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, Fluoxetine, Budesonide and Pegilatrd Interferon Lambda in SARS-CoV-2 infections and observational studies have suggested a reduced complications in patients with COVID-19 disease.
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 prospective, double-blinded, randomized evaluation of potential
therapies 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.
Important considerations on TOGETHER Trial:
1. Vaccinated patients were proposed to be an exclusion criteria on amendment 3 which was
received final National Ethics Committee (CONEP) decision letter number 4.747.755_E3
dated June 01, 2021. We evaluated vaccination data and outcomes on two large cities
involving 150.000 individuals and based on these results we submitted to the IRB a
notification request to withdraw the exclusion criteria 4 (vaccination > 14 days) on
July 14, 2021, which was granted.
2. The amendment 5 proposed a collaborative partnership with ANTICOV Consortia and
incorporating the fluoxetine + budesonide and its active comparator (paracetamol) arms,
as per ANTICOV protocol WHO ERC approval version 13.0. These generated data will be
analyzed along with ANTICOV fluoxetine + budesonide and paracetamol arms.
Drug: Fluvoxamine Maleate 100 MG [Luvox]
One tablet every 12 hours since randomization through day 09.
Drug: Budesonide Powder
One Fluvoxamine tablet every 12 hours since randomization through day 09. PLUS
01 Budesonide powder (inhalation) every 12 hours since randomization through day 09.
Other Name: Fluvoxamine Maleate 100 MG [Luvox]
Drug: Placebo (mild disease)
Placebo SC normal saline syringe (single day schedule):
Matching syringes containing 0,5 ml normal saline administered by SC route after randomization Day 0 (single dose SC).
OR
Placebo oral tablets (10-day schedule):
Matching tablets started 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) PLUS
Placebo Inhalation Therapy:
One dosing (inhalation) right after randomization (Day 0) followed by one dose BID for the following 09 days
OR
Paracetamol (07-day schedule - active comparator):
Paracetamol 500 mg tablets started after randomization using the dosing regimen of 01 tablet BID starting at Rand. Day (Day 0) until end of Day 06 (total of 07 days schedule)
OR
Placebo oral tablets (10-day schedule for patients with SPO2 < 94%):
One tablet after randomization (Day 0) followed by 01 tablet BID for the following 09 days (total of 10 days schedule)
Drug: Peginterferon Lambda-1a
One syringe of 180 mcg of Peginterferon Lambda SC right after randomization Day 0 (single dose SC administration).
Drug: Fluoxetine 20 MG
Two Fluoxetine tablets every day starting just after randomization through day 07.
PLUS
01 Budesonide powder (inhalation) every 12 hours since randomization through day 07.
A - Inclusion Criteria (except fluoxetine + budesonide and paracetamol arms):
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.
6. Specific inclusion criteria for the fluvoxamine arm: Present significant dyspnea,
arterial hypotension, severe dehydration or SpO2 between 85 to 93% in room air at
admission and medical decision to discharge patient home, with an observation period
at ER not exceeding 12 hours.
B - Inclusion criteria for the Fluoxetine + Budesonide combination arm (07 days of
treatment - partnership with the "ANTICOV Consortium"):
1. Patients over 18 years of age with the ability to provide free and informed consent.
2. Patients treated at a Basic Health Unit of the Unified Health System (SUS) or patients
treated at emergency care units of the SUS or supplementary medicine with an acute
clinical condition compatible with COVID 19.
3. Patients over 18 years of age and a history of at least ONE of the following criteria.
1. Diabetes mellitus, heart disease, chronic kidney disease, chronic obstructive
pulmonary disease, cerebrovascular diseases or patients considered to be
underweight or overweight according to the investigator's judgment (BMI ≤ 16 or
BMI > 25).
OR
2. Individuals aged ≥ 60 years without co-morbidities.
4. COVID-19 confirmed by molecular or antigenic test for SARS-CoV-2 within up to 24 hours
prior to screening and a maximum of 2 days after sample collection.
5. Viral syndrome with or without pneumonia and arterial O2 saturation > 94%.
6. Signing the Free and Informed Consent Form before any research procedures.
7. Willingness to use the proposed investigational treatment and follow the procedures
provided for in the research.
Exclusion Criteria:
1. Diagnostic test for negative SARS-CoV2 associated with acute flu symptoms (patient
with a negative test collected early and becomes positive a few days later is
eligible, as long as it is < 07 days since the onset of flu symptoms).
2. Patients with an acute respiratory condition compatible with COVID-19 treated in the
primary care network and with a decision to be hospitalized.
