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

Phase 3

Recruiting

• Conditions: Covid19; SARS-Associated Coronavirus
• Interventions: Dietary Supplement: Spirulin Platensis; Drug: Fluoxetine 20 MG; Drug: Budesonide Powder; Drug: Placebo

• Registration Number: NCT04727424
• Lead Sponsor: Cardresearch

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, Fluoxetine, Budesonide and Spirulin Platensis 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 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).

Study Timeline

• Study Start: 2021-01-19
• Study First Submitted: 2021-01-25
• Study First Submitted QC: 2021-01-26
• Study First Posted: 2021-01-27
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-06
• Last Update Posted: 2024-05-08
• Primary Completion: 2024-06-01
• Study Completion: 2024-07-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 7819

Inclusion Criteria

Not provided

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;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Budesonide Powder	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 puff) right after randomization (Day 0) followed by one puff 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 - ANTICOV Arm) OR Matching tablets started after randomization using the dosing regimen of 02 tablets every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule)
Fluvoxamine Maleate + Budesonide Inhalation powder	Budesonide Powder	Fluvoxamine 100 mg oral tablets: One tablet after randomization (Day 0) followed by 100 mg BID for the following 09 days PLUS Budesonide Inhalation powder 400 mcg capsule: One 400 mcg capsule (inhalation) after randomization (Day 0) followed by one puff of 400 mcg BID for the following 09 days
Fluvoxamine Maleate + Budesonide Inhalation powder	Placebo	Fluvoxamine 100 mg oral tablets: One tablet after randomization (Day 0) followed by 100 mg BID for the following 09 days PLUS Budesonide Inhalation powder 400 mcg capsule: One 400 mcg capsule (inhalation) after randomization (Day 0) followed by one puff of 400 mcg BID for the following 09 days
Spirulin Platensis	Spirulin Platensis	Spirulin Platensis 500mg oral tablets Two tablets right after randomization (day 0) followed by 1.000mg (two tablets) BID for the following 10 days.
Spirulin Platensis	Placebo	Spirulin Platensis 500mg oral tablets Two tablets right after randomization (day 0) followed by 1.000mg (two tablets) BID for the following 10 days.
Fluoxetine + Budesonide Inhalation powder	Fluoxetine 20 MG	Fluoxetine 20 mg oral tablets: Two tablets right after randomization (Day 0) followed by 40 mg MID for the following 06 days PLUS Budesonide Inhalation powder 400 mcg capsule: One 400 mcg capsule (inhalation) right after randomization (Day 0) followed by one puff of 400 mcg BID for the following 06 days
Fluoxetine + Budesonide Inhalation powder	Placebo	Fluoxetine 20 mg oral tablets: Two tablets right after randomization (Day 0) followed by 40 mg MID for the following 06 days PLUS Budesonide Inhalation powder 400 mcg capsule: One 400 mcg capsule (inhalation) right after randomization (Day 0) followed by one puff of 400 mcg BID for the following 06 days
Placebo	Spirulin Platensis	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 puff) right after randomization (Day 0) followed by one puff 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 - ANTICOV Arm) OR Matching tablets started after randomization using the dosing regimen of 02 tablets every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule)
Placebo	Fluoxetine 20 MG	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 puff) right after randomization (Day 0) followed by one puff 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 - ANTICOV Arm) OR Matching tablets started after randomization using the dosing regimen of 02 tablets every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule)

Primary Outcome Measures

Name	Time	Method
Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in changing the need for Hospitalization due to COVID-19 progression and related complications, including lower respiratory tract infection (LRTI)	28 days	Hospitalization due to COVID-19 progression and related complications
Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in changing SPO2 ≤ 93% after randomization	28 days	Reduction of SPO2 ≤ 93% after randomization
Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in emergency care visits due to the worsening of COVID-19;	28 days	Evaluation of emergency visits due to progression of COVID-19 symptoms and/or ocmplications

Secondary Outcome Measures

Name	Time	Method
Number of days with respiratory symptoms since randomization	Randomization through day 28	Days with symptoms
Number of days on Mechanical Ventilator	Randomization through day 28	Number of days on mechanical Ventilator
Numbers of days with respiratory symptoms on WURSS-21 scale after randomization	Randomization through day 28	Numbers of days with respiratory symptoms on WURSS-21 scale after randomization
Time to symptom resolution	randomization through day 28	Time to improvement \> 50% of baseline symptomatology based on WURSS-21 Scale.
Number of days on hospitalizations	Randomization through day 28	Number of days on Hospitalization
Health and Functioning after COVID-19 disease	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.
Adherence of Study drug	Randomization through day 10	Percentage of adherence on Study drug
Time to clinical changes (up to 28 days of randomization), defined as greater than 50% symptoms changing in reference to baseline symptoms.	Randomization through day 28	time to \> 50% clinical symptoms changes as reported on baseline visit (self reported)
Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 or associated complications.	Randomization through day 28	Time to hospitalization
Rate of all-cause hospitalizations	Randomization through day 28	All cause hospitalizations
Rate of COVID-19 related hospitalizations	Randomization through day 28	COVID-19 hospitalizations
Number of Days on Intensive Care Unit	Randomization through day 28	Number of days on Intensive Care Unit

Trial Locations

Locations (12)

City of Governador Valadares; 🇧🇷 Governador Valadares, MG, Brazil

Centro Universitário FIPMOC; 🇧🇷 Montes Claros, Minas Gerais, Brazil

City of Betim; 🇧🇷 Betim, MG, Brazil

Hospital e Maternidade Santa Rita; 🇧🇷 Contagem, 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

Universidade Federal de Ouro Preto; 🇧🇷 Ouro Preto, Minas Gerais, Brazil

City of Santa Luzia; 🇧🇷 Santa Luzia, MG, Brazil

City of Ibirité; 🇧🇷 Ibirité, MG, Brazil

City of Sete Lagoas; 🇧🇷 Sete Lagoas, MG, Brazil

City of Nova Lima; 🇧🇷 Nova Lima, MG, Brazil