Repurposed Approved Therapies for Outpatient Treatment of Patients With Early-Onset COVID-19 and Mild Symptoms

Overview

The COVID-19 pandemic has been characterized by high morbidity and mortality, especially in certain subgroups of patients. To date, no treatment has been shown to be effective in patients with early-onset disease and mild symptoms. Experimental studies have demonstrated a potential anti-inflammatory role of Fluvoxamine, Metformin and Ivermectin in SARS-CoV-2 infections and observational studies have suggested a reduced complications in patients with COVID-19 disease.

Full Title of Study: “A Multicenter, Prospective, Adaptive, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effect of Fluvoxamine, Ivermectin and Metformin in Reducing Hospitalization of Patients With Mild COVID-19 and a High Risk of Complications”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: February 1, 2022

Detailed Description

In December 2019 a series of viral pneumonia cases were reported in the city of Wuhan, China and a new subtype of coronavirus has been identified as the causative agent of this condition. On February 11, 2000 the disease has been characterized as COVID-19 and on March 11 the WHO declared a state of worldwide pandemic. On January 25, 2021 there are 98,794,942 cases and 2,124,193 documented deaths (global case-fatality ratio of 2.15%). To date, no early treatment has been identified as effective in combating this disease which has been identified as with high morbidity and mortality. Epidemiological data suggest that despite development of vaccines we will have hundreds od thousands of cases in the next two years. Thus, we propose the repositioning of three drugs which experimentally have shown anti-inflammatory activity against SARS-CoV2 and some clinical evidence derived from observational studies on reducing complications if used early on the disease, before inflammatory cascade is fully activated.

Interventions

  • Drug: Fluvoxamine Maleate 100 MG [Luvox]
    • One tablet every 12 hours since randomization through day 09.
  • Drug: Metformin Extended Release Oral Tablet
    • One 750 mg extended release tablet every 12 hours since randomization through day 09.
  • Drug: Ivermectin Tablets
    • 06 mg oral tablet: Three tablets if weight 40 – 60 kg, single dose; Four tablets if weight > 60 kg, single dose.
  • Drug: Placebo
    • Talc tablets: One tablet every randomization since randomization through day 09 OR Three tablets if weight 40 – 60 kg, single dose; Four tablets if weight > 60 kg, single dose.

Arms, Groups and Cohorts

  • Active Comparator: Fluvoxamine Maleate
    • Fluvoxamine 100 mg oral tablets: One tablet right after randomization followed by 100 mg twice a day for the following 09 days
  • Active Comparator: Metformin HCL
    • Metformin HCL 750 mg extended release tablets: one tablet right after randomization followed by 750 mg twice a day for the following 09 days
  • Active Comparator: Ivermectin
    • Ivermectin 06 mg oral tablets: Three tablets right after randomization if weight 40 – 60 kg, single dose; Four tablets right after randomization if weight > 60 kg, single dose;
  • Placebo Comparator: Placebo (talc)
    • Placebo oral tablets: one tablet right after randomization followed by one tablet twice a day for the following 09 days; OR Placebo oral tablets: Three tablets right after randomization if weight 40 – 60 kg, single dose; Four tablets right after randomization if weight > 60 kg, single dose

Clinical Trial Outcome Measures

Primary Measures

  • To evaluate the effect of fluvoxamine, ivermectin and metformin in reducing need for emergency care AND observation for more than 12 hours due to the worsening of COVID-19;
    • Time Frame: 28 days
    • Evaluation of emergency visits and observation unit stay > 12 hours
  • To evaluate the effect of fluvoxamine, ivermectin and metformin in reducing need for Hospitalization due to lower respiratory tract infection (LRTI) related to COVID-19
    • Time Frame: 28 days
    • Hospitalization due to COVID-19 progression