3. Patients with acute respiratory symptoms due to other causes.
4. Dyspnea secondary to other acute and chronic respiratory causes or infections (eg,
decompensated COPD, Acute bronchitis, Pneumonia other than viral, Primary pulmonary
arterial hypertension).
5. Patients requiring hospitalization due to COVID-19 or SpO2 ≤ 93%. NOTE: Patients
allocated to the fluvoxamine arm alone may be included if SpO2 is below 94%, with no
evidence of acute respiratory failure, provided that the attending physician decides
to discharge the unit and continue treatment on an outpatient basis.
6. Exclusion criteria applicable to injectable medication arms:
a. Patients on chronic use of prednisone, prednisolone or other corticosteroids with
doses > 10 mg/day equivalent to prednisone.
7. Exclusion criteria applicable to 07-day treatment arms:
1. Abnormal findings on physical examination: Respiratory rate ≥ 25 sisters; blood
pressure < 90/60 mmHg or > 160/100 mmHg; Weight < 45 kg; recent episodes of
vomiting within the last 24 hours or recurrent diarrhea or serum potassium below
3.5 mEq/L.
2. Severe organ damage that requires resuscitation and ongoing treatment.
3. Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day
4. Immunosuppressive treatment in progress
5. History of known pulmonary arterial hypertension or pulmonary fibrosis
6. Patients who have received a previous dose of SARS-CoV-2 vaccine
7. Use of serotonin reuptake inhibitors (all).
8. Exclusion criteria applicable to 10-day treatment arms:
1. Chronic use of serotonin reuptake inhibitors other than sertraline
2. Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day;
9. Continued use of monoamine oxidative inhibitors (MAOI): Phenelzine, Tranylcypromine,
Selegiline, Isocarboxazid, moclobemide.
10. Patients with severe psychiatric disorders - schizophrenia, uncontrolled bipolar
disorders, major depression with suicidal ideation.
11. Pregnant or breastfeeding patients.
12. History of severe ventricular cardiac arrhythmia (Ventricular tachycardia, recovered
ventricular fibrillation patients) or Long QT Syndrome.
13. Known history of decompensated heart failure (NYHA III or IV), recent myocardial
infarction (event < 90 days of screening), unstable angina, recent coronary bypass
surgery (procedure < 90 days of screening), recent stroke ( event < 90 days from
screening), symptomatic carotid disease, or moderate to severe mitral or aortic
stenosis.
14. Surgical procedure or hospitalization planned (for other indications) to occur during
treatment or up to 5 days after the last dose of study medication.
15. Current daily and/or uncontrolled alcohol consumption, which, in the investigator's
view, could compromise participation in the study.
16. History of seizures in the last month or uncontrolled seizures.
17. Clinical history of moderate to severe hepatic impairment or hepatic cirrhosis with
Child-Pugh C classification.
18. Patients with known serious degenerative neurological diseases and/or serious mental
illnesses as assessed by the investigator.
19. Inability of the patient or representative to give consent or adhere to the procedures
proposed in the protocol.
20. Any clinical conditions, including psychiatric conditions, which, in the
investigator's view, could prevent the use of research drugs.
21. Known hypersensitivity and/or intolerance to Fluvoxamine, Budesonide, Pegylated
Interferon Lambda and Fluoxetine.
22. Use of drugs which have a known interaction with Fluvoxamine, Budesonide, Pegylated
Interferon Lambda and Fluoxetine.
23. Inability to use the drugs and formulations provided for in this research.
City of Betim
Betim, MG, Brazil
Hospital e Maternidade Santa Rita
Contagem, MG, Brazil
City of Governador Valadares
Governador Valadares, MG, Brazil
City of Ibirité
Ibirité, MG, Brazil
City of Nova Lima
Nova Lima, MG, Brazil
City of Santa Luzia
Santa Luzia, MG, Brazil
City of Sete Lagoas
Sete Lagoas, MG, Brazil
CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
Belo Horizonte, Minas Gerais, Brazil
City of Brumadinho
Brumadinho, Minas Gerais, Brazil
City of Igarapé
Igarapé, Minas Gerais, Brazil
Centro Universitário FIPMOC
Montes Claros, Minas Gerais, Brazil
Universidade Federal de Ouro Preto
Ouro Preto, Minas Gerais, Brazil
Gilmar Reis, MD, PhD
+553132416574
administrador@cardresearch.org
Eduardo Santos, MD, PhD
+553132416574
duduaugusto1@yahoo.com.br