Covid19Phase 3NCT04727424
Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms
A Phase 3 study testing Spirulin Platensis, Budesonide Powder and Fluoxetine 20 MG in people with Covid19 and SARS-Associated Coronavirus, run by Cardresearch at 12 sites in Brazil.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Covid19, SARS-Associated Coronavirus
- What is being tested?
- Spirulin Platensis, Budesonide Powder and Fluoxetine 20 MG
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 7,819 participants
- Where
- 12 sitesBrazil
- Study dates
- 19 Jan 2021to 1 Jul 2024
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- 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%.
- Exclusion criteria applicable to the 7-day treatment arms:
Show all 34Show fewer
- 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.
- Exclusion criteria applicable to the 10-day treatment arm:
- Chronic use of serotonin reuptake inhibitors other than sertraline B. Chronic use of corticosteroid therapy with prednisone equivalent doses of > 40 mg/day
- Exclusion criteria applicable to the 14-day treatment arm: Patients with phenylketonuria;
- Continued use of monoamine oxidation inhibitors (MAOIs): Phenelzine, Tranylcypromine, Selegiline, Isocarboxazid, moclobemide;
- Patients with severe psychiatric disorders - schizophrenia, uncontrolled bipolar disorders, major depression with suicidal ideation.
- Pregnant or breastfeeding patients;
- History of severe ventricular cardiac arrhythmia (Ventricular Tachycardia, recovered ventricular fibrillation patients) or Long QT Syndrome;
- 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;
- Surgical procedure or hospitalization planned (for other indications) to occur during treatment or up to 5 days after the last dose of study medication;
- Current daily and/or uncontrolled alcohol consumption, which in the investigator's view could compromise participation in the study;
- History of seizures in the last month or uncontrolled seizures;
- Clinical history of moderate to severe hepatic impairment or liver cirrhosis with Child-Pugh classification C;
- Patients with known severe degenerative neurological diseases and/or serious mental illnesses as assessed by the investigator;
- Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol;
- Any clinical conditions, including psychiatric conditions, which in the investigator's view could be an impediment to the use of research medications;
- Known hypersensitivity and/or intolerance to Spirulin Platensis, Budesonide, Fluvoxamine and Fluoxetine;
- Use of medications which have a known interaction with Spirulin platensis, Budesonide, Fluvoxamine and Fluoxetine;
- Inability to use the medications and formulations provided for in this research;
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
Brazil12 sites, 12 recruiting
- Recruiting
CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
Belo Horizonte, Minas Gerais, 30150240
Izabel Silva, SC, 553132416574, coordpesq@cardresearch.org
Gilmar Reis, MD,PhD
- Recruiting
City of Betim
Betim, Minas Gerais, 32550770
Daniela C Medeiros, MD,PhD
Tainara S Vieira
- Not yet recruiting
City of Brumadinho
Brumadinho, Minas Gerais, 35.460-000
Eduardo D Calegari, MD
Eduardo Calegari, MD
- Recruiting
Hospital e Maternidade Santa Rita
Contagem, Minas Gerais, 32215000
Thiago S Ferreira, MD
- Recruiting
City of Governador Valadares
Governador Valadares, Minas Gerais, 35010-000
Adhemar DF Neto, MD, PhD
Marina L Marques, SC
- Recruiting
City of Ibirité
Ibirité, Minas Gerais, 30240528
Aline Milagres, RN
Carla Silva, SC, hsfapesq@cardresearch.org
- Recruiting
City of Igarapé
Igarapé, Minas Gerais, 32900-000
Luciene B Ribeiro, RN, +55313657574
- Recruiting
Centro Universitário FIPMOC
Montes Claros, Minas Gerais, 39.408-007
Ana Maria, MD
Ana Maria R Nogueira, MD
- Recruiting
City of Nova Lima
Nova Lima, Minas Gerais, 34000000
Leticia F Costa, RN
Rosemary M Silva
- Recruiting
Universidade Federal de Ouro Preto
Ouro Preto, Minas Gerais, 35400000
Leonardo CM Savassi, MD, PhD, leosavassi@gmail.com
Leonardo Savassi, MD, PhD
- Recruiting
City of Santa Luzia
Santa Luzia, Minas Gerais, 33105160
Eduardo Augusto SM Silva, MD, PhD
Vitoria HS Campos, SC
- Recruiting
City of Sete Lagoas
Sete Lagoas, Minas Gerais, 35700-000
Vinicius A Correa, MD
Castilho Vitor Quirino, SC, vitor-quirino@hotmail.com
About this study
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
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.
