known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The first case of this unprecedented outbreak pneumonia of unknown etiology was reported in Wuhan City, Hubei Province, China on December 8th, 2019 and reported to the World Health Organization (WHO) on December 31st, 2019. WHO declared a COVID-19 global emergency on January 30, 2020, and then categorized the outbreak as a pandemic on March 11, 2020. As of April 22, 2020, more than 2,628,894 confirmed cases of COVID-19 worldwide and 182,740 people globally have died from COVID-19 since it emerged in China, according to the data from Johns Hopkins University. While the majority of patients with COVID-19 develop mild or uncomplicated illness, approximately 20-30% of hospitalized patients have required intensive care support and 5% of those have multi-organ failure or shock. The case fatality rate ranges from 1 to 4% and it is higher among those with pre-existing comorbid conditions such as cardiovascular disease, diabetes mellitus, obesity, chronic respiratory disease, hypertension and cancer. The vast majority of patients present with fever (83-99%), cough (59-82%), fatigue (44-70%), anorexia (40-84%), shortness of breath (31-40%), sputum production (28-33%), myalgias (11-35%). Less than 10% of patients will present with headache, confusion, rhinorrhea, sore throat, hemoptysis, vomiting, or diarrhea. Anosmia or ageusia proceeding the onset of respiratory symptoms has been anecdotally reported. To date, treatments for COVID-19 in high risks individuals remain experimental and therapeutic strategies to deal with the infection are at best supportive, with prevention aimed at reducing transmission in the community as the best weapon. No proven therapies have been demonstrated to prevent the progression of COVID-19 to severe illness and this is a critical unmet need for high-risk individuals and warrants study. Recently, the Infectious Disease Society of America has made recommendations for the treatment of patients with COVID-19, focusing on inpatient care, and recommending randomized trials where possible as the best step to improve treatment outcomes and to increase our understanding of this coronavirus pandemic. Discoveries in this area may inform clinicians on effective treatment for low-risk individuals who progress to severe illness, as well.

Official Title
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Randomized, Multi-arm Phase II Trial of Novel Agents for Treatment of High-risk COVID-19 Positive Patients

Conditions
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COVID, Sars-CoV2

Intervention / Treatment
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* Drug: Ivermectin
* Drug: Camostat Mesilate
* Dietary Supplement: Artemesia annua
* Drug: Artesunate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥18 years Laboratory-confirmed SARS-CoV-2 infection within the past 7 days or the presence of symptoms or physical examination signs providing high probability of COVID-19 disease Patients must have adequate organ and marrow function measured within the last 6 months Subjects must have at least one of the following high-risk features for clinical deterioration: Hypertension Diabetes Mellitus Moderate to severe Chronic Obstructive Pulmonary Disease, Emphysema, Cystic Fibrosis, or Asthma Cancer patients who have received any immunosuppressive drugs within a year from enrollment Sickle Cell disease or thalessemia Age > or = 50 BMI > or = 30 Living in a nursing home or long-term facility Underlying serious heart condition as determined by the treating physician Immunocompromised subject as defined by the treating physician or COVID-19 Telehealth Treatment Team Exclusion Criteria Severe or life threating COVID Weight less than 45 kg. Pregnant or breast-feeding females Subjects on dialysis or with creatinine clearance < 45 ml/min Existing DMID Toxicity Scale for Determining Severity of Adverse Events grade 3 or greater hepatic failure Previously documented moderate or severe retinopathy or macular degeneration Uncontrolled Seizure disorder Prolonged QT, defined as QTc ≥470 milliseconds for men and as QTc ≥480 for women using Bazett's formula Known allergy to artesunate, artemisia annua, hydroxychloroquine, macrolides, 4-aminoquinolines, camostat mesilate, or other agents to be used in the trial. Currently receiving any study medications for other indications Concurrent use of medication that would cause drug-drug interactions Patients with psychiatric illness/social situations that would limit compliance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm C: Ivermectin<br>Ivermectin | Drug: Ivermectin<br>* Ivermectin: Days 1-2: Weight < 75kg: 4 tabs (12 mg total daily dose) Days 1-2: Weight > 75kg: 5 tabs (15 mg total daily dose)<br>|
| Experimental: Arm D: Camostat Mesilate<br>Camostat Mesilate | Drug: Camostat Mesilate<br>* Days 1-14: 2 tab TID after a meal (600 mg total daily dose)<br>|
| Experimental: Arm E: Artemesia annua<br>Artemesia annua tea or coffee | Dietary Supplement: Artemesia annua<br>* Days 1-14: tea or coffee pod TID (1350 mg total daily dose)<br>|
| Experimental: Arm F: Artesunate<br>Artesunate | Drug: Artesunate<br>* Days 1-14:<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Deterioration | Number of patients experiencing clinical deterioration. Clinical deterioration is defined as a less than a 2-point change from the initial COVID 7-Point Ordinal Outcomes Scale within 14 days from the study start. This scale ranges from 1-7. Lower scores indicate worse outcomes (death); higher scores indicate fewer symptoms and better outcomes. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Viral Load | The change in (clearance of) viral RNA will be measured by PCR testing at days 1, 14, 28, and 40 days. | 40 days | 
| Rate of Organ Failure | Number of patients that experienced severe respiratory or other organ failure. | 28 days | 
| Progression to ICU Care or Ventilation | Percentage of patients requiring ICU admission or ventilation. | 28 days | 
| Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale | Number of participants who died or had greater than a 2-point decrease in COVID 7-Point Ordinal Outcomes Scale from Day to Day 14. COVID 7-point ordinal outcomes scale: Death Hospitalized on invasive mechanical ventilation or ECMO Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms) | 14 days | 
| Mortality | Percentage of patients who have died by day 14. | 14 days | 
| Rate of Severe Adverse Events | Percentage of patients experiencing severe adverse events, defined as grade 3 non-hematologic or greater by DMID Toxicity Scale for Determining Severity of Adverse Events. | 14 days | 
| Number of Patients That Required Oxygen Supplementation | Number of patients that required oxygen supplementation during study treatment Days 1-28 | 28 days | 
| Number of Patients That Required Mechanical Ventilation | Number of patients that required mechanical ventilation during the study period. Days 1-28 | 28 days | 
| Number of Patients Who Required Vasopressors | Number of patients who required vasopressor treatment Days 1 to 28 | 28 days | 
| Number of Patients Who Required ICU Services | Number of patients who required ICU services during study treatment Days 1-28. | 28 days | 
| Number of Patients That Required Hospitalization | Number of patients that required hospitalization during study treatment | 28 days | 
| Heart Function | Proportion of patients with significant changes in ECG findings, including heart rate, ECG intervals (PR, QTcB, QTcF), conduction changes, or abnormalities including severe QTc prolongation of > 500 ms. | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high-risk