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

Covid19 Clinical Trial

Official title:

A Multicenter, Prospective, Adaptive, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effect of Fluvoxamine Plus Budesonide, Fluoxetine Plus Budesonide and Spirulin Platensis, in High Risk Patients With Mild COVID-19

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04727424
• Other study ID #: TOGETHER_2
• Status: Recruiting
• Phase: Phase 3
• Start date: January 19, 2021
• Est. completion date: July 1, 2024

Study information

• Verified date: May 2024
• Source: Cardresearch
• Contact: Gilmar Reis, MD, PhD
• Phone: +553132416574
• Email: administrador[@]cardresearch.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 7819
• Est. completion date: July 1, 2024
• Est. primary completion date: June 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• COVID-19
• Covid19
• SARS-Associated Coronavirus
• Severe Acute Respiratory Syndrome

Intervention

Dietary Supplement:
• Spirulin Platensis
Two tablets every 12 hours since randomization through day 09 following randomization

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.
• 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.
• Placebo
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)

Locations

Country	Name	City	State
Brazil	CARDRESEARCH - Cardiologia Assistencial e de Pesquisa	Belo Horizonte	Minas Gerais
Brazil	City of Betim	Betim	MG
Brazil	City of Brumadinho	Brumadinho	Minas Gerais
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 Igarapé	Igarapé	Minas Gerais
Brazil	Centro Universitário FIPMOC	Montes Claros	Minas Gerais
Brazil	City of Nova Lima	Nova Lima	MG
Brazil	Universidade Federal de Ouro Preto	Ouro Preto	Minas Gerais
Brazil	City of Santa Luzia	Santa Luzia	MG
Brazil	City of Sete Lagoas	Sete Lagoas	MG

Sponsors (6)

Lead Sponsor	Collaborator
Cardresearch	Cytel Inc., Eiger BioPharmaceuticals, Fastgrants, McMaster University, RainWater Foundation

Country where clinical trial is conducted

Brazil, 

References & Publications (18)

Dillman A, Park JJH, Zoratti MJ, Zannat NE, Lee Z, Dron L, Hsu G, Smith G, Khakabimamaghani S, Harari O, Thorlund K, Mills EJ. Reporting and design of randomized controlled trials for COVID-19: A systematic review. Contemp Clin Trials. 2021 Feb;101:106239. doi: 10.1016/j.cct.2020.106239. Epub 2020 Dec 3. — View Citation

Dron L, Dillman A, Zoratti MJ, Haggstrom J, Mills EJ, Park JJH. Clinical Trial Data Sharing for COVID-19-Related Research. J Med Internet Res. 2021 Mar 12;23(3):e26718. doi: 10.2196/26718. — View Citation

Forrest JI, Rawat A, Duailibe F, Guo CM, Sprague S, McKay P, Reis G, Mills EJ. Resilient Clinical Trial Infrastructure in Response to the COVID-19 Pandemic: Lessons Learned from the TOGETHER Randomized Platform Clinical Trial. Am J Trop Med Hyg. 2022 Jan 7;106(2):389-393. doi: 10.4269/ajtmh.21-1202. — View Citation

Jhuti D, Rawat A, Guo CM, Wilson LA, Mills EJ, Forrest JI. Interferon Treatments for SARS-CoV-2: Challenges and Opportunities. Infect Dis Ther. 2022 Jun;11(3):953-972. doi: 10.1007/s40121-022-00633-9. Epub 2022 Apr 21. — View Citation

Lee Z, Rayner CR, Forrest JI, Nachega JB, Senchaudhuri E, Mills EJ. The Rise and Fall of Hydroxychloroquine for the Treatment and Prevention of COVID-19. Am J Trop Med Hyg. 2021 Jan;104(1):35-38. doi: 10.4269/ajtmh.20-1320. — View Citation

Park JJH, Detry MA, Murthy S, Guyatt G, Mills EJ. How to Use and Interpret the Results of a Platform Trial: Users' Guide to the Medical Literature. JAMA. 2022 Jan 4;327(1):67-74. doi: 10.1001/jama.2021.22507. — View Citation

Park JJH, Dron L, Mills EJ. Moving forward in clinical research with master protocols. Contemp Clin Trials. 2021 Jul;106:106438. doi: 10.1016/j.cct.2021.106438. Epub 2021 May 14. — View Citation

Park JJH, Ford N, Xavier D, Ashorn P, Grais RF, Bhutta ZA, Goossens H, Thorlund K, Socias ME, Mills EJ. Randomised trials at the level of the individual. Lancet Glob Health. 2021 May;9(5):e691-e700. doi: 10.1016/S2214-109X(20)30540-4. — View Citation

