Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms

• ClinicalTrials.gov Identifier: NCT04727424
• Recruitment Status: Recruiting
• First Posted: January 27, 2021
• Last Update Posted: July 8, 2021
• Sponsor: Cardresearch
• Collaborators: Cytel Inc.; McMaster University; Fastgrants; Eiger BioPharmaceuticals; RainWater Foundation
• Information provided by (Responsible Party): Cardresearch

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Covid19; SARS-Associated Coronavirus	Drug: Fluvoxamine Maleate 100 MG [Luvox]; Drug: Doxazosin 2 Mg Oral Tablet; Drug: Ivermectin 06 mg Oral Tablet; Drug: Placebo; Drug: Peginterferon Lambda-1a; Drug: Peginterferon Beta-1A Prefilled Syringe	Phase 3

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 World Health Organization (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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 3645 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Patients will be randomly allocated to one of six treatment arms in a 1:1:1:1:1:1 ratio:

1. Fluvoxamine
2. Ivermectin
3. Doxazosin
4. Peginterferon Lambda
5. Peginterferon Beta
6. Placebo We will use a centralized random allocation schedule, generated by computer and stratified by site and age.

• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description

The investigational medical product will be packaged in similar bottles by a third party who will keep the allocation confidential until the end of the study. The bottles will be sealed and identified as "Research Product with no commercial value" and coded. They will be randomly allocated among the participants using a centralized randomization system The research subjects, medical assistance, administrative and health staff will not have access to the contents of the bottles. All arms will have a placebo counterpart with same dose schedule.

All planned Data and Safety Monitoring Board (DSMB) interim analysis will be blinded. If needed a unblinded statistician will be provided if DSMB decides to stop any arm. At the end of the study, or early termination as per DMSB interim analysis plan, the arms will then be identified.

• Primary Purpose: Treatment
• Official Title: A Multicenter, Prospective, Adaptive, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effect of Fluvoxamine, Ivermectin, Doxasozin and Interferon Lambda 1A in Mild COVID-19 and High Risk of Complications
• Actual Study Start Date: January 19, 2021
• Estimated Primary Completion Date: February 1, 2022
• Estimated Study Completion Date: March 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Fluvoxamine Maleate; Fluvoxamine 100 mg oral tablets: One tablet right after randomization (Day 0) followed by 100 mg BID for the following 09 days	Drug: Fluvoxamine Maleate 100 MG [Luvox]; One tablet every 12 hours since randomization through day 09.
Active Comparator: Doxasoxin; Dosaxozin oral tablets (1 or 2 mg): One tablet right after randomization (Day 0) until Day 3, when uptritation of tablets will happen as per protocol, up to 4 pills daily (08 mg/ day) ending on Day 13.	Drug: Doxazosin 2 Mg Oral Tablet; One to four tablets daily, as per uptritation schedule up to 08 mg/ day since randomization through day 13.
Active Comparator: Ivermectin; Ivermectin 06 mg oral tablets: Tablets started right after randomization (Day 0; 400mcg/ kg dosing), administered once a day for 03 consecutive days.	Drug: Ivermectin 06 mg Oral Tablet; Oral tablets administered once a day for three consecutive days (as of randomization day 0).
Placebo Comparator: Placebo; Placebo SC normal saline syringe (single day dosing schedule): Matching syringes containing 0,5 ml normal saline will be administered by SC route just after randomization Day 0 (single dose SC administration). OR Placebo oral tablets (3-day dosing schedule): Matching tablets started right after randomization using the dosing regimen of a medium 400mcg/ kg up to 90 kg weight, administered once a day for three consecutive days (including randomization day, which is designed as Day 0). OR Placebo oral tablets (10-day dosing schedule): Matching tablets started right after randomization using the dosing regimen of 01 tablet every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule) OR Placebo oral tablets (14-day dosing schedule): Matching tablets started right after randomization (Day 0) until Day 3, when uptritation of tablets will happen as per protocol, up to 4 pills daily (08 mg/ day) ending on Day 13.	Drug: Placebo; Placebo SC normal saline syringe (single day dosing schedule): Matching syringes containing 0,5 ml normal saline will be administered by SC route just after randomization Day 0 (single dose SC administration). OR Placebo oral tablets (3-day dosing schedule): Matching tablets started right after randomization using the dosing regimen of a medium 400mcg/ kg up to 90 kg weight, administered once a day for three consecutive days (including randomization day, which is designed as Day 0). OR Placebo oral tablets (10-day dosing schedule): Matching tablets started right after randomization using the dosing regimen of 01 tablet every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule) OR Placebo oral tablets (14-day dosing schedule): Matching tablets started right after randomization (Day 0) until Day 3, when uptritation of tablets will happen as per protocol, up to 4 pills daily (08 mg/ day) ending on Day 13.
Active Comparator: Peginterferon Lambda; Peginterferon Lambda 180 mcg syringe: One syringe of Peginterferon Lambda will be administered by SC route just after randomization (Day 0 - single dose SC administration).	Drug: Peginterferon Lambda-1a; One syringe of 180 mcg of Peginterferon Lambda SC right after randomization Day 0 (single dose SC administration).
Active Comparator: Peginterferon Beta; Peginterferon Beta 125 mcg syringe: One syringe of Peginterferon Beta 1A will be administered by SC route just after randomization (Day 0 - single dose SC administration).	Drug: Peginterferon Beta-1A Prefilled Syringe; One syringe of 125 mcg of Peginterferon Beta SC right after randomization Day 0 (single dose SC administration).

