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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04374019
Recruitment Status : Recruiting
First Posted : May 5, 2020
Last Update Posted : November 6, 2020
Sponsor:
Information provided by (Responsible Party):
Susanne Arnold, University of Kentucky

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 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
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ivermectin

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:




Primary Outcome Measures :
  1. Clinical Deterioration [ Time Frame: 14 days ]
    Proportion 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 [ Time Frame: 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 [ Time Frame: 28 days ]
    Percentage of patients that experience severe respiratory or other organ failure.

  3. Progression to ICU Care or Ventilation [ Time Frame: 28 days ]
    Percentage of patients requiring ICU admission or ventilation.

  4. Change in Clinical Status [ Time Frame: 14 days ]
    Clinical status will be assessed using the COVID 7-Point Ordinal Outcomes Scale. This scale ranges from 1-7. Lower scores indicate worse outcomes; higher scores indicate fewer symptoms and better outcomes.

  5. Mortality [ Time Frame: 14 days ]
    Percentage of patients who have died by day 14.

  6. Rate of severe adverse events [ Time Frame: 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. Oxygen-free days [ Time Frame: 28 days ]
    Number of days patients do not require oxygen supplementation.

  8. Ventilator-free days [ Time Frame: 28 days ]
    Number of days patients do not require mechanical ventilation.

  9. Vasopressor-free days [ Time Frame: 28 days ]
    Number of days patients do not require vasopressor treatment.

  10. ICU-free days [ Time Frame: 28 days ]
    Number of days patients do not require ICU services.

  11. Hospital-free days [ Time Frame: 28 days ]
    Number of days patients do not require hospitalization.

  12. Patients meeting Hy's Law criteria [ Time Frame: 28 days ]
    Proportion of patients meeting Hy's law criteria.

  13. Liver Function [ Time Frame: 28 days ]

    Proportion of patients with changes in the following liver function tests:

    1. Any ALT or AST ≥ 5 x ULN;
    2. any AST or ALT ≥ 3 x ULN together with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (eosinophil percent or count above the ULN);
    3. Persistent ALT ≥ 3 x ULN for a period of more than 4 weeks

  14. Heart Function [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04374019


Locations
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United States, Kentucky
University of Kentucky Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40532
Contact: Susanne Arnold, M.D.    859-323-8043    susanne.arnold@uky.edu   
Principal Investigator: Susanne Arnold, M.D.         
Sponsors and Collaborators
Susanne Arnold
Investigators
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Principal Investigator: Susanne Arnold, MD University of Kentucky
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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    Key Record Dates
Last Update Posted: November 6, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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, University of Kentucky:
high-risk
Additional relevant MeSH terms:
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Ivermectin
Artesunate
Camostat
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Trypsin Inhibitors
Serine Proteinase Inhibitors