Clinical trial NCT04727424: Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Covid19
SARS-Associated Coronavirus
Keywords: COVID-19
Randomized study
Fluvoxamine
Budesonide
Fluoxetine
Spirulin Platensis
Lead sponsor: Cardresearch
Sponsor class: OTHER
Collaborators: name: Cytel Inc.
name: McMaster University
name: Fastgrants
name: Eiger BioPharmaceuticals
name: RainWater Foundation
First posted: 2021-01-27
Enrollment: 7819
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).

Eligibility 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. 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;

Primary outcomes:
measure: Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in emergency care visits due to the worsening of COVID-19;
timeFrame: 28 days
measure: 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)
timeFrame: 28 days
measure: Rate of fluvoxamine + budesonide, fluoxetine + budesonide, Spirulin platensis in changing SPO2 ≤ 93% after randomization
timeFrame: 28 days
Secondary outcomes:
measure: Time to clinical changes (up to 28 days of randomization), defined as greater than 50% symptoms changing in reference to baseline symptoms.
timeFrame: Randomization through day 28
measure: Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 or associated complications.
timeFrame: Randomization through day 28
measure: Number of days with respiratory symptoms since randomization
timeFrame: Randomization through day 28
measure: Rate of all-cause hospitalizations
timeFrame: Randomization through day 28
measure: Rate of COVID-19 related hospitalizations
timeFrame: Randomization through day 28
measure: Number of days on Mechanical Ventilator
timeFrame: Randomization through day 28
measure: Number of Days on Intensive Care Unit
timeFrame: Randomization through day 28
measure: Number of days on hospitalizations
timeFrame: Randomization through day 28
measure: Health and Functioning after COVID-19 disease
timeFrame: Day 14 and Day 28
measure: Numbers of days with respiratory symptoms on WURSS-21 scale after randomization
timeFrame: Randomization through day 28
measure: Time to symptom resolution
timeFrame: randomization through day 28
measure: Adherence of Study drug
timeFrame: Randomization through day 10
Other outcomes:
Locations:
city: Betim
country: Brazil
facility: City of Betim
state: MG
city: Contagem
country: Brazil
facility: Hospital e Maternidade Santa Rita
state: MG
city: Governador Valadares
country: Brazil
facility: City of Governador Valadares
state: MG
city: Ibirité
country: Brazil
facility: City of Ibirité
state: MG
city: Nova Lima
country: Brazil
facility: City of Nova Lima
state: MG
city: Santa Luzia
country: Brazil
facility: City of Santa Luzia
state: MG
city: Sete Lagoas
country: Brazil
facility: City of Sete Lagoas
state: MG
city: Belo Horizonte
country: Brazil
facility: CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
state: Minas Gerais
city: Brumadinho
country: Brazil
facility: City of Brumadinho
state: Minas Gerais
city: Igarapé
country: Brazil
facility: City of Igarapé
state: Minas Gerais
city: Montes Claros
country: Brazil
facility: Centro Universitário FIPMOC
state: Minas Gerais
city: Ouro Preto
country: Brazil
facility: Universidade Federal de Ouro Preto
state: Minas Gerais
Study officials:
affiliation: Cardresearch - Cardiologia Assistencial e de Pesquisa
name: Gilmar Reis, MD,PhD.
role: STUDY_CHAIR
affiliation: McMaster University
name: Edward J Mills, FRCP
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
citation: 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.
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, 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.
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, 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.
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, 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.
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, 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.
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.
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.