Outcome Measures

Primary Outcome Measures :

1. Rate of fluvoxamine, ivermectin, doxasozin, peginterferon Lambda and peginterferon beta in changing the need for emergency care AND observation for more than 06 hours due to the worsening of COVID-19; [ Time Frame: 28 days ]
   Evaluation of emergency visits and observation unit stay > 06 hours
2. Rate of fluvoxamine, ivermectin, doxasozin, peginterferon lambda and peginterferon beta in changing need for Hospitalization due to COVID-19 progression and related complications, including lower respiratory tract infection (LRTI) [ Time Frame: 28 days ]
   Hospitalization due to COVID-19 progression and related complications

Secondary Outcome Measures :

1. Change in viral load on day 03 and 07 after randomization (first 400 enrolled participants on the IV arms) [ Time Frame: Day 3 and Day 7 ]
   Viral load
2. Time to clinical changes (up to 28 days of randomization), defined as greater than 50% symptoms changing in reference to baseline symptoms) [ Time Frame: Randomization through day 28 ]
   time to > 50% clinical symptoms changes as reported on baseline visit (self reported)
3. Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 or associated complications. [ Time Frame: Randomization through day 28 ]
   Time to hospitalization
4. Number of days with respiratory symptoms since randomization [ Time Frame: Randomization through day 28 ]
   Days with symptoms
5. Rate of all-cause hospitalizations [ Time Frame: Randomization through day 28 ]
   All cause hospitalizations
6. Rate of COVID-19 related hospitalizations [ Time Frame: Randomization through day 28 ]
   COVID-19 hospitalizations
7. Number of days on Mechanical Ventilator [ Time Frame: Randomization through day 28 ]
   Number of days on mechanical Ventilator
8. Number of Days on Intensive Care Unit [ Time Frame: Randomization through day 28 ]
   Number of days on Intensive Care Unit
9. Number of days on hospitalizations [ Time Frame: Randomization through day 28 ]
   Number of days on Hospitalization
10. Health and Functioning after COVID-19 disease [ Time Frame: Day 14 and Day 28 ]
    Self evaluation of health functioning post COVID using Promis Global Health Score. Short term scale is a 10 item patient-reported questionnaire using response options as a 5-point and one 11 point rating scale. Higher scores means better global health.
11. WHO ordinal scale for clinical improvement [ Time Frame: Randomization through day 28 ]
    An 8 item Ordinal Scale for clinical status on COVID-19. Higher numbers means worse clinical status.
12. Number os days on respiratory Symptoms [ Time Frame: randomization through day 28 ]
    Number of days on respiratory symptoms
13. Adherence of Study drug [ Time Frame: Randomization through day 14 ]
    Percentage of adherence on Study drug

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Gender will be assumed as patient self-reported
• Accepts Healthy Volunteers: No

Criteria

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. Patients with at least ONE enhancement criteria:

   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. Fever > 38 C at baseline
   8. Obesity, defined as BMI> 30 kg / m2 body weight
   9. Transplanted patients
   10. Patient with stage IV chronic kidney disease or on dialysis.
   11. Immunosuppressed patients/ using corticosteroid therapy (equivalent to maximum 10 mg of prednisone per day) and/ or immunosuppressive therapy)
   12. Patients with a history of cancer in the last 05 years or undergoing treatment of a current cancer
   13. Chronic renal disease KDIGO IV or End-Stage Renal Disease on chronic ambulatory renal replacement therapy
   14. Patients with important limitation of daily activities due to: Dyspnea, chest pain myalgia (limited to 25% of all randomizations)
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 being referred for hospitalization;
4. > 14 days of vaccination for SARS-CoV-2.
5. Patients with acute respiratory conditions due to other causes;
6. Dyspnea secondary to other acute and chronic respiratory causes or infections (eg: Decompensated COPD, acute bronchitis, pneumonia, primary pulmonary arterial hypertension)
7. Patients with clinical evidence of moderate disease and/or hospitalization indication
8. Patients using serotonin reception inhibitors (Donepezil, Sertraline)

