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

NCT04727424 | Recruiting Phase 3 DMC

• 1 other identifier: TOGETHER_2
• Study Type: interventional
• Target: 7,819
• Locations: 1 country
• Sites: 12

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.

Conditions

Covid19; SARS-Associated Coronavirus

Keywords

COVID-19; Randomized study; Fluvoxamine; Budesonide; Fluoxetine; Spirulin Platensis

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in changing SPO2 ≤ 93% after randomization

  Reduction of SPO2 ≤ 93% after randomization

  28 days

Secondary Outcomes (12)

• 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 clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 or associated complications.

  Randomization through day 28

• Number of days with respiratory symptoms since randomization

  Randomization through day 28

• Rate of all-cause hospitalizations

  Randomization through day 28

• Rate of COVID-19 related hospitalizations

  Randomization through day 28

Study Arms (4)

Fluvoxamine Maleate + Budesonide Inhalation powder

ACTIVE COMPARATOR

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

Drug: Budesonide Powder; Drug: Placebo

Spirulin Platensis

ACTIVE COMPARATOR

Spirulin Platensis 500mg oral tablets Two tablets right after randomization (day 0) followed by 1.000mg (two tablets) BID for the following 10 days.

Dietary Supplement: Spirulin Platensis; Drug: Placebo

Fluoxetine + Budesonide Inhalation powder

ACTIVE COMPARATOR

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

Drug: Fluoxetine 20 MG; Drug: Placebo

Placebo

PLACEBO COMPARATOR

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)

Dietary Supplement: Spirulin Platensis; Drug: Budesonide Powder; Drug: Fluoxetine 20 MG

Interventions

Spirulin Platensis DIETARY_SUPPLEMENT

Two tablets every 12 hours since randomization through day 09 following randomization

Placebo; Spirulin Platensis

Budesonide Powder DRUG

One Fluvoxamine tablet every 12 hours since randomization through day 09. PLUS 01 Budesonide powder (inhalation) every 12 hours since randomization through day 09.

Also known as: Fluvoxamine Maleate 100 MG [Luvox]

Fluvoxamine Maleate + Budesonide Inhalation powder; Placebo

Fluoxetine 20 MG DRUG

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.

Also known as: Budesonide powder

Fluoxetine + Budesonide Inhalation powder; Placebo

Placebo DRUG

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)

Fluoxetine + Budesonide Inhalation powder; Fluvoxamine Maleate + Budesonide Inhalation powder; Spirulin Platensis

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Gender will be assumed as patient self-reported
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients over 18 years old with the ability to provide free and informed consent
• Acute Flu-Like symptoms \< 07 days.
• Patients with at least ONE enhancement criteria:
• The. Age \> 50 years old (does not need any of the other criteria)
• Diabetes mellitus requiring oral medication or insulin
• Systemic arterial hypertension requiring at least 01 oral medication for treatment
• Known cardiovascular diseases (heart failure, congenital heart disease, valvular disease, coronary artery disease, cardiomyopathies under treatment, clinically manifest heart diseases with clinical repercussions)
• Symptomatic and/or treated lung disease (emphysema, fibrosing diseases)
• Patients with symptomatic asthma requiring chronic use of agents to control symptoms.
• Obesity, defined as BMI \> 30 kg/m2 in weight and height information provided by the patient;
• Transplant patients
• Patient with stage IV chronic kidney disease or on dialysis.
• Patient with temperature measured at screening \> 38º C.
• 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)
• Immunosuppressed patients/using corticosteroid therapy (equivalent to a maximum of 10 mg of prednisone per day) and/or immunosuppressive therapy)

You may not qualify if:

• 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);
• Patients with an acute respiratory condition compatible with COVID-19 treated in the primary care network and with a decision to be hospitalized;
• Patients with acute respiratory symptoms due to other causes;
• 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);
• Patients requiring hospitalization due to COVID-19 or SpO2 ≤ 93%.
• 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.
• Serious injury to any organ that requires resuscitation and continuous treatment.
• Use of chronic systemic corticosteroid therapy with prednisone equivalent doses of \> 40 mg/day
• Ongoing immunosuppressive treatment
• History of known pulmonary arterial hypertension or pulmonary fibrosis
• 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.
• Use of serotonin reuptake inhibitors (all)
• 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.
• 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.
• 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.

