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

• Sponsor: Susanne Arnold (Other)
• Overall Status: Terminated
• CT.gov ID: NCT04374019
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 4
• Actual Duration (Months): 20.4
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID; Sars-CoV2	Drug: Ivermectin; Drug: Camostat Mesilate; Dietary Supplement: Artemesia annua; Drug: Artesunate	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Multi-arm Phase II Trial of Novel Agents for Treatment of High-risk COVID-19 Positive Patients
• Actual Study Start Date: May 1, 2020
• Actual Primary Completion Date: Dec 21, 2020
• Actual Study Completion Date: Jan 12, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm C: Ivermectin Ivermectin	Drug: 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)
Experimental: Arm D: Camostat Mesilate Camostat Mesilate	Drug: Camostat Mesilate; Days 1-14: 2 tab TID after a meal (600 mg total daily dose)
Experimental: Arm E: Artemesia annua Artemesia annua tea or coffee	Dietary Supplement: Artemesia annua; Days 1-14: tea or coffee pod TID (1350 mg total daily dose)
Experimental: Arm F: Artesunate Artesunate	Drug: Artesunate; Days 1-14:

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Rate of Organ Failure [28 days]

   Number of patients that experienced severe respiratory or other organ failure.

3. Progression to ICU Care or Ventilation [28 days]

   Percentage of patients requiring ICU admission or ventilation.

4. 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: 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)

5. Mortality [14 days]

   Percentage of patients who have died by day 14.

6. 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.

7. Number of Patients That Required Oxygen Supplementation [28 days]

   Number of patients that required oxygen supplementation during study treatment Days 1-28

8. Number of Patients That Required Mechanical Ventilation [28 days]

   Number of patients that required mechanical ventilation during the study period. Days 1-28

9. Number of Patients Who Required Vasopressors [28 days]

   Number of patients who required vasopressor treatment Days 1 to 28

10. Number of Patients Who Required ICU Services [28 days]

    Number of patients who required ICU services during study treatment Days 1-28.

11. Number of Patients That Required Hospitalization [28 days]

    Number of patients that required hospitalization during study treatment

12. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kentucky Markey Cancer Center	Lexington	Kentucky	United States	40532

Sponsors and Collaborators

• Susanne Arnold

Investigators

• Principal Investigator: Susanne Arnold, MD, University of Kentucky

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 28, 2020

More Information

Publications

None provided.

• Responsible Party: Susanne Arnold, Professor, University of Kentucky
• ClinicalTrials.gov Identifier: NCT04374019
• Other Study ID Numbers: MCC-20-COVID-01-PMC
• First Posted: May 5, 2020
• Last Update Posted: Jan 20, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Susanne Arnold, Professor, University of Kentucky: high-risk
• Additional relevant MeSH terms: Artesunate; Ivermectin; Camostat

Study Results

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

Arm/Group Title	Arm A - Hydrozychloroquine	Arm B - Hydroxychloroquine + Azithromycin	Arm C - Ivermectin	Arm D - Camostat
Arm/Group Description	Hydroxychloroquine 600 mg daily Days 1-14	Hydroxychloroquine 600 mg daily Days 1-14 + Azithromycin 500 mg Day 1; 250 mg daily Days 2-5	Ivermectin 12-15- mg (weight based) on Day 1 and 2	Camostat 200mg TID Days 1-14
Period Title: Overall Study
STARTED	1	1	6	5
COMPLETED	1	1	5	5
NOT COMPLETED	0	0	1	0

Baseline Characteristics

Arm/Group Title	Arm A	Arm B	Arm C	Arm D	Total
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	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)	Camostat Mesilate Camostat Mesilate: Days 1-14: 2 tab TID after a meal (600 mg total daily dose)	Total of all reporting groups
Overall Participants	1	1	6	5	13
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 100%	1 100%	5 83.3%	3 60%	10 76.9%
>=65 years	0 0%	0 0%	1 16.7%	2 40%	3 23.1%
Sex: Female, Male (Count of Participants)
Female	1 100%	0 0%	3 50%	4 80%	8 61.5%
Male	0 0%	1 100%	3 50%	1 20%	5 38.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	1 100%	1 100%	6 100%	5 100%	13 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	1 100%	1 100%	6 100%	5 100%	13 100%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%	1 100%	6 100%	5 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Deterioration
Description	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

Outcome Measure Data

Analysis Population Description

1 subject was inevaluable in Arm C. No subjects clinically deteriorated as defned above

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Change in Viral Load
Description	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

Outcome Measure Data

Analysis Population Description

study terminated due to low accrual, no subjects analyzed for this outcome.

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	0	0	0	0

3. Secondary Outcome

Title	Rate of Organ Failure
Description	Number of patients that experienced severe respiratory or other organ failure.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Progression to ICU Care or Ventilation
Description	Percentage of patients requiring ICU admission or ventilation.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale
Description	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)
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

6. Secondary Outcome

Title	Mortality
Description	Percentage of patients who have died by day 14.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Rate of Severe Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	1 100%	0 0%	1 16.7%	0 0%

8. Secondary Outcome

Title	Number of Patients That Required Oxygen Supplementation
Description	Number of patients that required oxygen supplementation during study treatment Days 1-28
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	1 100%	1 100%	1 16.7%	1 20%

9. Secondary Outcome

Title	Number of Patients That Required Mechanical Ventilation
Description	Number of patients that required mechanical ventilation during the study period. Days 1-28
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

10. Secondary Outcome

Title	Number of Patients Who Required Vasopressors
Description	Number of patients who required vasopressor treatment Days 1 to 28
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

11. Secondary Outcome

Title	Number of Patients Who Required ICU Services
Description	Number of patients who required ICU services during study treatment Days 1-28.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

12. Secondary Outcome

Title	Number of Patients That Required Hospitalization
Description	Number of patients that required hospitalization during study treatment
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	4 66.7%	4 80%

13. Secondary Outcome

Title	Heart Function
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A	Arm B	Arm C	Arm D
Arm/Group Description	Hydroxychloroquine	Hydroxychloroquine + Azithromycin	Ivermectin	Camostat
Measure Participants	1	1	5	5
Count of Participants [Participants]	0 0%	0 0%	1 16.7%	0 0%

Adverse Events

Time Frame	AEs were collected from study entry until Day 28.
Arm/Group Title	Arm A		Arm B		Arm C		Arm D
Arm/Group Description	Hydroxychloroquine		Hydroxychloroquine + Azithromycin		Ivermectin		Camostat
All Cause Mortality
	Arm A		Arm B		Arm C		Arm D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)		0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Arm A		Arm B		Arm C		Arm D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/1 (0%)		1/5 (20%)		0/5 (0%)
Blood and lymphatic system disorders
anemia	1/1 (100%)	1	0/1 (0%)	0	0/5 (0%)	0	0/5 (0%)	0
Cardiac disorders
supraventricular tachycardia	0/1 (0%)	0	0/1 (0%)	0	1/5 (20%)	1	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A		Arm B		Arm C		Arm D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		1/1 (100%)		1/5 (20%)		0/5 (0%)
Ear and labyrinth disorders
tinnitus	0/1 (0%)	0	1/1 (100%)	1	0/5 (0%)	0	0/5 (0%)	0
Gastrointestinal disorders
mucositis	0/1 (0%)	0	0/1 (0%)	0	1/5 (20%)	1	0/5 (0%)	0
GERD	0/1 (0%)	0	1/1 (100%)	1	0/5 (0%)	0	0/5 (0%)	0

Limitations/Caveats

Thsi study was closed to accrual due to slow accrual rate. No conclusions on efficacy can be made due to a lack of statistical power in each arm.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.