Read the 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:
- The Pegylated Lambda interferon arm was ended on early February 2022.
- The Proposal of a new arm: Spirulin platensis.
- The Modification on primary endpoints that will be effective only for new arms added to the trial (Spirulin platensis).
- Conditions
- Covid19, SARS-Associated Coronavirus
- Being tested
- Spirulin Platensis, Budesonide Powder, Fluoxetine 20 MG, Placebo
- Keywords
- COVID-19, Randomized study, Fluvoxamine, Budesonide, Fluoxetine, Spirulin Platensis
- Medical subject headings
- COVID-19, Severe Acute Respiratory Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Spirulin PlatensisDietary supplement
Two tablets every 12 hours since randomization through day 09 following randomization
Budesonide PowderDrug
Also called Fluvoxamine Maleate 100 MG [Luvox]
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 MGDrug
Also called Budesonide powder
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.
PlaceboDrug
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)
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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. Receives: 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 Receives: 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) Receives: Dietary Supplement: Spirulin Platensis; Drug: Budesonide Powder; Drug: Fluoxetine 20 MG |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 28 days
Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in changing SPO2 ≤ 93% after randomization
Reduction of SPO2 ≤ 93% after randomization
Measured: 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.
time to > 50% clinical symptoms changes as reported on baseline visit (self reported)
Measured: 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.
Time to hospitalization
Measured: Randomization through day 28
Number of days with respiratory symptoms since randomization
Days with symptoms
Measured: Randomization through day 28
Rate of all-cause hospitalizations
All cause hospitalizations
Measured: Randomization through day 28
Rate of COVID-19 related hospitalizations
COVID-19 hospitalizations
Measured: Randomization through day 28
Number of days on Mechanical Ventilator
Number of days on mechanical Ventilator
Measured: Randomization through day 28
Number of Days on Intensive Care Unit
Number of days on Intensive Care Unit
Measured: Randomization through day 28
Number of days on hospitalizations
Number of days on Hospitalization
Measured: Randomization through day 28
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.
Measured: Day 14 and Day 28
Numbers of days with respiratory symptoms on WURSS-21 scale after randomization
Numbers of days with respiratory symptoms on WURSS-21 scale after randomization
Measured: Randomization through day 28
Time to symptom resolution
Time to improvement > 50% of baseline symptomatology based on WURSS-21 Scale.
Measured: randomization through day 28
Adherence of Study drug
Percentage of adherence on Study drug
Measured: Randomization through day 10
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2021
- Study start19 Jan 2021
- Primary completion1 Jun 2024 (estimated)
- Study completion1 Jul 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for Covid19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 7,819 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Cardresearch
- Sponsor type
- University, hospital or other
- Collaborators
- Cytel Inc., McMaster University, Fastgrants, Eiger BioPharmaceuticals, RainWater Foundation
- Responsible party
- Sponsor
- Investigators
- Gilmar Reis, MD,PhD., Study chair, Cardresearch - Cardiologia Assistencial e de PesquisaEdward J Mills, FRCP, Study director, McMaster University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04727424
- Sponsor's protocol ID
- TOGETHER_2
- Status last verified
- May 2024
- First submitted
- 25 Jan 2021
- Last updated
- 8 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Patient tables and main data.
Publications
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.
PubMed 32828137Park 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.
PubMed 33865476Forrest 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.
PubMed 34996047Reis 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.
PubMed 35180413Thorlund 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.
PubMed 35294804Park 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.
PubMed 34982138Jhuti 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.
PubMed 35445964Park 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.
PubMed 34000408Park 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.
PubMed 33865474Lee 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.
PubMed 33236703Dron 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.
PubMed 33684053Dillman 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.
PubMed 33279656Reis 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.
PubMed 34717820Reis 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.
PubMed 34927127Reis 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.
PubMed 35353979
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04727424
- Acronym / sponsor ID
- TOGETHER_2
- Conditions
- Covid19, SARS-Associated Coronavirus
- Keywords
- COVID-19, Randomized study, Fluvoxamine, Budesonide, Fluoxetine, Spirulin Platensis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 7,819 participants (estimated)
- Lead sponsor
- CardresearchUniversity, hospital or other
- Collaborators
- Cytel Inc., McMaster University, Fastgrants, Eiger BioPharmaceuticals, RainWater Foundation
- Study start
- 19 Jan 2021 (actual)
- Primary completion
- 1 Jun 2024 (estimated)
- Study completion
- 1 Jul 2024 (estimated)
- First posted
- 27 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- The Pegylated Lambda interferon arm was ended on early February 2022.