Sponsors & Collaborators

• Cardresearch: lead
• Cytel Inc.: collaborator
• McMaster University: collaborator
• Fastgrants: collaborator
• Eiger BioPharmaceuticals: collaborator
• RainWater Foundation: collaborator

Study Sites (12)

CARDRESEARCH - Cardiologia Assistencial e de Pesquisa

Belo Horizonte, Minas Gerais, 30150240, Brazil

RECRUITING

City of Betim

Betim, Minas Gerais, 32550770, Brazil

RECRUITING

City of Brumadinho

Brumadinho, Minas Gerais, 35.460-000, Brazil

NOT YET RECRUITING

Hospital e Maternidade Santa Rita

Contagem, Minas Gerais, 32215000, Brazil

RECRUITING

City of Governador Valadares

Governador Valadares, Minas Gerais, 35010-000, Brazil

RECRUITING

City of Ibirité

Ibirité, Minas Gerais, 30240528, Brazil

RECRUITING

City of Igarapé

Igarapé, Minas Gerais, 32900-000, Brazil

RECRUITING

Centro Universitário FIPMOC

Montes Claros, Minas Gerais, 39.408-007, Brazil

RECRUITING

City of Nova Lima

Nova Lima, Minas Gerais, 34000000, Brazil

RECRUITING

Universidade Federal de Ouro Preto

Ouro Preto, Minas Gerais, 35400000, Brazil

RECRUITING

City of Santa Luzia

Santa Luzia, Minas Gerais, 33105160, Brazil

RECRUITING

City of Sete Lagoas

Sete Lagoas, Minas Gerais, 35700-000, Brazil

RECRUITING

Related Publications (20)

• 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.

  PMID: 32828137 BACKGROUND

• 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.

  PMID: 33865476 BACKGROUND

• 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.

  PMID: 34996047 BACKGROUND

• 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.

  PMID: 35180413 BACKGROUND

• 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.

  PMID: 35294804 BACKGROUND

• 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.

  PMID: 34982138 BACKGROUND

• 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.

  PMID: 35445964 BACKGROUND

• 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.

  PMID: 34000408 BACKGROUND

• 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.

  PMID: 33865474 BACKGROUND

• 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.

  PMID: 33236703 BACKGROUND

• 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.

  PMID: 33684053 BACKGROUND

• 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.

  PMID: 33279656 BACKGROUND

• 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, Forrest JI, Ruton H, Sprague S, McKay P, Glushchenko AV, Rayner CR, Lenze EJ, Reiersen AM, Guyatt GH, Mills EJ; TOGETHER investigators. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022 Jan;10(1):e42-e51. doi: 10.1016/S2214-109X(21)00448-4. Epub 2021 Oct 28.

  PMID: 34717820 RESULT

• 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, Forrest JI, Glushchenko A, Sprague S, McKay P, Rayner CR, Ruton H, Guyatt GH, Mills EJ. Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial. Lancet Reg Health Am. 2022 Feb;6:100142. doi: 10.1016/j.lana.2021.100142. Epub 2021 Dec 14.

  PMID: 34927127 RESULT

• 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, Guo CM, Rowland-Yeo K, Guyatt GH, Boulware DR, Rayner CR, Mills EJ; TOGETHER Investigators. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022 May 5;386(18):1721-1731. doi: 10.1056/NEJMoa2115869. Epub 2022 Mar 30.