Secondary Measures

  • Change in viral load on day 03 and 07 after randomization (first 600 enrolled participants)
    • Time Frame: Day 3 and Day 7
    • Viral load
  • Time to clinical improvement (up to 28 days of randomization), defined as improvement greater than 50% in reference to baseline symptoms)
    • Time Frame: Randomization through day 28
    • time to > 50% clinical improvement (self reported)
  • Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19
    • Time Frame: Randomization through day 28
    • Time to hospitalization
  • Number of days with respiratory symptoms since randomization
    • Time Frame: Randomization through day 28
    • Days with symptoms
  • All-cause hospitalizations
    • Time Frame: Randomization through day 28
    • All cause hospitalizations
  • COVID-19 related hospitalizations
    • Time Frame: Randomization through day 28
    • COVID-19 hospitalizations
  • All-Cause Death
    • Time Frame: Randomization through day 28
    • Death all cause
  • Cardiovascular death
    • Time Frame: Randomization through day 28
    • Cardiovascular death
  • Respiratory death
    • Time Frame: Randomization through day 28
    • REspiratory death
  • Promis Global-10 scale
    • Time Frame: Randomization, Day 14 and Day 28
    • Ordinal scale
  • WHO ordinal scale for clinical improvement
    • Time Frame: Randomization through day 14
    • Ordinal Scale
  • Adverse Events
    • Time Frame: randomization through day 28
    • Adverse events
  • Adherence of Study drug
    • Time Frame: Randomization through day 10
    • Percentage of adherence on Study drug

Participating in This Clinical Trial

Inclusion Criteria

1. Patients over 18 years old with the ability to provide free and informed consent 2. Acute Flu-Like symptoms < 07 days. 3. All patient need to have at lease ONE enhancement factor: 1. Age > 50 years; 2. Diabetes mellitus requiring oral medication or insulin 3. Systemic arterial hypertension requiring at least 01 oral medication for BP control; 4. Known cardiovascular diseases (heart failure, congenital heart disease, valvar heart valve disease, coronary artery disease, cardiomyopathies) 5. Symptomatic lung disease (emphysema, chronic bronchitis) 6. Symptomatic asthma patients requiring chronic use of agents for control of symptoms. 7. Smoking 8. Obesity, defined as BMI> 30 kg / m2 body weight 9. Transplanted patients 10. SARS-CoV2 vaccinated patients 11. Patient with stage IV chronic kidney disease or on dialysis. 12. Immunosuppressed patients / using corticosteroid therapy (equivalent to at least 10 mg of prednisone per day) and / or immunosuppressive therapy) 13. Patients with a history of cancer in the last 05 years or undergoing treatment of a current cancer 4. Patient with positive rapid test for SARS-CoV2 antigen performed on occasion of the screening or patient with a positive SARS-CoV2 diagnostic test within 07 days of the onset of symptoms. 5. Willingness to use the proposed investigative treatment and follow the protocol-related procedures foreseen in the research Exclusion Criteria:

1. Negative SARS-CoV2 test. 2. Flu-like symptom onset 08 days or more. 3. Patients with COVID-19 and hospitalization referral 4. Patients with acute respiratory conditions due to other causes; 5. Dyspnea secondary to other acute and chronic respiratory causes or infections (eg: Decompensated COPD, acute bronchitis, pneumonia, primary pulmonary arterial hypertension) 6. Acute flu condition presenting at least ONE of the criteria below: 1. Respiratory Rate> 28 / min; 2. SaO2 <90% or <93% in nasal oxygen therapy at 10 l / min; 3. PaO2 / FIO2 <300 mmHg 7. Patients using serotonin reception inhibitors (Donepezil, Sertraline) 8. Use of the following medications in the last 14 days: 1. Monoamine Oxide Inhibitors (MAOIs): Phenelzine, Tranylcypromine, Selegiline, Isocarboxazide, moclobemide; 2. Use of iodinated contrasts during start of treatment through D14; 3. Use of antiretroviral agents 9. Patients with severe psychiatric disorders or major uncontrolled depression or controlled with any of the prohibited drugs (see above); 10. Pregnant or breastfeeding patients; 11. History of severe ventricular cardiac arrhythmia (ventricular tachycardia, patients with ventricular fibrillation recovered) or Long QT Syndrome; 12. History of diabetic ketoacidosis or clinical condition that maintains persistent acidosis 13. Surgical procedure or use of contrast designed to occur during treatment or up to 04 days after the last dose of the study medication; 14. Current daily and / or uncontrolled alcoholism; 15. History of seizures in the last month or uncontrolled medical condition; 16. Clinical history of Liver Cirrhosis or Child-Pugh C classification; 17. Patients with known severe degenerative neurological diseases and / or diseases serious mental disorders; 18. Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol; 19. Known hypersensitivity and / or intolerance to Fluvoxamine, Ivermectin or Metformin; 20. Inability to take oral medications;

Gender Eligibility: All

Gender will be assumed as patient self-reported

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Cardresearch
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Gilmar Reis, MD, PhD, +553132416574, administrador@cardresearch.org

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