- The Proposal of a new arm: Spirulin platensis.
- The Modification on primary endpoints that will be effective only for new arms added to the trial (Spirulin platensis).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Fluvoxamine Maleate + Budesonide Inhalation powder | Active comparator | Drug: Budesonide Powder, Drug: PlaceboFluvoxamine 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 | Active comparator | Dietary Supplement: Spirulin Platensis, Drug: PlaceboSpirulin 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 | Active comparator | Drug: Fluoxetine 20 MG, Drug: PlaceboFluoxetine 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 | Placebo comparator | Dietary Supplement: Spirulin Platensis, Drug: Budesonide Powder, Drug: Fluoxetine 20 MGPlacebo 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) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (34 listed)
- 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%.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Spirulin PlatensisTwo tablets every 12 hours since randomization through day 09 following randomization | Dietary supplement | Placebo, Spirulin Platensis |
| Budesonide PowderAlso: Fluvoxamine Maleate 100 MG [Luvox]One Fluvoxamine tablet every 12 hours since randomization through day 09. PLUS 01 Budesonide powder (inhalation) every 12 hours since randomization through day 09. | Drug | Fluvoxamine Maleate + Budesonide Inhalation powder, Placebo |
| Fluoxetine 20 MGAlso: Budesonide powderTwo Fluoxetine tablets every day starting just after randomization through day 07. PLUS 01 Budesonide powder (inhalation) every 12 hours since randomization through day 07. | Drug | Fluoxetine + Budesonide Inhalation powder, Placebo |
| PlaceboPlacebo 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) | Drug | Fluoxetine + Budesonide Inhalation powder, Fluvoxamine Maleate + Budesonide Inhalation powder, Spirulin Platensis |
Primary outcome
Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in emergency care visits due to the worsening of COVID-19;
Time frame: 28 days
Evaluation of emergency visits due to progression of COVID-19 symptoms and/or ocmplications
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)
Time frame: 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
Time frame: 28 days
Reduction of SPO2 ≤ 93% after randomization
12 secondary outcomes
Time to clinical changes (up to 28 days of randomization), defined as greater than 50% symptoms changing in reference to baseline symptoms.
Time frame: 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.
Time frame: Randomization through day 28
Number of days with respiratory symptoms since randomization
Time frame: Randomization through day 28
Rate of all-cause hospitalizations
Time frame: Randomization through day 28
Rate of COVID-19 related hospitalizations
Time frame: Randomization through day 28
Number of days on Mechanical Ventilator
Time frame: Randomization through day 28
Number of Days on Intensive Care Unit
Time frame: Randomization through day 28
Number of days on hospitalizations
Time frame: Randomization through day 28
Health and Functioning after COVID-19 disease
Time frame: Day 14 and Day 28
Numbers of days with respiratory symptoms on WURSS-21 scale after randomization
Time frame: Randomization through day 28
Time to symptom resolution
Time frame: randomization through day 28
Adherence of Study drug
Time frame: Randomization through day 10
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2024.
- Background: PubMed 32828137Rayner 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.
- Background: PubMed 33865476Park 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.
- Background: PubMed 34996047Forrest 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.
- Background: PubMed 35180413Reis 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.
- Background: PubMed 35294804Thorlund 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.
- Background: PubMed 34982138Park 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.
- Background: PubMed 35445964Jhuti 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.
- Background: PubMed 34000408Park 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.
- Background: PubMed 33865474Park 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.
- Background: PubMed 33236703Lee 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.
- Background: PubMed 33684053Dron 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.
- Background: PubMed 33279656Dillman 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.
- Individual participant dataSharing planned: Yes. Patient tables and main data.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gilmar Reis, MD,PhD. study chair
Cardresearch - Cardiologia Assistencial e de Pesquisa
Edward J Mills, FRCP study director
McMaster University
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Spirulin Platensis, Budesonide Powder and Fluoxetine 20 MG in people with Covid19 and SARS-Associated Coronavirus, run by Cardresearch at 12 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 8 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Gilmar Reis, MD, PhD (+553132416574, administrador@cardresearch.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in emergency care visits due to the worsening of COVID-19; (time frame: 28 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04727424, which also lists 20 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2024.