Covid19, SARS-Associated Coronavirus
Conditions
Keywords
COVID-19, Randomized study, Fluvoxamine, Budesonide, Fluoxetine, Spirulin Platensis
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).
Interventions
DIETARY_SUPPLEMENTSpirulin Platensis
Two tablets every 12 hours since randomization through day 09 following randomization
One Fluvoxamine tablet every 12 hours since randomization through day 09. PLUS 01 Budesonide powder (inhalation) every 12 hours since randomization through day 09.
DRUGFluoxetine 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.
DRUGPlacebo
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)
Sponsors
Cytel Inc.
McMaster University
Fastgrants
Eiger BioPharmaceuticals
RainWater Foundation
Cardresearch
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
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.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 Mechanical Ventilator | Randomization through day 28 | Number of days on mechanical Ventilator |
| Number of Days on Intensive Care Unit | Randomization through day 28 | Number of days on Intensive Care Unit |
| 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) |
| 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. |
| 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. |
| Adherence of Study drug | Randomization through day 10 | Percentage of adherence on Study drug |
| Number of days on hospitalizations | Randomization through day 28 | Number of days on Hospitalization |
| 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 |
| Number of days with respiratory symptoms since randomization | Randomization through day 28 | Days with symptoms |
Countries
Brazil
Contacts
Primary ContactGilmar Reis, MD, PhD
Backup ContactEduardo Santos, MD, PhD
Outcome results
None listed