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 Spirulin Platensis 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 Adaptive Trial:

1. The Pegylated Lambda interferon arm was ended on early February 2022.
2. The Proposal of a new arm: Spirulin platensis.
3. The Modification on primary endpoints that will be effective only for new arms added to the trial (Spirulin platensis).

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. The. Age > 50 years old (does not need any of the other criteria)
   2. Diabetes mellitus requiring oral medication or insulin
   3. Systemic arterial hypertension requiring at least 01 oral medication for treatment
   4. Known cardiovascular diseases (heart failure, congenital heart disease, valvular disease, coronary artery disease, cardiomyopathies under treatment, clinically manifest heart diseases with clinical repercussions)
   5. Symptomatic and/or treated lung disease (emphysema, fibrosing diseases)
   6. Patients with symptomatic asthma requiring chronic use of agents to control symptoms.
   7. Obesity, defined as BMI > 30 kg/m2 in weight and height information provided by the patient;
   8. Transplant patients
   9. Patient with stage IV chronic kidney disease or on dialysis.
   10. Patient with temperature measured at screening > 38º C.
   11. Patients with at least one of the following symptoms: Cough, Dyspnea, Ventilator-dependent chest pain or myalgias with limitation of daily activities (Criterion limited to 25% of randomizations)
   12. Immunosuppressed patients/using corticosteroid therapy (equivalent to a maximum of 10 mg of prednisone per day) and/or immunosuppressive therapy)
   13. Patients with a history of cancer in the last 5 years or currently undergoing oncological treatment

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. Signing the Free and Informed Consent Form before any research procedures

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. Negative diagnostic test for SARS-CoV2 associated with acute flu-like symptoms (patients with a negative test taken early and becoming positive a few days later are eligible, as long as they are < 07 days from the onset of flu-like 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 (e.g. decompensated COPD, Acute bronchitis, Pneumonia other than viral, Primary pulmonary arterial hypertension);

5. Patients requiring hospitalization due to COVID-19 or SpO2 ≤ 93%.

6. Exclusion criteria applicable to the 7-day treatment arms:

   1. Abnormal findings on physical examination: Respiratory rate ≥ 25 irm; blood pressure < 90/ 60 mmHg or > 160/ 100 mmHg; Weight < 45 kg; recent episodes of vomiting in the last 24 hours or diarrhea > 3 episodes in the last 24 hours or serum potassium below 3.5 mEq/L.
   2. Serious injury to any organ that requires resuscitation and continuous treatment.
   3. Use of chronic systemic corticosteroid therapy with prednisone equivalent doses of > 40 mg/day
   4. Ongoing immunosuppressive treatment
   5. History of known pulmonary arterial hypertension or pulmonary fibrosis
   6. Patients previously vaccinated with two doses for SARS-CoV-2, with the last dose administered less than 180 days after screening; Patients with a single dose of Janssen SARS-CoV-2 vaccine received (except Janssen vaccine) and unvaccinated patients can participate regardless of the period.
   7. Use of serotonin reuptake inhibitors (all)
   8. Patients vaccinated for SARS-CoV-2 (complete vaccination - 02 doses) within 06 months of the last dose before randomization or patients who received a "booster" dose at any time before randomization.
   9. For any new antiviral included in the study, prior treatment with the antiviral, presence of contraindication to its use or concomitant intake of medication prohibited for its use.
   10. Enrolled in other clinical trials with unregistered medicines or with a registered medicine that may interact with any of the study PIs or contraindicated as concomitant treatment in the last 3 months before screening.

7. Exclusion criteria applicable to the 10-day treatment arm:

   A. Chronic use of serotonin reuptake inhibitors other than sertraline B. Chronic use of corticosteroid therapy with prednisone equivalent doses of > 40 mg/day

8. Exclusion criteria applicable to the 14-day treatment arm: Patients with phenylketonuria;

9. Continued use of monoamine oxidation inhibitors (MAOIs): 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 from screening), unstable angina, recent coronary bypass surgery (procedure < 90 days from screening), recent stroke ( event < 90 days from screening), symptomatic carotid disease, or mitral or aortic stenosis of moderate to severe intensity;

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 liver cirrhosis with Child-Pugh classification C;

18. Patients with known severe 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 be an impediment to the use of research medications;

21. Known hypersensitivity and/or intolerance to Spirulin Platensis, Budesonide, Fluvoxamine and Fluoxetine;

22. Use of medications which have a known interaction with Spirulin platensis, Budesonide, Fluvoxamine and Fluoxetine;

23. Inability to use the medications and formulations provided for in this research;

Gender will be assumed as patient self-reported

Patient tables and main data.

As of protocol termination

Upon request

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.