9. Use of the following medications in the last 14 days:

   1. Monoamine Oxide Inhibitors (MAOIs): Phenelzine, Tranylcypromine, Selegiline, Isocarboxazide, moclobemide;
   2. Alpha-1 antagonists, Sotalol, Clonidine, Phosphodiesterase 5 inhibitors, Methyldopa, Prazosin, terasozin, Doxazosin).
   3. Use of antiretroviral agents
10. Patients with severe psychiatric disorders or major uncontrolled depression or controlled with any of the prohibited drugs (see above);
11. Pregnant or breastfeeding patients;
12. History of severe ventricular cardiac arrhythmia (ventricular tachycardia, patients with ventricular fibrillation recovered) or Long QT Syndrome;
13. Known history of symptomatic orothosthatic hypotension, syncope, postural orthostatic tachycardia syndrome (POTS), Neurally-mediated syncope on the last 12 months, less than 12 weeks of cerebrovascular accident, myocardial infarction, cardiovascular intervention, moderate to severe mitral or aortic stenosis.
14. Surgical procedure designed to occur during treatment or up to 04 days after the last dose of the study medication;
15. Current daily and / or uncontrolled alcoholism;
16. History of seizures in the last month or uncontrolled medical condition;
17. Clinical history of Liver Cirrhosis or Child-Pugh C classification;
18. Patients with known severe degenerative neurological diseases and / or diseases serious mental disorders;
19. Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol;
20. Known hypersensitivity and / or intolerance to Fluvoxamine, Ivermectin or Metformin;
21. Inability to take oral medications;
22. Inability to follow protocol-related procedures

Contacts and Locations

Contacts

Contact: Gilmar Reis, MD, PhD; +553132416574; administrador@cardresearch.org

Contact: Eduardo Santos, MD, PhD; +553132416574; duduaugusto1@yahoo.com.br

Locations

Brazil

City of Betim; Recruiting

Betim, MG, Brazil, 32550770

Contact: Daniela C Medeiros, MD,PhD

Contact: Tainara S Vieira

Hospital e Maternidade Santa Rita; Recruiting

Contagem, MG, Brazil, 32215000

Contact: Thiago S Ferreira, MD

City of Governador Valadares; Recruiting

Governador Valadares, MG, Brazil, 35010-000

Contact: Adhemar DF Neto, MD, PhD

Contact: Marina L Marques, SC

City of Ibirité; Recruiting

Ibirité, MG, Brazil, 30240528

Contact: Aline Milagres, RN

Contact: Carla Silva, SC hsfapesq@cardresearch.org

City of Nova Lima; Recruiting

Nova Lima, MG, Brazil, 34000000

Contact: Leticia F Costa, RN

Contact: Rosemary M Silva

City of Santa Luzia; Recruiting

Santa Luzia, MG, Brazil, 33105160

Contact: Eduardo Augusto SM Silva, MD, PhD

Contact: Vitoria HS Campos, SC

City of Sete Lagoas; Recruiting

Sete Lagoas, MG, Brazil, 35700-000

Contact: Vinicius A Correa, MD

Contact: Castilho Vitor Quirino, SC vitor-quirino@hotmail.com

CARDRESEARCH - Cardiologia Assistencial e de Pesquisa; Recruiting

Belo Horizonte, Minas Gerais, Brazil, 30150240

Contact: Izabel Silva, SC 553132416574 coordpesq@cardresearch.org

Principal Investigator: Gilmar Reis, MD,PhD

City of Brumadinho; Recruiting

Brumadinho, Minas Gerais, Brazil, 35.460-000

Contact: Eduardo D Calegari, MD

Principal Investigator: Eduardo Calegari, MD

Centro Universitário FIPMOC; Recruiting

Montes Claros, Minas Gerais, Brazil, 39.408-007

Contact: Ana Maria, MD

Principal Investigator: Ana Maria R Nogueira, MD

Sub-Investigator: Ana Paula FG Alvarenga, MD

Universidade Federal de Ouro Preto; Recruiting

Ouro Preto, Minas Gerais, Brazil, 35400000

Contact: Leonardo CM Savassi, MD, PhD leosavassi@gmail.com

Principal Investigator: Leonardo Savassi, MD, PhD

Sponsors and Collaborators

Cardresearch

Cytel Inc.

McMaster University

Fastgrants

Eiger BioPharmaceuticals

RainWater Foundation

Investigators

• Study Chair: Gilmar Reis, MD,PhD.; Cardresearch - Cardiologia Assistencial e de Pesquisa
• Study Director: Edward J Mills, FRCP; McMaster University

More Information

• Responsible Party: Cardresearch
• ClinicalTrials.gov Identifier: NCT04727424
• Other Study ID Numbers: TOGETHER_2
• First Posted: January 27, 2021
• Last Update Posted: July 8, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Patient tables and main data.
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: As of protocol termination
• Access Criteria: Upon request

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cardresearch:

COVID-19; Randomized study; Fluvoxamine; Ivermectin; Doxasozin; Peginterferon Lambda; Peginterferon Beta

Additional relevant MeSH terms:

Severe Acute Respiratory Syndrome; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Ivermectin; Doxazosin; Fluvoxamine; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiparasitic Agents; Anti-Infective Agents; Antihypertensive Agents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents