COVID, Sars-CoV2
Conditions
Keywords
high-risk
Brief summary
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
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.
Interventions
DRUGIvermectin
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)
Days 1-14: 2 tab TID after a meal (600 mg total daily dose)
DIETARY_SUPPLEMENTArtemesia annua
Days 1-14: tea or coffee pod TID (1350 mg total daily dose)
DRUGArtesunate
Days 1-14:
Sponsors
Susanne Arnold
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Deterioration | 14 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Organ Failure | 28 days | Number of patients that experienced severe respiratory or other organ failure. |
| Progression to ICU Care or Ventilation | 28 days | Percentage of patients requiring ICU admission or ventilation. |
| Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale | 14 days | 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: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms) |
| Mortality | 14 days | Percentage of patients who have died by day 14. |
| Rate of Severe Adverse Events | 14 days | 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. |
| Change in Viral Load | 40 days | The change in (clearance of) viral RNA will be measured by PCR testing at days 1, 14, 28, and 40 days. |
| Number of Patients That Required Mechanical Ventilation | 28 days | Number of patients that required mechanical ventilation during the study period. Days 1-28 |
| Number of Patients Who Required Vasopressors | 28 days | Number of patients who required vasopressor treatment Days 1 to 28 |
| Number of Patients Who Required ICU Services | 28 days | Number of patients who required ICU services during study treatment Days 1-28. |
| Number of Patients That Required Hospitalization | 28 days | Number of patients that required hospitalization during study treatment |
| Heart Function | 28 days | 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. |
| Number of Patients That Required Oxygen Supplementation | 28 days | Number of patients that required oxygen supplementation during study treatment Days 1-28 |
Countries
United States
Participant flow
Recruitment details
Recruitment period 5/1/2020 to 11/23/2020; Study on hold for most of 2021, terminated in early 2022 due to low accrual
Participants by arm
| Arm | Count |
|---|---|
| Arm A Hydroxychloroquine | 1 |
| Arm B Hydroxychloroquine + Azithromycin | 1 |
| Arm C Ivermectin
Ivermectin: 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) | 6 |
| Arm D Camostat Mesilate
Camostat Mesilate: Days 1-14: 2 tab TID after a meal (600 mg total daily dose) | 5 |
| Total | 13 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Arm C | Arm D | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 5 Participants | 3 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 6 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 6 Participants | 5 Participants | 13 Participants |
| Region of Enrollment United States | 1 participants | 1 participants | 6 participants | 5 participants | 13 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 3 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 1 | 1 / 1 | 1 / 5 | 0 / 5 |
| serious Total, serious adverse events | 1 / 1 | 0 / 1 | 1 / 5 | 0 / 5 |
Outcome results
Primary
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.
Time frame: 14 days
Population: 1 subject was inevaluable in Arm C. No subjects clinically deteriorated as defned above
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Clinical Deterioration | 0 Participants |
| Arm B | Clinical Deterioration | 0 Participants |
| Arm C | Clinical Deterioration | 0 Participants |
| Arm D | Clinical Deterioration | 0 Participants |
Secondary
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.
Time frame: 40 days
Population: study terminated due to low accrual, no subjects analyzed for this outcome.
Secondary
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.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Heart Function | 0 Participants |
| Arm B | Heart Function | 0 Participants |
| Arm C | Heart Function | 1 Participants |
| Arm D | Heart Function | 0 Participants |
Secondary
Mortality
Percentage of patients who have died by day 14.
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Mortality | 0 Participants |
| Arm B | Mortality | 0 Participants |
| Arm C | Mortality | 0 Participants |
| Arm D | Mortality | 0 Participants |
Secondary
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: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms)
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale | 0 Participants |
| Arm B | Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale | 0 Participants |
| Arm C | Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale | 0 Participants |
| Arm D | Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale | 0 Participants |
Secondary
Number of Patients That Required Hospitalization
Number of patients that required hospitalization during study treatment
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients That Required Hospitalization | 0 Participants |
| Arm B | Number of Patients That Required Hospitalization | 0 Participants |
| Arm C | Number of Patients That Required Hospitalization | 4 Participants |
| Arm D | Number of Patients That Required Hospitalization | 4 Participants |
Secondary
Number of Patients That Required Mechanical Ventilation
Number of patients that required mechanical ventilation during the study period. Days 1-28
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients That Required Mechanical Ventilation | 0 Participants |
| Arm B | Number of Patients That Required Mechanical Ventilation | 0 Participants |
| Arm C | Number of Patients That Required Mechanical Ventilation | 0 Participants |
| Arm D | Number of Patients That Required Mechanical Ventilation | 0 Participants |
Secondary
Number of Patients That Required Oxygen Supplementation
Number of patients that required oxygen supplementation during study treatment Days 1-28
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients That Required Oxygen Supplementation | 1 Participants |
| Arm B | Number of Patients That Required Oxygen Supplementation | 1 Participants |
| Arm C | Number of Patients That Required Oxygen Supplementation | 1 Participants |
| Arm D | Number of Patients That Required Oxygen Supplementation | 1 Participants |
Secondary
Number of Patients Who Required ICU Services
Number of patients who required ICU services during study treatment Days 1-28.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients Who Required ICU Services | 0 Participants |
| Arm B | Number of Patients Who Required ICU Services | 0 Participants |
| Arm C | Number of Patients Who Required ICU Services | 0 Participants |
| Arm D | Number of Patients Who Required ICU Services | 0 Participants |
Secondary
Number of Patients Who Required Vasopressors
Number of patients who required vasopressor treatment Days 1 to 28
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Patients Who Required Vasopressors | 0 Participants |
| Arm B | Number of Patients Who Required Vasopressors | 0 Participants |
| Arm C | Number of Patients Who Required Vasopressors | 0 Participants |
| Arm D | Number of Patients Who Required Vasopressors | 0 Participants |
Secondary
Progression to ICU Care or Ventilation
Percentage of patients requiring ICU admission or ventilation.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Progression to ICU Care or Ventilation | 0 Participants |
| Arm B | Progression to ICU Care or Ventilation | 0 Participants |
| Arm C | Progression to ICU Care or Ventilation | 0 Participants |
| Arm D | Progression to ICU Care or Ventilation | 0 Participants |
Secondary
Rate of Organ Failure
Number of patients that experienced severe respiratory or other organ failure.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Rate of Organ Failure | 0 Participants |
| Arm B | Rate of Organ Failure | 0 Participants |
| Arm C | Rate of Organ Failure | 0 Participants |
| Arm D | Rate of Organ Failure | 0 Participants |
Secondary
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.
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Rate of Severe Adverse Events | 1 Participants |
| Arm B | Rate of Severe Adverse Events | 0 Participants |
| Arm C | Rate of Severe Adverse Events | 1 Participants |
| Arm D | Rate of Severe Adverse Events | 0 Participants |