Clinical trial NCT04374019: Novel Agents for Treatment of High-risk COVID-19 Positive Patients
Official title: Randomized, Multi-arm Phase II Trial of Novel Agents for Treatment of High-risk COVID-19 Positive Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID
Sars-CoV2
Keywords: high-risk
Lead sponsor: University of Kentucky
Sponsor class: OTHER
First posted: 2020-05-05
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Clinical Deterioration
timeFrame: 14 days
Secondary outcomes:
measure: Change in Viral Load
timeFrame: 40 days
measure: Rate of Organ Failure
timeFrame: 28 days
measure: Progression to ICU Care or Ventilation
timeFrame: 28 days
measure: Number of Participants Who Had a Change in Clinical Status Measured by Decrease in COVID 7-point Ordinal Scale
timeFrame: 14 days
measure: Mortality
timeFrame: 14 days
measure: Rate of Severe Adverse Events
timeFrame: 14 days
measure: Number of Patients That Required Oxygen Supplementation
timeFrame: 28 days
measure: Number of Patients That Required Mechanical Ventilation
timeFrame: 28 days
measure: Number of Patients Who Required Vasopressors
timeFrame: 28 days
measure: Number of Patients Who Required ICU Services
timeFrame: 28 days
measure: Number of Patients That Required Hospitalization
timeFrame: 28 days
measure: Heart Function
timeFrame: 28 days
Other outcomes:
Locations:
city: Lexington
country: United States
facility: University of Kentucky Markey Cancer Center
state: Kentucky
Study officials:
affiliation: University of Kentucky
name: Susanne Arnold, MD
role: PRINCIPAL_INVESTIGATOR
References: