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History of Changes for Study: NCT04727424
Repurposed Approved Therapies for Outpatient Treatment of Patients With Early-Onset COVID-19 and Mild Symptoms
Latest version (submitted July 3, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 January 26, 2021 None (earliest Version on record)
2 March 21, 2021 Outcome Measures, Arms and Interventions, Contacts/Locations, Study Status, Eligibility, Study Design and Study Description
3 July 5, 2021 Arms and Interventions, Outcome Measures, Contacts/Locations, Study Design, Study Status, Study Identification, Eligibility, Conditions and Sponsor/Collaborators
4 January 15, 2022 Arms and Interventions, Study Status, References, Outcome Measures, Study Design, Contacts/Locations, Eligibility and Conditions
5 July 3, 2022 Arms and Interventions, References, Outcome Measures, Study Design, Study Description, Eligibility, Conditions, Study Status and Study Identification
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Study NCT04727424
Submitted Date:  January 26, 2021 (v1)

Open or close this module Study Identification
Unique Protocol ID: TOGETHER_2
Brief Title: Repurposed Approved Therapies for Outpatient Treatment of Patients With Early-Onset COVID-19 and Mild Symptoms
Official Title: 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
Secondary IDs:
Open or close this module Study Status
Record Verification: January 2021
Overall Status: Recruiting
Study Start: January 19, 2021
Primary Completion: February 1, 2022 [Anticipated]
Study Completion: March 1, 2022 [Anticipated]
First Submitted: January 25, 2021
First Submitted that
Met QC Criteria:
January 26, 2021
First Posted: January 27, 2021 [Actual]
Last Update Submitted that
Met QC Criteria:
January 26, 2021
Last Update Posted: January 27, 2021 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Cardresearch
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: No
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module 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.
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.

Open or close this module Conditions
Conditions: Covid19
SARS-Associated Coronavirus
Keywords: COVID-19
Randomized study
Fluvoxamine
Ivermectin
Metformin
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment

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

  1. Fluvoxamine
  2. Metformin
  3. Ivermectin
  4. Placebo. We will use a centralized random allocation schedule, generated by computer and implemented using an online remote access system. Randomization will be stratified by participating basic health unit.
Number of Arms: 4
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 2724 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
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
Drug: Fluvoxamine Maleate 100 MG [Luvox]
One tablet every 12 hours since randomization through day 09.
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
Drug: Metformin Extended Release Oral Tablet
One 750 mg extended release tablet every 12 hours since randomization through day 09.
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;

Drug: Ivermectin Tablets
06 mg oral tablet: Three tablets if weight 40 - 60 kg, single dose; Four tablets 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

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.

Open or close this module Outcome Measures
Primary Outcome Measures:
1. 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
2. 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 Outcome Measures:
1. Change in viral load on day 03 and 07 after randomization (first 600 enrolled participants)
[ Time Frame: Day 3 and Day 7 ]

Viral load
2. 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)
3. 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
4. Number of days with respiratory symptoms since randomization
[ Time Frame: Randomization through day 28 ]

Days with symptoms
5. All-cause hospitalizations
[ Time Frame: Randomization through day 28 ]

All cause hospitalizations
6. COVID-19 related hospitalizations
[ Time Frame: Randomization through day 28 ]

COVID-19 hospitalizations
7. All-Cause Death
[ Time Frame: Randomization through day 28 ]

Death all cause
8. Cardiovascular death
[ Time Frame: Randomization through day 28 ]

Cardiovascular death
9. Respiratory death
[ Time Frame: Randomization through day 28 ]

REspiratory death
10. Promis Global-10 scale
[ Time Frame: Randomization, Day 14 and Day 28 ]

Ordinal scale
11. WHO ordinal scale for clinical improvement
[ Time Frame: Randomization through day 14 ]

Ordinal Scale
12. Adverse Events
[ Time Frame: randomization through day 28 ]

Adverse events
13. Adherence of Study drug
[ Time Frame: Randomization through day 10 ]

Percentage of adherence on Study drug
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based: Yes
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. 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;
Open or close this module Contacts/Locations
Central Contact Person: Gilmar Reis, MD, PhD
Telephone: +553132416574
Email: administrador@cardresearch.org
Central Contact Backup: Eduardo Santos, MD, PhD
Telephone: +553132416574
Email: duduaugusto1@yahoo.com.br
Locations: Brazil, MG
Coity of Ibirité
[Recruiting]
Ibirité, MG, Brazil, 30240528
Contact:Contact: Aline Milagres, RN
Contact:Contact: Carla Silva, SC hsfapesq@cardresearch.org
City of Sete Lagoas
[Recruiting]
Sete Lagoas, MG, Brazil, 35700-000
Contact:Contact: Vinicius Correa, MD
Contact:Contact: Castilho Vitor Quirino, SC vitor-quirino@hotmail.com
Brazil, Minas Gerais
CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
[Recruiting]
Belo Horizonte, Minas Gerais, Brazil, 30150240
Contact:Contact: Izabel Silva, SC 553132416574 coordpesq@cardresearch.org
Contact:Principal Investigator: Gilmar Reis, MD,PhD
Universidade Federal de Ouro Preto
[Not yet recruiting]
Ouro Preto, Minas Gerais, Brazil, 35400000
Contact:Contact: Leonardo Savassi, MD, PhD leosavassi@gmail.com
Contact:Principal Investigator: Leonardo Savassi, MD, PhD
Open or close this module IPDSharing
Plan to Share IPD: Yes
Patient tables and main data.
Supporting Information:
Statistical Analysis Plan (SAP)
Time Frame:
As of protocol termination
Access Criteria:
Upon request
URL:
Open or close this module References
Links:
Available IPD/Information:

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