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

• ClinicalTrials.gov Identifier: NCT04374019
• Recruitment Status: Recruiting
• First Posted: May 5, 2020
• Last Update Posted: November 6, 2020
• Sponsor: Susanne Arnold
• Information provided by (Responsible Party): Susanne Arnold, University of Kentucky

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 (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

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 [ 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.

Eligibility Criteria

• 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

Contacts and Locations

Locations

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

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

More Information

• 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: November 6, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• 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, University of Kentucky:

high-risk

Additional relevant MeSH terms:

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