Park JJH, Mogg R, Smith GE, Nakimuli-Mpungu E, Jehan F, Rayner CR, Condo J, Decloedt EH, Nachega JB, Reis G, Mills EJ. How COVID-19 has fundamentally changed clinical research in global health. Lancet Glob Health. 2021 May;9(5):e711-e720. doi: 10.1016/S2214-109X(20)30542-8. — View Citation

Rayner CR, Dron L, Park JJH, Decloedt EH, Cotton MF, Niranjan V, Smith PF, Dodds MG, Brown F, Reis G, Wesche D, Mills EJ. Accelerating Clinical Evaluation of Repurposed Combination Therapies for COVID-19. Am J Trop Med Hyg. 2020 Oct;103(4):1364-1366. doi: 10.4269/ajtmh.20-0995. — View Citation

Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, Thabane L, Cruz Milagres A, Ferreira TS, Quirino Dos Santos CV, de Figueiredo Neto AD, Diniz Callegari E, Monteiro Savassi LC, Campos Simplicio MI, Barra Ribeiro L, Oliveira R, Harari O, Bailey H, Fo — View Citation

Reis G, Dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, de Souza Campos VH, Nogueira AMR, de Almeida APFG, Callegari ED, de Figueiredo Neto AD, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forr — View Citation

Reis G, Mills E. Fluvoxamine for the treatment of COVID-19 - Author's reply. Lancet Glob Health. 2022 Mar;10(3):e333. doi: 10.1016/S2214-109X(21)00588-X. No abstract available. — View Citation

Reis G, Mills EJ, Glenn JS. Pegylated Interferon Lambda for Covid-19. Reply. N Engl J Med. 2023 Jun 1;388(22):2108. doi: 10.1056/NEJMc2303519. No abstract available. — View Citation

Reis G, Mills EJ. Ivermectin Treatment for Covid-19. Reply. N Engl J Med. 2022 Dec 15;387(24):e66. doi: 10.1056/NEJMc2207995. No abstract available. — View Citation

Reis G, Moreira Silva EAS, Medeiros Silva DC, Thabane L, Campos VHS, Ferreira TS, Santos CVQ, Nogueira AMR, Almeida APFG, Savassi LCM, Figueiredo-Neto AD, Dias ACF, Freire Junior AM, Bitaraes C, Milagres AC, Callegari ED, Simplicio MIC, Ribeiro LB, Olivei — View Citation

Reis G, Silva EASM, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, Campos VHS, Nogueira AMR, de Almeida APFG, Callegari ED, Neto ADF, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forrest JI, Ruton H, Sprague S, McKay P, G — View Citation

Thorlund K, Sheldrick K, Mills E. Molnupiravir for Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Mar 31;386(13):e32. doi: 10.1056/NEJMc2201612. Epub 2022 Mar 16. No abstract available. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in emergency care visits due to the worsening of COVID-19;	Evaluation of emergency visits due to progression of COVID-19 symptoms and/or ocmplications	28 days
Primary	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)	Hospitalization due to COVID-19 progression and related complications	28 days
Primary	Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in changing SPO2 = 93% after randomization	Reduction of SPO2 = 93% after randomization	28 days
Secondary	Time to clinical changes (up to 28 days of randomization), defined as greater than 50% symptoms changing in reference to baseline symptoms.	time to > 50% clinical symptoms changes as reported on baseline visit (self reported)	Randomization through day 28
Secondary	Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 or associated complications.	Time to hospitalization	Randomization through day 28
Secondary	Number of days with respiratory symptoms since randomization	Days with symptoms	Randomization through day 28
Secondary	Rate of all-cause hospitalizations	All cause hospitalizations	Randomization through day 28
Secondary	Rate of COVID-19 related hospitalizations	COVID-19 hospitalizations	Randomization through day 28
Secondary	Number of days on Mechanical Ventilator	Number of days on mechanical Ventilator	Randomization through day 28
Secondary	Number of Days on Intensive Care Unit	Number of days on Intensive Care Unit	Randomization through day 28
Secondary	Number of days on hospitalizations	Number of days on Hospitalization	Randomization through day 28
Secondary	Health and Functioning after COVID-19 disease	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.	Day 14 and Day 28
Secondary	Numbers of days with respiratory symptoms on WURSS-21 scale after randomization	Numbers of days with respiratory symptoms on WURSS-21 scale after randomization	Randomization through day 28
Secondary	Time to symptom resolution	Time to improvement > 50% of baseline symptomatology based on WURSS-21 Scale.	randomization through day 28
Secondary	Adherence of Study drug	Percentage of adherence on Study drug	Randomization through day 10