  PMID: 35353979 RESULT

• 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, Oliveira R, Harari O, Wilson LA, Forrest JI, Ruton H, Sprague S, McKay P, Guo CM, Limbrick-Oldfield EH, Kanters S, Guyatt GH, Rayner CR, Kandel C, Biondi MJ, Kozak R, Hansen B, Zahoor MA, Arora P, Hislop C, Choong I, Feld JJ, Mills EJ, Glenn JS; TOGETHER Investigators. Early Treatment with Pegylated Interferon Lambda for Covid-19. N Engl J Med. 2023 Feb 9;388(6):518-528. doi: 10.1056/NEJMoa2209760.

  PMID: 36780676 RESULT

• 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.

  PMID: 37256990 RESULT

• 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.

  PMID: 36516104 RESULT

• Reis G, Augusto Dos Santos Moreira Silva E, Carla Medeiros Silva D, Thabane L, Santiago Ferreira T, Vitor Quirino Dos Santos C, Paula Figueiredo Guimaraes Almeida A, Cancado Monteiro Savassi L, Dias de Figueiredo Neto A, Lanna Franca Reis L, Helena de Souza Campos V, Bitaraes C, Diniz Callegari E, Izabel Campos Simplicio M, Barra Ribeiro L, Oliveira R, Harari O, Forrest JI, Lat PK, Dron L, Thorlund K, Mills EJ. Effect of spirulina on risk of hospitalization among patients with COVID-19: the TOGETHER randomized trial. Am J Clin Nutr. 2024 Sep;120(3):602-609. doi: 10.1016/j.ajcnut.2024.06.016. Epub 2024 Aug 15.

  PMID: 39232602 DERIVED

• Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, Thabane L, de Souza Campos VH, Ferreira TS, Quirino Dos Santos CV, Ribeiro Nogueira AM, Figueiredo Guimaraes Almeida AP, Cancado Monteiro Savassi L, de Figueiredo Neto AD, Bitaraes C, Cruz Milagres A, Diniz Callegari E, Campos Simplicio MI, Barra Ribeiro L, Oliveira R, Harari O, Wilson LA, Forrest JI, Ruton H, Sprague S, McKay P, Guo CM, Guyatt GH, Rayner CR, Boulware DR, Ezer N, Lee TC, McDonald EG, Bafadhel M, Butler C, Rodrigues Silva J, Dybul M, Mills EJ; TOGETHER Investigators. Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial. Ann Intern Med. 2023 May;176(5):667-675. doi: 10.7326/M22-3305. Epub 2023 Apr 18.

  PMID: 37068273 DERIVED

MeSH Terms

Conditions

COVID-19; Severe Acute Respiratory Syndrome

Interventions

Fluvoxamine; Fluoxetine

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Oximes; Hydroxylamines; Amines; Organic Chemicals; Propylamines

Study Officials

• Gilmar Reis, MD,PhD.

  Cardresearch - Cardiologia Assistencial e de Pesquisa

  STUDY CHAIR

• Edward J Mills, FRCP

  McMaster University

  STUDY DIRECTOR

Central Study Contacts

Gilmar Reis, MD, PhD

CONTACT

+553132416574; administrador@cardresearch.org

Eduardo Santos, MD, PhD

CONTACT

+553132416574; duduaugusto1@yahoo.com.br

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: TOGETHER trial is a Multiplatform, adaptive trial started on 20 Jan 2021. This description is in allignment as per amendment seven with Brazilian National Ethics Committee final decision letter (letter# 5416996) issued on May 18, 2022. Patients with mild disease will be screened at primary and secondary care public health services and randomly allocated to one of three treatment arms in a 1:1:1:1 ratio, as per described in detail in approved protocol version 8.0 dated 12 APR 2022. 1. Fluvoxamine + Budesonide 2. Fluoxetine + Budesonide 3. Spirulin Platensis 4. Placebo We will use a centralized random allocation schedule, generated by computer and stratified by site and age.

Study Record Dates

• First Submitted: January 25, 2021
• First Posted: January 27, 2021
• Study Start: January 19, 2021
• Primary Completion: June 1, 2024
• Study Completion: July 1, 2024
• Last Updated: May 8, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• Time Frame: As of protocol termination
• Access Criteria: Upon request

Locations

BR (12)